Tie2 activators, blood vessel maturation agents or blood vessel stabilizers, food and drink products thereof, capillary improvement agents, and food and drink products for improving capillaries

Abstract

To provide a Tie2 activation agent that activates Tie2 with an active principle thereof, accelerates blood circulation, and heightens an absorption coefficient of the active principle into body, thereby capable of realizing capillary improvement; a maturation agent for blood vessel or a stabilization agent for blood vessel; a beverage food product; a capillary improving agent; and a capillary improving beverage food product.SOLUTION: Tea includes as active principles: a processed product of rooibos leaf part and / or a processed product of Cinnamomum sieboldii leaf part; a processed product of cinnamon twig part and / or skin part; a processed product of safflower; and a processed product of black soybean. Having asked 16 volunteers to take the tea and observed and measured by microscope capillary state and blood flow rate of a fingertip before and after the intake, it has been examined if an improvement effect of the capillary by the beverage food product is present or not. As a result, it has been confirmed that the beverage food product has an improvement effect in a capillary shape, a length of blood vessel loop, thickness of blood vessel, brightness of a tissue around the capillary, and the blood flow rate.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a Tie2 activator, a blood vessel maturation agent or a blood vessel stabilization agent, foods and beverages containing the same, as well as a capillary blood vessel improving agent and capillary blood vessel improving foods and beverages. [Background technology]

[0002] Capillaries are thin, mesh-like blood vessels with a diameter of 6 to 15 μm that are located between small arteries and small veins at the periphery of blood vessels, and account for 99% of the blood vessels in the body. They deliver nutrients, oxygen, hormones, etc. to tissues and expel waste products from the body, as well as being involved in regulating water and body temperature. For this reason, the health of capillaries has a profound effect on the health of the body.

[0003] The formation of capillaries is related to vascular endothelial growth factor (VEGF). When VEGF acts on vascular endothelial cells, it induces cell division, migration, differentiation, etc., resulting in the formation of new blood vessels branching off from existing blood vessels. Meanwhile, the structural maturation of new capillaries and the structural stabilization of mature capillaries depend on angiopoietin-1 (Ang-1) secreted from mural cells and receptor tyrosine kinase with Ig and EGF homology domain-2 (Tie2) present on the vascular endothelial cell membrane (see, for example, Non-Patent Documents 1 to 3).

[0004] The capillary wall is formed by direct adhesion of a single parietal cell to the outer luminal surface of multiple endothelial cells. Specifically, Ang-1 secreted from parietal cells binds to the Tie2 receptor on the vascular endothelial cell membrane, phosphorylating and activating Tie2, and the activated vascular endothelial cells tightly adhere to each other, forming focal adhesions between the endothelial cells. The parietal cells then line the endothelial cells, forming a sturdy capillary wall.

[0005] When the function of parietal cells weakens due to aging, poor lifestyle habits, inflammatory responses, excessive reactive oxygen species, etc., the secretion of angiopoietin-1 decreases, Tie2 activation becomes impossible, parietal cells become more likely to peel off from endothelial cells, the adhesion focal points between endothelial cells also collapse, the stability of blood vessels collapses, and the shape of the capillaries can no longer be maintained. Then, capillaries with the collapse of adhesion focal points between endothelial cells become tortuous, atrophy, and the lumen expands. Because gaps are formed between the endothelial cells, internal environmental factors such as cells and humoral factors in the capillaries easily leak out of the blood vessels, and the blood flow rate slows.

[0006] Capillaries begin to deteriorate from around the age of 45 (see, for example, Non-Patent Document 4), and of the fingertip capillary test subjects (see below) in their 30s to 70s who were tested by the inventors, more than 80% showed symptoms of deterioration such as bent, twisted, shrunken, thickened blood vessels, vascular deformation such as the formation of bypass blood vessels, abnormal vascular leakage such as a dark brown or pink haze, and reduced blood flow velocity. [Prior art documents] [Patent documents]

[0007] [Non-Patent Document 1] Suni C et al.: Requisite role of Angiopoietin-1, a ligand for the TIE 2 receptor, during embryonic angiogenesis. Cell 87: 1171-1180, 1996. [Non-Patent Document 2] Fukuhara S et al.: Angiopoietin-1 / Tie2 receptor signaling in vascular quiescence and angiogenesis, Histol Histopathol. 25, 2010. [Non-Patent Document 3] Shigetomo Fukuhara, Naoki Mochizuki: Vascular stabilization mechanism by angiopoietin-1, Japanese Pharmacological Journal, Medicine and the Body, Japanese Pharmacological Society, 136(1):26-30, 2010. [Non-Patent Document 4] Kajiya K et al.: Structural alterations of the cutaneous vasculature in aged and in photoaged human skin in vivo. J Dermatol Sci. 61:206-207, 2011. Summary of the Invention [Problem to be solved by the invention]

[0008] As a result of intensive research by the inventors to solve the above-mentioned problems, in order to deal with deterioration of capillaries caused by aging and other factors, the inventors discovered an active ingredient that activates Tie2 and promotes blood circulation, and also devised the present invention, which promotes the absorption of this active ingredient in the intestine. [Means for solving the problem]

[0009] The present inventors have found that the extract of the leaves of Okinawa cinnamomum (Cinnamomum sieboldii, also known as Okinawa Karaki) has the effect of activating Tie2, maturing blood vessels, or stabilizing blood vessels, and have completed the present invention. Furthermore, based on the four elements of a plant extract that activates Tie2, a component that promotes blood circulation, and a lactic acid bacteria extract that promotes the absorption of active ingredients into the intestines, the present inventors have completed the present invention, which is composed of a blend (mixture) of cinnamon and rooibos, which have components that activate Tie2, safflower, which has a blood circulation promoting effect, black beans, which increase blood and promote blood flow, and lactic acid bacteria, which improve the intestinal flora and enhance the digestive and absorptive functions of the intestines, in addition to the above-mentioned Okinawa cinnamomum sieboldii.

[0010] In other words, the means for solving the above-mentioned problems are as follows. [1] Contains Okinawan cinnamon (Cinnamomum sieboldii) leaf extract as an active ingredient. Tie2 activator. [2] Contains Okinawan cinnamon (Cinnamomum sieboldii) leaf extract as an active ingredient, and has a vascular maturation or vascular stabilization effect based on Tie2 activation. Vascular maturation agents or vascular stabilization agents. [3] A food or drink used for at least one of Tie2 activation, vascular maturation, and vascular stabilization, [1] The Tie2 activator according to the present invention, [2] the vascular maturation agent according to the present invention, and [2] the vascular stabilization agent according to the present invention are contained in the composition. Food and drink. [4] Processed rooibos leaves and / or branches; Processed leaves of Okinawan cinnamon (Cinnamomum sieboldii) and A processed product of cinnamon branches and / or bark; Safflower processed products, Processed black beans and A capillary improvement agent containing as an active ingredient. [5] All of the processed products are dry ground products. [4] A capillary improvement agent according to the present invention. [6] Further containing lactic acid bacteria, [4] A capillary improvement agent according to the present invention. [7] A food or drink used for improving capillaries, comprising the capillary improvement agent described in [4]. Effect of the Invention

[0011] According to the present invention, the active ingredient activates Tie2 and promotes blood circulation, while increasing the absorption rate of the active ingredient into the body, thereby improving capillaries.

