Vasodilatation composition containing ergothioneine

Abstract

The purpose of the present invention is to provide a composition for vasodilatation. The present invention relates to a composition for vasodilatation containing ergothioneine or a salt thereof as an active ingredient.

Description

Technical Field

[0001] The present invention relates to a vasodilator composition containing ergothioneine, etc. Background Art

[0002] In recent years, research and development of food ingredients with physiological regulatory functions to prevent lifestyle-related diseases has been booming. For example, circulatory function is a crucial function for maintaining good health. It is generally believed that foods that can maintain or improve circulatory function through daily intake can not only improve circulatory function, but also improve blood pressure, stiff shoulders, headaches, chills, and decreased cerebral circulation, which are related to circulatory function.

[0003] ATP-sensitive potassium (KATP) channels close when intracellular ATP concentrations increase, and conversely open when ATP concentrations decrease or intracellular ADP concentrations increase. KATP channels have been confirmed in various tissues, including pancreatic β cells, cardiac muscle, skeletal muscle, smooth muscle, and central and peripheral nerve cells. Potassium channel openers (KCO), developed as antihypertensive drugs, activate KATP channels and are currently attracting attention as new therapeutic targets for circulatory diseases (Non-Patent Document 1).

[0004] Ergothioneine exists naturally as an L-form due to its presence as an amino acid in mushrooms and other substances. Patent Document 1 discloses a vascular wall strengthening agent containing soy protein and / or ergothioneine as active ingredients. The document states that subjects who applied the vascular wall strengthening agent under their eyes experienced improved blood flow and lighter dark circles.

[0005] Patent Literature Patent Document 1: Japanese Patent Application Laid-Open No. 2022-006753

[0006] Non-patent literature Non-patent document 1: Folia Pharmacol. Jpn. 126, 311-316 (2005) Summary of the Invention

[0007] However, Patent Document 1 does not describe any information regarding the vasodilatory effect of ergothioneine or its influence on KATP channels.

[0008] The object of the present invention is to provide a vasodilator composition.

[0009] The present inventors conducted intensive studies to solve the above-mentioned problems and found that L-ergothioneine or a salt thereof has a vasodilatory effect.

[0010] That is, although not limited to the following, the present invention relates to the following vasodilator compositions. [1] A vasodilator composition comprising ergothioneine or a salt thereof as an active ingredient. [2] The composition according to [1] above, characterized in that it is used for preventing or improving hypertension. [3] The composition according to [1] or [2] above, characterized in that it dilates blood vessels via ATP-sensitive potassium channels. [4] The composition according to any one of [1] to [3] above, which is a composition for oral administration. [5] The composition according to any one of [1] to [4] above, which is a food or beverage. [6] The composition according to any one of [1] to [5] above, characterized in that it is labeled with at least one function selected from "dilation of blood vessels to maintain blood flow", "promotion of blood circulation", "prevention or improvement of hypertension", "prevention or improvement of shoulder stiffness", "prevention or improvement of headache", "prevention or improvement of chills", "prevention of decreased cerebral circulation" and "improvement of cerebral circulation". [7] A method for dilating blood vessels, characterized in that ergothioneine or a salt thereof is administered to a subject. [8] An application characterized in that ergothioneine or its salt is used to dilate blood vessels.

[0011] According to the present invention, a vasodilator composition is provided. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 This is a graph showing the evaluation of the substrate binding inhibitory activity of L-ergothioneine-based ATP-sensitive potassium channels. Figure 2 It is a graph showing the changes in diastolic blood pressure in the test food group and the control food group. Figure 3 It is a graph showing the changes in systolic blood pressure in the test food group and the control food group. DETAILED DESCRIPTION

[0013] The vasodilator composition of the present invention contains ergothioneine or a salt thereof as an active ingredient. Hereinafter, the vasodilator composition of the present invention is also referred to as the composition of the present invention. Ergothioneine is a type of sulfur-containing amino acid. In the present invention, ergothioneine is preferably L-ergothioneine. As the salt of ergothioneine, as long as it is a salt allowed in pharmacology or a salt allowed in a diet, it is not particularly limited and can be any of an acidic salt and a basic salt. As an acidic salt, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate can be listed; organic acid salts such as acetate, citrate, maleate, malate, oxalate, lactate, succinate, fumarate, propionate, etc. can be listed. As a basic salt, for example, alkali metal salts such as sodium salt, potassium salt can be listed; alkaline earth metal salts such as calcium salt, magnesium salt, etc.