[0012] The present invention has been briefly described above. Furthermore, the details of the present invention will be further clarified by reading the following description of the embodiment of the present invention (hereinafter, also referred to as "embodiment") or examples thereof with reference to the accompanying drawings. [Brief description of the drawings]

[0013] [Figure 1] 1. Graph 1 showing changes in values ​​before and after ingesting the food and drink of the present invention (capillary diameter) [Diagram 2] A second graph showing the change in values ​​before and after taking the food and drink according to the present invention (length of blood vessel loop) [Diagram 3] The third graph shows the change in values ​​before and after taking the food and drink according to the present invention (blood flow velocity). [Figure 4] Photograph showing the state of blood vessels before ingesting the food and drink of the present invention (capillary image) [Diagram 5] Photograph showing the state of blood vessels after ingesting the food and drink of the present invention (capillary image) [Figure 6] Photograph showing the state of blood vessels before ingesting the food and drink of the present invention (length of capillary loop and blood flow velocity) [Figure 7] Photographs showing the state of blood vessels after ingesting the food and beverage of the present invention (length of capillary loop and blood flow velocity) [Figure 8] The effect of Rakukan tea and the control group (cinnamon + rooibos) on improving capillary blood flow velocity [Figure 9] The effect of Rakukan tea and the control group (cinnamon + rooibos) on improving capillary length [Figure 10] The effect of Rakukan tea and the control group (cinnamon + rooibos) on improving capillary thickness [Figure 11] The effect of Rakukan tea and the control group (cinnamon + rooibos) on improving the number of capillaries [Figure 12]Improvement effect of deformed capillaries by Rakukan tea and the control group (cinnamon + rooibos) [Figure 13] The effect of Rakukan tea and the control group (cinnamon + rooibos) on improving haze around capillaries [Figure 14] Comparison of capillary improvement effects between the Rakukan tea group and the control group (cinnamon + rooibos) [Figure 15] Rakukan Tea Group Test No. 15, Observation results of a 60-year-old woman [Figure 16] Test No. 11 of the Rakukan Tea Group, Observation results of a 52-year-old male [Figure 17] Rakukan Tea Group Test No. 4, Observation results of a 73-year-old male [Figure 18] Rakukan Tea Group Test No. 14, Observation results of a 54-year-old male [Figure 19] A diagram showing phosphorylated Tie2 protein bands in each sample detected by Western blotting. [Figure 20] Graph of Tie2 phosphorylation data [Figure 21] Photograph showing the first test result of Case 1 in the fourth embodiment [Figure 22] Photograph showing the second test result of Case 1 in the fourth embodiment [Figure 23] Photograph showing the third test result of Case 1 in the fourth embodiment [Figure 24] Photograph showing the fourth test result of Case 1 in the fourth embodiment [Diagram 25] Photograph showing the first test result of Case 2 in the fourth embodiment [Figure 26] Photograph showing the second test result of Case 2 in the fourth embodiment [Figure 27] Photograph showing the third test result of Case 2 in the fourth embodiment [Figure 28] Photograph showing the fourth test result of Case 2 in the fourth embodiment [Figure 29] Western blot results from the fifth example [Diagram 30] Data graph showing the test results in the fifth embodiment DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Hereinafter, one or more embodiments that specifically disclose the capillary improving agent, capillary improving food and beverage product, as well as the Tie2 activator, vascular maturation agent or vascular stabilizing agent, and the food and beverage product of the present invention will be described in detail.

[0015] However, in some cases, more detailed explanations than necessary may be omitted. For example, detailed explanations of already well-known matters or duplicate explanations of substantially the same configurations may be omitted. This is to avoid the following explanation becoming unnecessarily redundant and to facilitate understanding by those skilled in the art.

[0016] The following description is provided to enable those skilled in the art to fully understand the present disclosure, and is not intended to limit the subject matter described in the claims.

[0017] Also, unless otherwise noted, all numbers expressing parameters, reaction conditions, component concentrations, and the like used in this specification and appended claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and appended claims are approximations that may vary depending at least on particular analytical techniques.

[0018] <Terminology explanation> The terms "comprising" or "characterized by," which are synonymous with "comprising" and "containing," are to be construed in an inclusive or open-ended sense and do not exclude additional, unrecited elements or method steps. "Comprising" is a term of art used in claim language that means that the named claim element is required, but that other claim elements may be added to further form a structure within the scope of the claim.

[0019] Also, as used herein, the phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. When the phrase "consisting of (or variations thereof)" appears in a section of the body of a claim rather than immediately following the preamble, it limits only the elements set forth in that section and does not exclude other elements from the claim as a whole. As used herein, the phrase "consisting essentially of" limits the scope of a claim to those elements or method steps specified in addition to those that do not materially affect the main and novel feature(s) of the claimed subject matter.

[0020] With respect to the terms "comprising," "consisting of," and "consisting essentially of," when one of these three terms is used herein, the presently disclosed and claimed subject matter may also include the use of either of the other two terms. Thus, in some embodiments not expressly recited otherwise, any instance of "comprising" may be replaced by "consisting of" or "consisting essentially of."

[0021] The term "process" or "step" may be used explicitly or implicitly in connection with a process or method feature, but no limitation is imposed on the order or sequence between such explicit processes or steps or between implicit processes or steps, unless the order or sequence is stated.

[0022] First Embodiment A first embodiment of the present invention will be described below. The first embodiment relates to a capillary blood vessel improving agent and a capillary blood vessel improving food and drink.

[0023] In this embodiment, the capillary blood vessel improving food and drink (hereinafter also referred to as "food and drink") is a tea provided containing, as capillary blood vessel improving agents, at least one processed product of rooibos leaves and branches, at least one processed product of cinnamon leaves and branches, processed safflower, and processed black beans as active ingredients. In other words, all of the above-mentioned processed products are dried and ground. The food and drink of this embodiment further contains lactic acid bacteria.

[0024] In other words, the food and drink of this embodiment is based on the three elements of a plant extract that activates Tie2, a component that promotes blood circulation, and a lactic acid bacteria extract that promotes the absorption of active ingredients into the intestines, and is a tea that is a blend of cinnamon and rooibos, which have components that activate Tie2, safflower, which has a blood circulation promoting effect, black beans, which increase blood and promote blood flow, and lactic acid bacteria that improve the intestinal flora and improve the digestive and absorption functions of the intestines. The inventors also call this tea "rakukan tea" (see below).

[0025] The active ingredients of the food and beverage according to this embodiment, cinnamon (Cinnamomum) and rooibos (Aspalathus linearis), contain a substance called piperine, which activates Tie2 similar to angiopoietin-1. When piperine reaches capillaries through the bloodstream, it binds to the Tie2 receptor of vascular endothelial cells, phosphorylating (activating) Tie2, repairing capillaries and strengthening the vascular structure, thereby maintaining the normalization and stabilization of capillaries.

[0026] Cinnamon has a hot and sweet taste and is a warming agent that acts on many meridians, warming them and their side branches, dispersing cold, improving the circulation of yang energy and strengthening the yang of the heart, activating blood circulation, and relieving abdominal pain, joint pain, menstrual pain, and other pains caused by cold. Rooibos is caffeine-free, low in tannins, and contains more polyphenols than green tea.

[0027] Safflower, a herbal medicine often used in traditional Chinese medicine, has a warming effect that warms the body, smooths stagnant blood circulation, and has an excellent blood-activating effect that improves various symptoms caused by blood circulation disorders, activates blood circulation and relieves congestion, and is useful for relieving pain, menstrual irregularities, and poor circulation. Because it has the effect of promoting blood circulation and warming the body, it is included in the Japanese Pharmacopoeia as a herbal medicine for promoting blood circulation.

[0028] Black soybeans contain a lot of anthocyanin, which is known to be a functional substance that increases blood flow and blood volume. Anthocyanin has a strong antioxidant effect and also has the effect of suppressing platelet coagulation, so it is expected to protect capillaries and improve vascular and circulatory functions. It has also been confirmed that the application of anthocyanin can reduce the risk of death related to blood vessels.

[0029] The processed products of rooibos, cinnamon, safflower and black beans are not particularly limited, and the parts to be processed can be appropriately selected depending on the purpose, and examples thereof include leaves, branches, stems, flowers, fruits, roots and skin. Among these, in the case of rooibos, leaves and / or branches are preferred. In the case of cinnamon, skin is preferred. In the case of safflower, flowers are preferred. In the case of black beans, the beans themselves and / or skin are preferred.

[0030] The method for preparing the processed parts is to dry the parts, and then use them as they are or crush them using a crusher to use the dried and crushed product as the tea ingredient. That is, in this embodiment, the crushed product of each dried product is stored in a storage bag such as a tea bag and provided as a food or drink for improving capillaries in the form of tea. The drying may be done in the sun or using a commonly used dryer.

[0031] The person who eats or drinks the product puts the storage bag into, for example, hot or cold water, and eats or drinks the product in a state in which the active ingredient is extracted into the hot or cold water. Through eating or drinking, the person who eats or drinks the product can ingest the active ingredient.

[0032] In this embodiment, all the processed products are dried and ground, but the present invention is not limited thereto, and the extracts thereof may be used. The extracts can be easily obtained by methods generally used for plant extraction. The extracts are not particularly limited and can be appropriately selected according to the purpose, and examples of the extracts include diluted extracts, concentrated extracts, and dried extracts.

[0033] The extraction method is not particularly limited and can be appropriately selected depending on the purpose. For example, an example of the method is to place the extraction part of the above-mentioned plant, which is the extraction raw material, in a treatment tank filled with an extraction solvent, and, if necessary, to elute the soluble components while stirring appropriately, and then to obtain an extract by filtering to remove the extraction residue.

[0034] The food and drink of this embodiment also contains lactic acid bacteria that regulate the intestines. Among lactic acid bacteria, the EC-12 strain is preferred. The EC-12 strain improves the intestinal flora and improves the digestive and absorptive functions of the intestine. It has been experimentally confirmed that when lactic acid bacteria EC-12 strain is ingested, the bifidobacteria in the intestine increase by about 2.3 times, and the amount of stool increases (Terada A et al.: Effects of the consumption of heat-killed Enterococcus faecalis EC-12 preparation on microbiota and metabolic activity of the faeces in healthy adults. Microbial Ecology in Health and Disease.16(4):188-194, 2004.). In addition, this lactic acid bacteria strain is added to many supplements to promote the absorption of active ingredients.

[0035] Furthermore, the extraction conditions (extraction time and extraction temperature) and the amount of extraction solvent used are not particularly limited and can be appropriately selected depending on the purpose.

[0036] <Second embodiment> A second embodiment of the present invention will be described below. This embodiment relates to a Tie2 activator, a blood vessel maturation agent or a blood vessel stabilization agent, and foods and drinks containing the same.

[0037] In this embodiment, the Tie2 activator, blood vessel maturation agent, or blood vessel stabilizer, and food and drink thereof use an extract of Okinawa karaki (scientific name: Cinnamomum sieboldii Meisn.) leaves (leaves) extracted with alcohol (e.g., methanol). In other words, they contain an extract of Okinawa karaki (Cinnamomum sieboldii) leaves as an active ingredient. Note that Okinawa karaki is also called Okinawa karaki in Okinawa.

[0038] Previous findings demonstrated that extracts from cinnamon (the bark of the trunk of karaki) activate Tie2 in test tubes, but it was not clear whether the leaves have the effect of activating Tie2. In addition, conservation activities are being carried out for Okinawa karaki, a precious tree in Okinawa designated as a near-threatened species, and since the bark of the trunk can no longer be used, further research and development of applications for Okinawa karaki leaves are considered to be of great value. As a result of intensive research, the inventors have found that extracts from Okinawa karaki leaves, which are characterized by their high content of aldehydes, cloves, polyphenols, and catechin trimers, and have the effects of expanding peripheral blood vessels, increasing blood flow, reducing fever, and warming the body, have the effect of activating Tie2.

[0039] In this embodiment, an extract from the leaves of Okinawa Karaki is used. The extract can be easily obtained by a method generally used for plant extraction. There is no particular limitation on the extract, and it can be appropriately selected depending on the purpose, and examples of the extract include a diluted extract, a concentrated extract, and a dried extract.

[0040] The extraction method is not particularly limited and can be appropriately selected depending on the purpose, for example, a method in which the extracting part of the above-mentioned plant, which is the extraction raw material, is placed in a treatment tank filled with an extraction solvent, and the soluble components are dissolved while stirring as necessary, and then the extraction residue is removed by filtration to obtain an extract liquid is exemplified. In addition, in the case of this embodiment, it is preferable to use alcohol as the extraction solvent.

[0041] Furthermore, the capillary blood vessel improving food and drink as the capillary blood vessel improving agent of the above-mentioned first embodiment may be configured to be mixed with an extract or powder (e.g., dried and pulverized product) of the leaves (leaves) of Okinawa cinnamon (scientific name: Cinnamomum sieboldii, also known as Okinawa karaki) of this embodiment. In this case, it is preferable because the Tie2 activation action, blood vessel maturation action, blood vessel stabilization action, etc. can be further enhanced.

[0042] Here, we will explain from the perspective of traditional Chinese medicine (another point of view) capillary improvement agents or foods and beverages that contain as active ingredients processed Okinawan cinnamon leaves of this embodiment, as well as processed rooibos leaves and / or branches, processed cinnamon branches and / or bark, processed safflower, and processed black beans.

[0043] In China, there is a traditional Chinese medicine concept of "Kyoku-ketoshi-kao." Stagnant blood occurs due to poor lifestyle habits, but certain plants and foods are said to have the effect of improving blood flow in blood vessels, relieving pain and poor circulation, and promoting skin metabolism and blood flow circulation.

[0044] In the present invention, the inventors have conducted intensive research based on the ideas of traditional Chinese medicine. As a result, they have developed food and drink (tea is one example) that can improve blood flow in capillaries, mainly using "cinnamon", "safflower", and "black beans", which have been known since ancient times among the Chinese people for their blood-activating effects, and also adding Okinawan cinnamon (Okinawa), which is precious in Okinawa, as mentioned in this embodiment.

[0045] In traditional Chinese medicine, emphasis is placed on the properties of plants and foods (five properties: warm, hot, cool, cold, neutral), tastes (five tastes: sour, bitter, sweet, spicy, salty), meridians (Liver meridian, Heart meridian, Kidney meridian, Spleen meridian, Lung meridian) and efficacy of yin and yang (see, for example, the following sources: "Chinese Pharmacopoeia 2020 Edition," "Chinese-Japanese Medical Dictionary (China People's Health Publishing House)," "Toyama University Institute of Japanese and Chinese Medicine Japanese and Chinese Medicine Database Portal," and "Medicinal Plants Comprehensive Information Database [National Institute of Biomedical Innovation]").

[0046] In the first or second embodiment, cinnamon has properties of heat, tastes of hot and sweet, and meridians of kidney, spleen, heart, and liver. It is said to replenish yang. Specifically, its efficacy is said to be to replenish yang, disperse sebum, improve cold pain in the stomach and abdomen, meridian pain, frequent urination, etc., and increase yang energy. As mentioned above, in this embodiment, Okinawan cinnamon (Okinawa karaki leaves) are added as a new material (ingredient), and it is expected that the effect of warming the internal organs by promoting blood circulation, expanding the peripheral nerves, increasing blood flow, inducing sweating and reducing fever, and warming the body.

[0047] Safflower is said to have warm properties, spicy taste, guiding meridians to the heart and liver, and yin and yang to enhance yin energy. Specifically, its effects are known to be "blood-stimulating," "dispersing," and "opening the meridians." Black beans are said to have neutral properties, sweet taste, guiding meridians to the kidneys and spleen, and to enhance yin and yang. Specifically, its effects are known to be "blood-stimulating," "water-relieving," "wind-removing," and "detoxifying."

[0048] By combining these plants, which have a good yin-yang balance and exhibit various properties, with cinnamon bark, safflower, and black beans at the center, plus rooibos tea from South Africa and lactic acid bacteria for easy absorption, it is possible to promote capillary circulation, and achieve the beneficial effects of revitalizing the blood and improving blood flow (details will be explained in the examples below). EXAMPLES

[0049] The usefulness of the present invention will now be described in more detail with reference to one or more tests as examples (application examples and / or specific examples) of the present invention. It should be noted that the present invention is not limited to these embodiments or examples.

[0050] <First Example> In this example, a confirmation test was carried out to confirm the effectiveness of the food and drink according to the present invention (tea, the above-mentioned first embodiment) in improving blood vessels. The contents of the test for confirming the usefulness will be described with reference to Figs. FIG. 1 is a first graph (capillary blood vessel diameter) showing changes in values ​​before and after intake of a food or drink according to the present invention. FIG. 2 is a second graph (vascular loop length) showing the change in values ​​before and after taking the food and drink according to the present invention. FIG. 3 is a third graph (blood flow velocity) showing the change in values ​​before and after taking the food and drink according to the present invention. FIG. 4 is a photograph (capillary blood vessel image) showing the state of blood vessels before ingestion of the food or drink according to the present invention. FIG. 5 is a photograph (capillary blood vessel image) showing the state of blood vessels after ingesting the food and drink according to the present invention. FIG. 6 is a photograph showing the state of blood vessels (length of capillary loop and blood flow velocity) before ingestion of the food or drink according to the present invention. FIG. 7 is a photograph showing the state of blood vessels (length of capillary loop and blood flow velocity) after ingestion of the food and drink according to the present invention.