[0014] Ergothioneine or its salt is not limited by its form or production method. Ergothioneine or its salt can be chemically synthesized or extracted and purified from natural sources. L-ergothioneine is abundant in the golden top mushroom (Golden / Yellow Oyster mushroom) (scientific name: Pleurotus cornucopiae var. citrinopileatus), which belongs to the genus Pleurotus of the family Pleurotaceae. L-ergothioneine is also found in mushrooms such as Agaricus bisporus (scientific name: Agaricus bisporus), white button mushrooms, portabella mushrooms, and gray oyster mushrooms (scientific name: Pleurotus ostreatus); shiitake mushrooms (scientific name: Lentinula edodes); maitake mushrooms (scientific name: Grifola Frondosa); Ganoderma lucidum (scientific name: Ganoderma lucidum); Hericium erinaceus (scientific name: Hericium erinaceus); Agrocybe aegerita (scientific name: Agrocybe aegerita); Chanterelles (scientific name: Cantharellus cibarius); Boletus edulis (scientific name: Boletus edulis); and Morchella esculenta (scientific name: Morchella esculenta). When obtaining L-ergothioneine from natural sources, extraction from Pleurotus eryngii is preferred. Ergothioneine or its salts can also be produced by microbial fermentation. Ergothioneine or its salts can also be isolated.

[0015] L-ergothioneine or its salt is contained in natural products or food and beverages and is a compound with edible experience. Therefore, from the viewpoint of safety, it is believed that ergothioneine or its salt, for example, has few problems even if it is taken for a long time. According to the present invention, a safe and high vasodilator composition can be provided.

[0016] As shown in the examples described below, L-ergothioneine blocks the binding of substrates to ATP-sensitive potassium (KATP) channels. In addition, when taking L-ergothioneine, diastolic blood pressure and systolic blood pressure are lowered compared to when not taking it. When the combination of known substrate and KATP channel is hindered, KATP channel is opened and vasodilation occurs. Thus, thioneine is dilated by KATP channel. Thiioneine or its salt can be dilated by KATP channel. Thiioneine or its salt has the effect of lowering blood pressure etc. by dilating blood vessels.

[0017] The compositions of the present invention have vasodilatory effects and can be used to prevent or ameliorate conditions or diseases for which vasodilation is effective. Prevention of a condition or disease includes preventing symptoms, delaying onset, reducing the incidence of symptoms, and alleviating the risk of onset. Amelioration of a condition or disease includes recovering from the condition or disease, alleviating symptoms of the condition or disease, improving symptoms of the condition or disease, and delaying or preventing the progression of the condition or disease. Recovery includes partial recovery.

[0018] Examples of conditions or diseases for which vasodilation is effective in preventing or improving include hypertension, stiff shoulders, headaches, chills, and decreased cerebral circulation. Vasodilatory action is expected to prevent or improve hypertension, stiff shoulders, headaches, chills, and decreased cerebral circulation. Among them, the composition of the present invention is preferably used for preventing or improving hypertension.

[0019] The composition of the present invention may be either an oral composition or a parenteral composition, but is preferably an oral composition. As oral composition, specifically can enumerate food and drink, oral pharmaceutical product, quasi-medicine, feed etc., be preferably food and drink or oral pharmaceutical product, more preferably food and drink.Composition of the present invention also can be for being deployed in the material or preparation etc. used in food and drink, pharmaceutical product, quasi-medicine, feed etc.

[0020] The composition of the present invention can be used for either therapeutic (medical) or non-therapeutic (non-medical) applications. The term "non-therapeutic" refers to a concept that does not include medical procedures, i.e., human surgery, treatment, or diagnosis.

[0021] The composition of the present invention, as long as not to damage the effect of the present invention, except thioneine or its salt, can contain any additive, any composition.These additives and composition can be selected according to the form of composition etc. When the composition of the present invention is made into oral composition, the additive etc. that can be generally used for oral composition such as food and beverage, pharmaceuticals, quasi-drugs, feed can be used.