[0051] [Subjects and Methods] The study subjects were five volunteers (one male, four females) aged between 50 and 73 years old. Each volunteer placed the food and beverage product of the present invention (tea, one packet (3g) per day) in approximately 150ml of freshly boiled water, allowed to soften for five minutes, and then drank it.

[0052] Using a microscope (manufactured by GOKO Visual Equipment Co., Ltd., Japan) equipped with high-performance image analysis and measurement software GOKO Measure Plus and GOKO Bscan-Z / ZD-specific flow velocity measurement software GOKO-VIP, the condition of the capillaries in the nail bed of the ring finger of the non-dominant hand was observed and measured twice, before and 30 days after consuming the food and beverage of the present invention.

[0053] The parameters (variables) measured were (1) capillary shape, (2) brightness of the tissue surrounding the capillary, (3) vascular loop length, (4) blood vessel thickness, and (5) blood flow velocity. Of these, the vascular loop length, blood vessel thickness, and blood flow velocity of each examinee were the average values ​​of three measurements taken at the same location. The probability of the p-value of the difference between the two average values ​​before and after drinking the food and drink of the present invention was calculated using Student's paired data t-test.

[0054] [·result] The observation and measurement results are shown in Table 1 and Figures 1 to 7.

[0055] [Table 1]

[0056] Table 1 shows the capillary parameters measured before and after ingesting the food and beverage of the present invention.

[0057] (1) Regarding the shape of blood vessels, the ideal capillary loop in a fingertip is straight, has no lateral bypass, and is not twisted or deformed.

[0058] (2) The brightness of the tissue surrounding the capillaries is affected by factors such as vascular aging, inflammation, and vascular leakage. These factors cause waste products, substances that have leaked from the blood vessels, and inflammatory reaction products to accumulate in the tissue, forming a thick haze.

[0059] (3) The ideal capillary thickness in a fingertip is approximately 6 to 15 μm. The average capillary thickness before drinking the food and drink according to the present invention was 16.4±2.5 μm, while the average thickness after drinking was 14.3±3.0 μm.

[0060] (4) The ideal length of the capillary loop on a fingertip is 250 μm or more. The average length of the capillary loop before drinking the food or beverage according to the present invention was 259.2±58.1 μm, while the average length after drinking was 321.3±141.4 μm.

[0061] (5) The faster the capillary blood flow velocity, the better. The average capillary blood flow velocity before drinking the food and drink according to the present invention was 204.2±166.4 μm / s, while the average after drinking it was 459.1±311.6 μm / s.

[0062] Then, with reference to Figs. 1 to 3, the changes in capillary thickness, blood vessel loop length, and blood flow velocity (*, p<0.05) before and after drinking the food and drink according to the present invention will be described.

[0063] Regarding blood vessel thickness, the average value after drinking was 2.1μm narrower than before drinking (p<0.046, significant difference). Regarding blood vessel loop length, the average value after drinking was 62.1μm longer than before drinking, but the difference was not significant (p>0.11). Regarding blood flow velocity, the average value after drinking was 254.9μm / s faster than before drinking (p<0.018, significant difference).

[0064] 4 and 5 show images (140x) of capillaries of a 61-year-old woman before and after consuming the food and drink according to the present invention for 30 days (3 g per day).

[0065] As shown in Figures 4 and 5, before drinking, the tissue around the capillaries was covered with a thick brown haze, making the capillaries invisible. After drinking, the brown haze disappeared, the capillaries were clearly visible, and the capillary loops were stretched.

[0066] 6 and 7 show the change (560 times) in capillary loop length and blood flow velocity before and after 30 days (3 g per day) of a 61-year-old woman taking the food and drink according to the present invention.

[0067] As shown in Figures 6 and 7, the length of the capillary loop marked with symbol 1 in the photograph was 201.3 μm before drinking and 296.2 μm after drinking, increasing by 1.5 times. The blood flow velocity changed from 286.6 μm / s before drinking to 424.8 μm / s, increasing by 1.6 times.

[0068] The length of the blood vessel loop marked with symbol 2 in the photograph was 331.9 μm before drinking and increased to 561.3 μm after drinking, a 1.7-fold increase. The blood flow velocity increased from 238.8 μm / s before drinking to 411.1 μm / s, a 1.8-fold increase.

[0069] The blood flow velocity of the blood vessel marked with symbol 3 in the photograph was 50.7 μm / s before drinking, and 331.9 μm / s after drinking, which was 3.8 times faster. Also, the capillary loops marked with symbols 1 and 2 were tortuous before drinking, but became straight after drinking.

[0070] [Discussion and conclusions] In this test, it was confirmed that after drinking the food and drink (tea) made of a blend of cinnamon, rooibos, safflower, black beans and EC-12 lactic acid bacteria, which have the health-improving effects described above, for about one month, the shape of the capillaries, the brightness of the tissue surrounding the capillaries, the thickness of the capillaries, the length of the capillary loop, and the blood flow rate of the capillaries were all improved. In particular, the thickness of the capillaries and the blood flow rate of the capillaries were significantly improved, confirming that the present invention has a health-improving effect on human capillaries.

[0071] <Second Example> In this example, a confirmation test was carried out on the food and drink according to the present invention (tea, the above-mentioned first embodiment) to confirm the effectiveness in improving the function of capillaries in the nail groove. In this embodiment, the tea food or beverage is also called "Rakukancha" (see below).

[0072] [·the purpose] Of the subjects in this example, aged between 30 and 80, who underwent fingertip capillary testing, more than 80% showed signs of deterioration, including vascular deformation such as bending, twisting, atrophy, thickening, and the formation of bypass blood vessels, abnormal phenomena such as a dark brown (accumulation of waste products) or pink (vascular leakage) mist, and a decrease in blood flow velocity (see below).

[0073] In a test tube, the effect of activating Tie2 by extracts from cinnamon, rooibos, and long pepper has been demonstrated, but since factors such as intestinal absorption and blood flow state are influential, it has not yet been elucidated what effect taking them will have on capillaries in vivo. Based on the three elements of a component that activates Tie2, a component that promotes blood circulation, and a lactic acid bacteria extract that promotes the absorption of active ingredients into the intestine, the inventors have blended cinnamon and rooibos, which have the effect of activating Tie2, safflower, which has the effect of promoting blood circulation, black beans, which increase blood and promote blood flow, and lactic acid bacteria, which improve the intestinal flora and improve the digestive and absorptive functions of the intestine, to create a food and drink called "Rakukancha," and verified the effect on capillaries through an in vivo experiment.

[0074] [Subjects, Materials and Methods] [··subject] Thirty-two volunteers aged between 38 and 81 years (average age 57 years, 18 men and 14 women) were randomly selected and divided into a "Rakukan tea verification group" and a "cinnamon + rooibos control group," with 16 participants each.

[0075] [··material] [1] The test group was given "Rakukancha" (a blend of Okinawan karaki leaf powder, cinnamon, rooibos, safflower, black soybean, and lactic acid bacteria extract). [2] The control group was given "cinnamon plus rooibos" (a blend of the same amounts of cinnamon and rooibos found in Rakukan tea).

[0076] [··method] [1] The test and control groups were given one packet (3g) of "Rakukan Tea" per day and one packet (2g) of "Cinnamon + Rooibos" powder per day, each placed in approximately 150ml of freshly boiled water and left to soften for at least five minutes before drinking. They continued to drink the tea without interruption for 30 days. [2] Using a microscope (manufactured by GOKO Visual Equipment Co., Ltd. of Japan) equipped with the high-performance image analysis and measurement software GOKO Measure Plus and the GOKO Bscan-Z / ZD-specific flow velocity measurement software GOKO-VIP, the condition of the capillaries in the nail bed of the ring finger of the non-dominant hand was observed and measured twice: on the day before drinking "Rakukan Tea" and "Cinnamon + Rooibos" and 30 days after drinking them. [3] Precautions when measuring: The room temperature was 26±1℃, the subject was seated, and the measurement finger and heart were at the same height. The same area was observed and measured both times. [4] Measurement and observation parameters (variables): (1) Capillary shape (score for deformed blood vessels, such as twisted): The percentage of deformed blood vessels in one field of view (140x magnification) is: <10%=0; >10%,<30=1; >30%,<60%=2; > 60%=3. Regarding blood vessel shape, the ideal capillary loop in the fingertip is straight, with no sideways bypasses, and the blood vessel loop is not twisted or deformed. (2) Brightness of the tissue around the capillaries (haze): The percentage of haze in one field of view (140x magnification) is: none = 0; 1 / 3 field of view = 1; 1 / 2 field of view = 2; >1 / 2 field of view = 3. The brightness of the tissue surrounding the capillaries is affected by factors such as aging of blood vessels, inflammation, and vascular leakage, which causes waste products, substances leaking from blood vessels, and inflammatory reaction products to accumulate in the tissue and form a thick haze. (3) Length of vascular loop: The average length (μm) of the five longest vascular loops at 140x magnification. The ideal length of a capillary loop on a fingertip is considered to be 250μm or longer. (4) Blood vessel size: The average diameter (μm) of five blood vessels at 140x or 560x magnification. The ideal diameter of capillaries in a fingertip is thought to be approximately 6 to 14 μm. (5) Number of capillaries: Number of capillary loops in the top row of one field at 140x magnification. The ideal number of capillaries on a fingertip is considered to be >20. (6) Blood flow velocity: The average blood flow velocity (μm / s) on the arterial side of the three capillary loops taken from the video. The faster the blood flow velocity in the capillaries, the better. [5] Statistics: Data are expressed as the mean ± SEM of the values ​​obtained for each group (n = 16). Differences in the means were analyzed using the ANOVA program and unpaired two-way t-test. The threshold for significance was the value divided by the number of comparisons (P < 0.05).

[0077] [·Measurement results] The measurement results are shown in Tables 2 and 3. Table 2 shows the Rakukan tea community data and subject list. Table 3 shows the control group data and subject list.

[0078] [Table 2]

[0079] [Table 3]

[0080] [Statistical analysis] The measurement results were subjected to statistical analysis, and the analysis results are shown in Tables 4 and 5 and Figs. 8 to 14. Table 4 shows the effects of drinking "Rakukan Tea" and "Cinnamon + Rooibos" on capillaries. Table 5 shows a comparison of the capillary improvement effects of "Rakukan Tea" and "Cinnamon + Rooibos". Figure 8 shows the effect of improving capillary blood flow velocity in Rakukan tea and the control group (cinnamon + rooibos). FIG. 9 shows the effect of improving capillary length in Rakukan tea and the control group (cinnamon + rooibos). Figure 10 shows the effect of improving capillary thickness in Rakukan tea and the control group (cinnamon + rooibos). FIG. 11 shows the effect of improving the number of capillaries in Rakukan tea and the control group (cinnamon + rooibos). FIG. 12 shows the improving effect of deformed capillaries by Rakukan tea and the control group (cinnamon + rooibos). FIG. 13 shows the effect of Rakukan tea and the control group (cinnamon + rooibos) in improving haze around the capillaries. FIG. 14 shows a comparison of the capillary improvement effects between the Rakukan tea group and the control group (cinnamon + rooibos).

[0081] [Table 4]

[0082] [Table 5]

[0083] As shown in Table 4, Rakukan tea had an improving effect on all measured items, but cinnamon + rooibos only showed an improving effect on blood vessel length, thickness, and number of blood vessels. ***, P<0.001; **, P<0.01; *, P<0.05. As shown in Table 5, there is a difference between "Rakukan Tea" and "Cinnamon + Rooibos" in the average increase or decrease in the length, thickness and number of capillaries. *, P<0.05.

[0084] As shown in Figure 8, an increase in blood flow velocity was observed in both groups, but there was no significant difference before and after drinking in the control group. As shown in Figure 9, there was an improvement effect in both groups. **, P<0.01; ***, P<0.001. As shown in Figure 10, there was an improvement in capillary narrowing in both groups. *, P<0.05. As shown in Figure 11, the improvement effect was significant in both groups. *, P<0.05; **, P<0.01. As shown in Figure 12, there was no significant difference between before and after drinking in the control group. *, P<0.05. As shown in Figure 13, the control group showed a tendency towards improvement, but the difference was not significant. ***, P<0.001. As shown in Figure 14, both groups showed improvement in the length (A), thickness (B) and number of blood vessels (C) of capillaries, but the difference in the effect between the two groups was significant, indicating that the effect of Rakukan tea was better than that of the control group. *, P<0.05.

[0085] [Regarding the first example in this embodiment] With reference to FIG. 15, a first case observed in the above-mentioned confirmatory test will be described. FIG. 15 shows the observation results of a 60-year-old woman, Rakukan Tea Group Verification No. 15 (see Table 2).

[0086] FIG. 15 shows the improvement in capillary blood flow velocity, vascular loop length, perivascular clarity, and vascular loop shape before (left) and after (right) drinking Rakukancha for 30 days (3 g daily). [··Photo above (magnification = 140)]: Before drinking, thick brown and pink haze (inflammation, vascular leakage and poor metabolism) was visible, and the blood vessels were short and not clearly visible. After drinking, the brown and pink haze became significantly lighter, and the blood vessels became longer and more clearly visible. [Photo below (magnification = 560)]: (1) Blood flow velocity before and after drinking: 1=286.6μm / s → 424.8μm / s; 2=238.9μm / s → 411.1μm / s; 3=50.75μm / s → 196.58μm / s; 4=184.3μm / s → 295.7μm / s. They were 1.6, 1.8, 3.8, and 1.4 times faster, respectively. (2) The length of the vascular loop before and after drinking: 1=201.3μm → 296.2μm; 2=181.4μm → 253.7μm; 3=159.1μm → 277.2μm; 4=212.8μm → 394.9μm. The length increased by 1.5, 1.4, 1.7, and 1.9 times, respectively. (3) Compared to before drinking the supplement, the pink haze around blood vessels decreased and vascular leakage improved after drinking the supplement. (4) After drinking the medicine, the deformed vascular loops 1 to 4 were straightened and the deformation was improved.

[0087] [Regarding the second case in this embodiment] A second case observed in the above-mentioned confirmatory test will be described with reference to FIG. Figure 16 shows the observation results of a 52-year-old male, Rakukan Tea Group Verification No. 11 (see Table 2).

[0088] FIG. 16 shows the improvement in capillary blood flow velocity, vascular loop length, and blood vessel thickness before (left) and after (right) drinking Rakukancha for 30 days (3 g daily). [··Photo above (magnification = 140)]: Before drinking, the blood vessels were short and thick. After drinking, the blood vessels became longer, thinner and more clearly visible. [Photo below (magnification = 560)]: (1) The average blood flow velocity before and after drinking increased from 107.6 μm / s to 706.5 μm / s, which is 6.5 times faster. (2) The average length of the vascular loops before and after drinking increased from 103.7 μm to 208.8 μm, doubling in length. (3) The average thickness of blood vessels before and after drinking the tea decreased from 13.5 μm to 9.3 μm, a decrease of 4.2 μm. "↓" is a marker indicating the same place.

[0089] [Regarding the third case in this example] A third case observed in the above-mentioned confirmatory test will be described with reference to FIG. Figure 17 shows the observation results of Rakukan Tea Group Verification No. 4 (see Table 2), a 73-year-old male.

[0090] Figure 17 shows the improvement in capillary blood flow velocity, blood vessel length, blood vessel thickness, deformed blood vessels, and clarity of blood vessels (magnification = 140) before (left) and after (right) drinking "Rakukancha" for 30 days (3g per day). Before drinking, the blood vessels were short and thick, the blood vessel loops were twisted, and there was a thick pink haze around the blood vessels. After drinking, the blood vessels became longer and thinner, and the blood vessel loops became straight. The pink haze also became lighter.

[0091] (1) The average blood flow velocity before and after drinking increased from 194.1 μm / s to 489.7 μm / s, which is 2.5 times faster. (2) The average length of the vascular loops before and after drinking increased from 175.2 μm to 283.7 μm, a 1.6-fold increase. (3) The average thickness of blood vessels before and after drinking the tea decreased from 18.6 μm to 12.3 μm, a decrease of 5.3 μm. (4) The proportion of twisted blood vessels (deformed blood vessels) decreased from 60% before drinking to 10% after drinking, and the degree of deformation was significantly reduced. "↓" is a mark indicating the same place.