[0022] When the composition of the present invention is prepared as a food or beverage, a pharmaceutical product, a quasi-drug, a feed, or the like, the production method is not particularly limited and the composition can be produced by a general method. The form of the oral composition of the present invention is not particularly limited, and may be solid (powder, granule, tablet, etc.), liquid, paste, or the like.

[0023] When such as compositions of the present invention are made into food and drink, various food and drink can be made in thioneine or its salt, allocating spendable composition (such as, food material, the food additive used as required etc.) in food and drink.Food and drink are not particularly limited, and such as general food and drink, health food, health supplement food, health drink, functional label food, specific health food, patient food and drink etc. can be enumerated.Above-mentioned health food, health supplement food, functional label food, specific health food etc. such as can be used in the various preparation forms such as fine granule, tablet, granule, powder, capsule, chewable, dry syrup, syrup, liquid, beverage, oral liquid, liquid food.

[0024] When pharmaceuticals or quasi-medicines are made into compositions of the present invention, for example, the carrier allowed in pharmacology can be allotted in thioneine or its salt, the additive etc. added as needed, make pharmaceuticals or quasi-medicines of various dosage forms.Such carrier, additive etc., for the material allowed in the pharmacology that can be used for pharmaceuticals or quasi-medicines, for example, one or more than two kinds of excipients, binding agents, disintegrants, lubricants, antioxidants, coloring agents etc. can be enumerated. As the mode of administration of pharmaceuticals or quasi-medicines, the mode of administration of oral or non-oral (percutaneous, through mucosa, enteral, injection etc.) can be enumerated. When pharmaceuticals or quasi-medicines are made into compositions of the present invention, it is preferably made into oral pharmaceuticals or oral quasi-medicines. As the dosage form for oral administration of pharmaceuticals or quasi-medicines, liquid, tablet, powder, fine granules, granules, sugar-coated tablets, capsules, suspensions, emulsions, chewing agents etc. can be enumerated. Examples of dosage forms for parenteral administration include injections, drops, ointments, lotions, patches, suppositories, nasal preparations, pulmonary preparations (inhalants), etc. The pharmaceutical product may be a pharmaceutical for non-human animals.

[0025] When the composition of the present invention is prepared into feed, ergothioneine or its salt is mixed into the feed. Feed also includes feed additives. Examples of feed include feed for livestock such as cattle, pigs, chickens, sheep, and horses; feed for small animals such as rabbits, rats, and mice; and pet food for dogs, cats, and birds.

[0026] The subject to which the composition of the present invention is ingested or administered (also referred to as the subject of administration) is not particularly limited, but is preferably a human or a non-human mammal, and more preferably a human. In one embodiment, the subjects for administration include those who need or desire vasodilation, and those who need or desire the prevention or amelioration of a condition or disease for which vasodilation is effective. Examples of such subjects include middle-aged and elderly individuals. In one embodiment, the composition of the present invention is preferably used as a vasodilator composition for middle-aged and elderly individuals, or a composition for the prevention or amelioration of a condition or disease for which vasodilation is effective. Middle-aged and elderly individuals include the elderly. For example, middle-aged and elderly individuals may be humans aged 40 or older. In one embodiment, the elderly are preferably used among middle-aged and elderly individuals. For example, the elderly may be humans aged 60 or older or 65 or older. The subjects for administration may be healthy individuals. The composition of the present invention may be used, for example, in healthy individuals for the purpose of vasodilation and the prevention or amelioration of a condition or disease for which vasodilation is effective. In the present invention, particularly preferred subjects are healthy humans aged 60 or older and younger than 75, and most preferred subjects are healthy humans aged 60 or older and younger than 65.

[0027] The content of ergothioneine or a salt thereof contained in the composition of the present invention is not particularly limited and can be set according to its form and the like. The content of ergothioneine or a salt thereof contained in the composition of the present invention is preferably 0.0001% by weight or more, more preferably 0.001% by weight or more, and is preferably 90% by weight or less, more preferably 50% by weight or less, for example, calculated as ergothioneine. In one embodiment, the content of thioneine or its salt contained in the composition of the present invention is preferably 0.0001 to 90% by weight, more preferably 0.001 to 50% by weight, calculated as thioneine. The content of thioneine or its salt can be measured by high performance liquid chromatography (HPLC).