[0092] [Regarding the fourth case in this embodiment] A fourth case observed in the above-mentioned confirmatory test will be described with reference to FIG. Figure 18 shows the observation results of a 54-year-old male, Rakukan Tea Group Verification No. 14 (see Table 2).

[0093] Figure 18 shows the improvement in capillary blood flow velocity, blood vessel thickness, and deformed blood vessels before (left) and after (right) drinking Rakukancha for 30 days (3g per day) (magnification = 560).

[0094] (1) The average blood flow velocity before and after drinking increased from 238.5 μm / s to 360.9 μm / s, which is 1.5 times faster. (2) The average thickness of blood vessels before and after drinking the tea decreased from 12.6 μm to 9.9 μm, a decrease of 2.7 μm. (3) The vascular loops that were stuck together before drinking (deformed vascular loops) returned to the normal vascular loop shape after drinking. The proportion of deformed blood vessels was 70% before drinking and 20% after drinking. The black "↓" indicates a deformed vascular loop that was stuck together; the white "↓" indicates a normal vascular loop. (4) Comments from the monitor: Many people reported that it was easy to drink and improved poor circulation. Other reactions included lowered blood pressure, increased appetite, improved bowel movements, improved complexion, improved sleep, feeling refreshed in the morning, and generally feeling better.

[0095] [Discussion and conclusions] The ingredients of "Rakukancha" - cinnamon (Cinnamomum) and rooibos (Aspalathus linearis) - contain substances such as s-syringaresinol, which activates Tie2, such as angiopoietin-1, and have been shown in test tubes to bind to the Tie2 receptors of vascular endothelial cells and phosphorylate (activate) Tie2. Cinnamon also has a hot and sweet taste, and is a warming agent that warms the body. It acts on many meridians, improving the circulation of yang energy, activating blood circulation, and relieving pain such as abdominal pain, joint pain, and menstrual pain caused by cold. Rooibos is caffeine-free, low in tannins, and contains more polyphenols than green tea.

[0096] Safflower, a medicinal herb commonly used in traditional Chinese medicine, has warming properties that warm the body, smooth out sluggish blood circulation, and improve various symptoms caused by poor blood circulation with its excellent blood-activating properties. It activates blood circulation and eliminates congestion, and is useful for relieving pain, irregular menstruation, and poor circulation. It is included in the Japanese Pharmacopoeia as a herbal medicine for promoting blood circulation because it has the effect of promoting blood circulation and warming the body.

[0097] Black beans contain a lot of anthocyanin, which is known as a functional substance that increases blood flow and improves blood circulation. Anthocyanin has a strong antioxidant effect and also has the effect of inhibiting platelet coagulation, so it is expected to protect capillaries and improve vascular and circulatory functions. It has also been found that the application of anthocyanin can reduce the risk of death related to blood vessels. Furthermore, it has been suggested that black bean polyphenols promote NO production in vascular endothelial cells, increasing blood flow.

[0098] The EC-12 strain of lactobacillus, which has an intestinal regulating effect, is known to improve the intestinal flora and improve the intestinal digestive and absorptive functions. Experiments have confirmed that taking the EC-12 strain of lactobacillus increases the number of bifidobacteria in the intestine by about 2.3 times, and increases the amount of stool. This lactobacillus strain is added to many supplements to promote the absorption of active ingredients.

[0099] It has already been reported that cinnamon and rooibos each have the effect of activating the Tie2 receptors in capillary endothelial cells in test tubes, but since the effect of improving capillaries in the body is influenced by factors such as the absorption of active ingredients in the intestines and the state of blood flow, it is thought that the effect in the body will be further increased by adding something that promotes absorption in the intestines and blood circulation.

[0100] In this example, "Rakukan Tea," a blend of cinnamon, rooibos, safflower, black beans, and EC-12 lactic acid bacteria, which have the health-improving effects described above, showed significant differences before and after drinking in all six parameters measured, suggesting an improving effect on capillaries, but "Cinnamon + Rooibos" only improved three parameters: blood vessel length, blood vessel thickness, and blood vessel number. Furthermore, in these three parameters, the average increase (length and number) or decrease (thickness) by "Rakukan Tea" was greater than that of "Cinnamon + Rooibos" (all P<0.05).

[0101] In conclusion, (1) "Rakukan Tea" including those that promote absorption and blood circulation improved the shape of capillaries, the thickness of the tissue surrounding the capillaries, the thickness of the capillaries, the length of the capillaries, the number of capillaries, and the blood flow rate of the capillaries, and had the effect of improving the health of human capillaries. (2) It was suggested that the important thing for the components that are good for the capillaries verified in a test tube to play a role in the body when consumed is to promote absorption in the intestines and blood circulation.

[0102] Furthermore, based on the so-called considerations described below, it is possible to further enhance the activation of Tie2 by mixing an extract or powder (e.g., dried and ground) of the leaves (leaf part) of Okinawa cinnamon (scientific name: Cinnamomum sieboldii Meisn.: also known as Okinawa karaki) with the "Rakukan tea."

[0103] <Third Example> In this example, a confirmation test was conducted to confirm the Tie2 activation effect using Okinawa Karaki leaves, which are characterized by their high content of aldehydes, cloves, polyphenols, catechin trimers, etc., and have effects such as dilating peripheral blood vessels, increasing blood flow, and reducing fever and warming.

[0104] Materials and Methods [··material]: Dried Okinawa Karaki (Cinnamomum sieboldii Meisn.) leaf powder grown at Ogimi Village Farm. [··Extraction method]: Extraction was performed using methanol. Specifically, 60 L of methanol was added to 3 g of powdered leaves and left at 50°C for 3 hours. After suction filtration, the filtrate was concentrated under reduced pressure. [··Analysis method]: Mouse pro-B cells (Ba / F3) overexpressing human Tie2 (Ba / F3-human Tie2) were used for Tie2 phosphorylation analysis. Ba / F3-human Tie2 was stimulated with the physiological ligand of Tie2, Angiopoietin-1 (Ang1 300ng / ml), negative control (PBS or DMSO), and test substances. After adding various concentrations of test substances directly to standard culture medium (10% FBS RPMI1640 + 1pg / ml mouse IL-3) for 15 minutes, the cells were washed with PBS and cell extracts were collected using RIPA lysis buffer and Halt Protease and Phosphatase Inhibitor Cocktail. The cell extracts were electrophoresed on 7.5% SDS gel and transferred to nylon membranes. The transferred nylon membranes were blocked for nonspecific proteins with 100% skim milk + 0.5% BSA / TBST for 60 minutes, and then blotted with anti-Tie2 antibody (Ab33, Upstate) and anti-phosphorylated Tie2 antibody (Tyr992, Cell Signaling Technology). Subsequently, the membranes were blotted with HRP-labeled secondary antibodies, and the reaction products were visualized with ECL solution and photographed. The presence or absence of Tie2 phosphorylation was measured using Amersham Imager 680 software.

[0105] [·result] 19, 20 and Table 6 show the test results for this example. FIG. 19 shows phosphorylated Tie2 protein bands in each sample detected by Western blotting. FIG. 20 is a graph of the Tie2 phosphorylation data from Table 6. Table 6 shows the values ​​calculated by Western blot.

[0106] [Table 6]

[0107] As shown in Figure 19, the intensity of the detected bands is proportional to the amount of phosphorylated Tie2 protein. Higher band intensity indicates higher amount of phosphorylated Tie2 protein. (1) Band is DMSO control, (2) Band is Ang1 positive control, (5) Band is Okinawa Karaki leaf extract (500ug / mL), (6) Band is Okinawa Karaki leaf extract (1000ug / mL). The phosphorylated Tie2 (P-Tie2) of (6) band is more intense than the DMSO control (1), and as shown in Table 6, the phosphorylation rate of Tie2 was 1.8 times that of the DMSO control (if it is 1.5 times or more, it is highly likely that Tie2 is phosphorylated).

[0108] As shown in Table 6, (6) is an extract of Okinawa Karaki leaves (1000 ug / mL), and the phosphorylated Tie2 was 130,991 compared to 99,361 in the DMSO control (1), and the phosphorylation rate of Tie2 was 1.8 times that of the DMSO control.

[0109] As shown in FIG. 20, the Tie2 phosphorylation rate of the Okinawa Karaki leaf extract (6) (1000 ug / mL) was 1.8-fold higher than that of the DMSO control.

[0110] [·Consideration] Since phosphorylation of Tie2 by Angiopoietin-1 was observed compared to the DMSO control in Western blot, it was determined that this analysis was valid. In the Okinawa Karaki leaf (leaf) extract sample (1000ug / mL), the phosphorylation rate of Tie2 was 1.8 times that of the DMSO control (a rate of 1.5 times or more indicates a high possibility that Tie2 is phosphorylated), and although it was slight, phosphorylation of Tie2 was observed. The density of the visual band also indicates a high possibility that Tie2 is phosphorylated. The usefulness of the present invention was confirmed.

[0111] In addition, in this embodiment, alcohol was used as the extraction method, but this is not the only option. As with the above-mentioned Rakukan tea, the leaves of Okinawa Karaki may be dried and ground into a powder, and then extracted with hot water (high-temperature water) like tea and drunk. In such cases, the same effect can be achieved.

[0112] <Fourth Example> In this example, a confirmation test was conducted to confirm the usefulness of the present invention in improving the capillaries of patients with COVID-19 by using the aforementioned Rakukan tea. The confirmation test was conducted in two cases.

[0113] [·the purpose] The symptoms and organs affected by the novel coronavirus (SARS-CoV-2) infection are extremely diverse. Recent research has revealed that the SARS-CoV-2 spike protein in COVID-19 induces fibrin that is resistant to fibrinolysis, forming microclots in capillaries (Lize M.et.al. SARS-CoV-2 spike protein S1induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19. Biosci Rep. 2021 Aug 27; 41:8). When microclots form and block capillaries, the blood vessels become deformed, affecting the flow of blood and oxygen, leading to various symptoms. In this regard, we confirmed whether the present invention is also effective in patients with COVID-19.

[0114] [·method] Using a microscope (manufactured by GOKO Visual Equipment Co., Ltd. of Japan) equipped with the high-performance image analysis measurement software GOKO Measure Plus and the GOKO Bscan-Z / ZD-specific flow velocity measurement software GOKO-VIP, changes in the capillaries (blood vessel length, blood vessel thickness, blood flow velocity, haze, etc.) in the nail bed of the non-dominant ring finger of two patients with COVID-19 were measured several times before and after infection with the new coronavirus, and before and after drinking Rakukan Tea (one packet (3g) / day was placed in approximately 150 ml of freshly boiled water and left to soften for at least 5 minutes before drinking), to investigate the impact of COVID-19 infection on capillaries and the effect of Rakukan Tea on that impact.

[0115] [Results of Case 1] The subject in this case was a 63-year-old woman. The results for this case are shown in Figs. 21 to 24. In the figure, the arrows "↓" indicate the same location. FIG. 21 is a photograph showing the results of the first inspection of Case 1 in this embodiment. Photographed on July 4, 2023 (first inspection) Magnification: 145 FIG. 22 is a photograph showing the results of the second test of Case 1 in this embodiment. Photographed on August 20, 2023 (second test) Magnification: 145 FIG. 23 is a photograph showing the results of the third test of Case 1 in this embodiment. Photographed on September 21, 2023 (third test) Magnification: 145 FIG. 24 is a photograph showing the results of the fourth test of Case 1 in this embodiment. Photographed on October 26, 2023 (fourth test) Magnification: 145

[0116] As shown in Figure 21, the blood vessel length was 147.2 μm, the blood vessel thickness was 13.4 μm, the blood flow velocity was 190.7 μm / s, and the haze was thick. In addition, the patient drank Rakukan tea from 2023.07.04 to 2023.07.17. On 2023.07.18, he was diagnosed with corona and stopped drinking Rakukan tea.

[0117] As shown in Figure 22, it was observed that the blood vessel length was 103.7 μm (shorter than the first 147.2 μm), the blood vessel thickness was 14.3 μm (thicker than the first 13.4 μm), and the blood flow velocity was 101.8 μm / s (significantly slower than the first 190.7 μm / s). In addition, the capillaries were significantly altered by the new coronavirus infection. Drinking of Rakukan tea was resumed between 2023.08.20 and 2023.09.20.

[0118] As shown in Figure 23, it was observed that the blood vessel length was 152.2 μm (longer than 103.7 μm the second time), the blood vessel thickness was 13.3 μm (thinner than 14.3 μm the second time), and the blood flow velocity was 215.9 μm / s (significantly slower than 101.8 μm / s the second time). I drank Rakukan tea continuously from 2023.09.21 to 2023.10.24.

[0119] As shown in Figure 24, the blood vessel length was 237.3 μm (longer than before infection), the blood vessel diameter was 12.1 μm (thinner than before infection), and the blood flow velocity was 406.3 μm / s (significantly faster than before infection). It was observed that the haze around the capillaries was significantly reduced compared to the previous three times (indicating improvement in metabolism).

[0120] Thus, in Case 1, Rakukan tea was shown to enable the capillaries to recover from the effects of COVID-19 infection and even become better than before infection.

[0121] [Results of Case 2] The subject in this case was a 69-year-old man. The results for this case are shown in Figs. 25 to 28. In the figure, the arrows "↓" indicate the same location. FIG. 25 is a photograph showing the results of the first inspection of Case 2 in this embodiment. Photographed on July 17, 2023 (first inspection) Magnification: 145 FIG. 26 is a photograph showing the results of the second inspection of Case 2 in this embodiment. Photographed on August 18, 2023 (second inspection) Magnification: 145 FIG. 27 is a photograph showing the results of the third test of Case 2 in this embodiment. Photographed on September 24, 2023 (third test) Magnification: 145 FIG. 28 is a photograph showing the results of the fourth test of Case 2 in this embodiment. Photographed on October 26, 2023 (fourth test) Magnification: 145

[0122] As shown in Figure 25, it was observed that the blood vessel length was 304.6 μm, the blood vessel thickness was 9.6 μm, and the blood flow velocity was 260.9 μm / s. In addition, Rakukan tea was drunk from 2023.07.17 to 2023.08.17.

[0123] As shown in Figure 26, the blood vessel length was 282.4 μm, the blood vessel diameter was 9.3 μm, and the blood flow velocity was 272.9 μm / s. Also, there was little difference from the first test. I drank Rakukan tea for only two days from 2023.08.18 to 2023.08.20, and was diagnosed with COVID-19 on 2023.08.21, so I stopped drinking Rakukan tea.

[0124] As shown in Figure 27, it was observed that the blood vessel length was 108.5 μm (significantly shorter than 304.6 μm in the first and 282.4 μm in the second), the blood vessel thickness was 11.7 μm (thicker than 9.6 μm in the first and 9.3 μm in the second), and the blood flow velocity was 129.3 μm / s (significantly slower than 206.9 μm / s in the first and 272.9 μm / s in the second). In addition, the capillaries were significantly altered by the novel coronavirus infection.

[0125] The blood vessel length was observed to be 352.7 μm (longer than before infection), the blood vessel thickness was 9.6 μm (returned to before infection), and the blood flow velocity was 610.9 μm / s (more than twice as fast as before infection).

[0126] Thus, in Case 2, Rakukan Tea was shown to enable the capillaries to fully recover from the effects of COVID-19 infection and even improve compared to before infection.

[0127] [·Consideration] Microthrombi were formed in the capillaries of patients infected with the new coronavirus, which reduced the function of the capillaries (Lize M. et.al. Biosci Rep. 2021 Aug 27; 41:8). In both patients in Case 1 and Case 2 in this example, the capillaries in the fingertips significantly atrophied, shortened, and thickened after infection with the new coronavirus, and the blood flow rate significantly slowed, revealing damage to the capillaries due to the infection. By continuing to drink Rakukan tea, the capillaries in both cases were completely restored from damage. In particular, the length and blood flow rate of the capillaries were significantly improved, even compared to before infection. This result suggests that Rakukan tea has an improving effect on the damage to the capillaries of patients infected with the new coronavirus.

[0128] <Fifth Example> In this example, a test was carried out to verify the reproducibility of the Tie2 activation effect of an extract from the leaves (leaves) of Okinawa Cinnamon (also known as Okinawa Karaki, hereinafter also referred to as "Okinawa Karaki").

[0129] [·the purpose] According to previous research, it has been observed that the extract of dried leaves of Okinawa Karaki extracted using methanol phosphorylates (activates) Tie2 at a concentration of 1000ug / mL (the highest verified concentration in the test). Therefore, in this example, the reproducibility of the phosphorylation effect of the extract of dried leaves of Okinawa Karaki at a concentration of 1000ug / mL was verified for the effect of inducing phosphorylation of Tie2, and further the effect of high concentrations of dried leaves at 1500ug / mL and 2000ug / mL and the effect of the extract of semi-dried leaves were verified.

[0130] Materials and Methods [··material] Powder of dried and semi-dried Okinawan karaki leaves grown at a farm in Ogimi Village, Okinawa Prefecture.

[0131] [··method] [1] Extraction method Extraction was performed with methanol. In detail, 60 L of methanol was added to 3 g of leaf powder and left at 50°C for 3 hours. After suction filtration, the filtrate was concentrated under reduced pressure.

[0132] [2] Analysis method Tie2 phosphorylation was analyzed using mouse pro-B cells (Ba / F3) overexpressing human Tie2 (Ba / F3-human Tie2). Ba / F3-human Tie2 was stimulated with angiopoietin-1 (Ang1 300ng / ml), a physiological ligand of Tie2, negative control (PBS or DMSO), and test substances. Test substances were added directly to normal culture medium (10% FBS RPMI1640 + 1pg / ml mouse IL-3) at various concentrations, and after 15 minutes, cells were washed with PBS and cell extracts were collected using RIPA lysis buffer and Halt Protease and Phosphatase Inhibitor Cocktail. Cell extracts were electrophoresed on a 7.5% SDS gel and transferred to nylon membranes. The transferred nylon membranes were blocked for nonspecific proteins with 4% skim milk + 0.5% BSA / TBST for 60 minutes. The reaction was then visualized with ECL solution and photographed. The presence or absence of Tie2 phosphorylation was measured using Amersham Imager 680 software.

[0133] [Test Results] The test results in this example are shown in FIG. 29, FIG. 30 and Table 7. FIG. 29 is a photograph of a Western blot showing the test results in this example. FIG. 30 is a data graph showing the test results in this example. Table 7 shows the values ​​calculated by Western blot based on FIG.

[0134] [Table 7]

[0135] FIG. 29 shows the phosphorylated Tie2 protein bands in each sample detected by Western blot.

[0136] As shown in Figure 29, the intensity of the detected bands is proportional to the amount of phosphorylated Tie2 protein. Higher band intensity indicates higher amount of phosphorylated Tie2 protein. Band numbers indicate (1) DMSO control, (2) Ang1 positive control, (3) dried leaf extract 1000ug / mL, (4) dried leaf extract 1000ug / mL, (5) dried leaf extract 1500ug / mL, (6) dried leaf extract 2000ug / mL, (7) semi-dried leaf extract 1000ug / mL, (8) semi-dried leaf extract 1000ug / mL, (9) semi-dried leaf extract 1500ug / mL, and (10) semi-dried leaf extract 2000ug / mL, respectively.

[0137] As shown in Figure 29, the phosphorylated Tie2 (P-Tie2) obtained by 1000 ug / mL of dried leaf extract (3) was more concentrated than the DMSO control (1). Furthermore, as shown in Table 7, the phosphorylation rate of Tie2 was 1.9-fold higher than that of the DMSO control, confirming reproducibility (previous studies showed that the phosphorylation rate was 1.8-fold at the same concentration, indicating that Tie2 was phosphorylated at 1.5-fold or higher).

[0138] Similarly, the dried leaf extracts at 1500 μg / mL (5) (Tie2 phosphorylation rate was 1.7-fold higher than the DMSO control, see Table 7) and 2000 μg / mL (6) (Tie2 phosphorylation rate was 2.4-fold higher than the DMSO control, see Table 7) induced Tie2 phosphorylation in a dose-dependent manner. The EC50 for the dried leaf extracts is estimated to be around 1000 μg / mL. As shown in Table 7, the semi-dried leaf extracts at 1000 μg / mL (7) and 2000 μg / mL (10) phosphorylated Tie2 (Tie2 phosphorylation rate was approximately 1.6-fold and 1.7-fold higher than the DMSO control, respectively). The visual band density also indicated that Tie2 was phosphorylated.

[0139] As mentioned above, Table 7 shows the values ​​calculated by Western blot. If the phosphorylation rate of Tie2 is 1.5 times or more than the DMSO control, it indicates that Tie2 is phosphorylated. Thus, phosphorylation of Tie2 was observed in the dried leaf extract at (3) 1000 ug / mL, (5) 1500 μg / mL, and (6) 2000 μg / mL, and in the semi-dried leaf extract at (7) 1000 ug / mL and (10) 2000 μg / mL.

[0140] As mentioned above, Figure 30 is a graph of the Tie2 phosphorylation data from Table 7. Compared to the DMSO control, Tie2 phosphorylation was observed in the dried leaf extract at (3) 1000 ug / mL, (5) 1500 μg / mL, and (6) 2000 μg / mL, and in the semi-dried leaf extract at (7) 1000 ug / mL and (10) 2000 μg / mL.

[0141] [·Consideration] Since phosphorylation of Tie2 by Angiopoietin-1 was observed compared to the DMSO control in Western blot, it is judged that the evaluation test (this analysis) in this example is valid. In other words, according to this example, the effect of the extract from dried leaves of Okinawa Karaki using methanol at a concentration of 1000ug / mL (the maximum verified concentration of the test) on phosphorylation of Tie2 was observed.

[0142] In order to verify the reproducibility and the effect at higher concentrations, an additional test was conducted using the same method. The additional test also examined semi-dried leaves of Okinawa Karaki. The results were as follows:

[0143] [1] Compared to the DMSO control, phosphorylated Tie2 was increased 1.9-fold at 1000ug / mL of dried leaf extract, reproducibly reproducing the effects of the same concentration in previous studies. [2] Dried leaf extract at 1,500 μg / mL and 2,000 μg / mL induced Tie2 phosphorylation in a dose-dependent manner. [3] The EC50 for the dried leaf extract was estimated to be around 1000 μg / mL. [4] Although the semi-dried leaf extract had a weaker effect on Tie2 phosphorylation than the dried leaves, it was shown that Tie2 phosphorylation was induced in a dose-dependent manner at 1000ug / mL and 2000μg / mL. [5] The EC50 for semi-dried leaf extract was estimated to be around 1000 μg / mL.

[0144] Thus, according to this example, the conclusion was that extracts of dried and semi-dried leaves of Okinawa Karaki have the effect of phosphorylating Tie2. The reason why the phosphorylation effect of Tie2 in the semi-dried leaf sample was weaker than that in the dried leaf sample is presumably due to excess moisture and oil caused by insufficient drying, which diluted the active ingredients.

[0145] <Conclusion> This concludes the description of one or more specific embodiments and one or more specific examples, but the aspects of the present invention are not limited to these embodiments or examples, and modifications, improvements, etc. are possible as appropriate. [Industrial Applicability]

[0146] The present invention is useful as a Tie2 activator, a vascular maturation agent or vascular stabilizer, food and beverage products thereof, as well as a capillary improvement agent and a food and beverage product for improving capillaries, which activates Tie2 with its active ingredient, promotes blood circulation, and increases the absorption rate of the active ingredient into the body, thereby improving capillaries.

Claims

1. A food or beverage used for at least one of activating Tie2, maturing blood vessels, and stabilizing blood vessels, comprising: Contains an extract of Okinawan cinnamon (Cinnamomum sieboldii) leaves as an active ingredient, contains a Tie2 activator, Food and drink.

2. Contains Okinawan cinnamon (Cinnamomum sieboldii) leaf extract as an active ingredient. It has a vascular maturation effect or vascular stabilization effect based on Tie2 activation effect. Vascular maturation agents or vascular stabilization agents.

3. A food or drink used for at least one of Tie2 activation, vascular maturation, and vascular stabilization, A method for treating a vascular malformation syndrome comprising administering to a patient a vascular malformation agent ... Food and drink.

4. A composition comprising an extract of Okinawan cinnamon (Cinnamomum sieboldii) leaves as an active ingredient. A herbal medicine composition for Tie2 activation.

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