[0028] In this specification, the amount converted to ergothioneine or an expression similar thereto refers to the amount of ergothioneine, and refers to the value obtained by multiplying the number of moles of the salt by the molecular weight of ergothioneine in the case of a salt of ergothioneine.

[0029] The composition of the present invention can be taken or administered by an appropriate method suitable for its form. In one embodiment, the composition of the present invention is preferably taken orally (orally administered). The dosage (also referred to as the intake amount) of the composition of the present invention is not particularly limited, as long as it is an amount that can achieve a vasodilatory effect, and can be appropriately set based on the dosage form, method of administration, and the subject's weight.

[0030] In one way, when the mankind (adult) is taken orally or the composition of the present invention is administered, its dosage is in the dosage (ergothioneine conversion) of thioneine or its salt, and is preferably more than 2mg per 1 day, more preferably more than 5mg, more preferably more than 7mg, in addition, is preferably less than 50mg, more preferably less than 25mg, more preferably less than 20mg. In one way, when the dosage of the composition of the present invention is in the dosage (ergothioneine conversion) of thioneine or its salt, for the mankind (adult), is preferably 2~50mg per 1 day, more preferably 5~25mg, more preferably 5~20mg, more preferably 7~20mg. Preferably, the above amount is divided into more than 1 time per day, for example, 1 time per day or multiple (for example 2~3 times) are taken or administered. In one way, preferably, the mankind is taken orally or the thioneine or its salt of the above amount is administered thereto. The above-mentioned dosage can be the dosage of every body weight 60kg. In one embodiment, the composition of the present invention can be used to allow humans, for example, to ingest or administer the above-mentioned amount of ergothioneine or a salt thereof per 60 kg body weight per day.

[0031] The content of ergothioneine or a salt thereof in the composition of the present invention is preferably in an adult's daily intake, calculated as ergothioneine, of 2 to 50 mg, more preferably 5 to 25 mg, further preferably 5 to 20 mg, and particularly preferably 7 to 20 mg.

[0032] The composition of the present invention may also be labeled with a function such as vasodilation or a function exerted through vasodilation. The composition of the present invention may also be labeled with at least one function selected from the group consisting of "dilate blood vessels to maintain blood flow", "promote blood circulation", "prevent or improve hypertension", "prevent or improve shoulder stiffness", "prevent or improve headaches", "prevent or improve chills", "prevent decreased cerebral circulation" and "improve cerebral circulation". In one embodiment, the composition of the present invention is preferably a food or beverage with the above-mentioned label. In addition, the above-mentioned label may be a label indicating the purpose of obtaining the above-mentioned function. The above-mentioned label may be attached to the composition itself or to the container or packaging of the composition.

[0033] As shown above, L-ergothioneine hinders the combination of substrate and KATP channel.Therefore, ergothioneine or its salt can be used as the effective ingredient for hindering the combination of substrate and KATP channel and use.In addition, also can use the composition of the present invention as the substrate for KATP channel in conjunction with inhibitor.Containing ergothioneine or its salt as the substrate for KATP channel in conjunction with inhibitor of effective ingredient is also one of the present invention.

[0034] The present invention also includes the following method. A method for vasodilation, characterized in that ergothioneine or a salt thereof is administered to a subject. The above methods may be therapeutic methods or non-therapeutic methods.

[0035] The present invention also includes the following applications. An application is characterized in that ergothioneine or a salt thereof is used for dilating blood vessels. The above applications may be therapeutic applications or non-therapeutic applications. By administering ergothioneine or a salt thereof to a subject, blood vessels can be dilated.

[0036] In the above-mentioned method and application, the preferred embodiment of thioneine or its salt is identical with the above-mentioned composition of the present invention. As thioneine or its salt, 1 kind of thioneine or its salt can be used, or 2 or more kinds can be used. In the above-mentioned method and application, preferably more than 1 time a day, for example, 1 time a day or multiple times (for example 2 to 3 times) thioneine or its salt is administered to the object (so that it is taken in). In the above-mentioned method and application, thioneine or its salt is preferably administered orally (taken in). The above-mentioned application is preferably human or non-human mammals, more preferably the application in the human being.

[0037] In said method and application, use the thioneine or its salt that can obtain the amount (also can be called effective dose) of desired effect.The preferred dosage of thioneine or its salt or the object of administration etc. are identical with above-mentioned composition of the present invention.Thioneine or its salt can directly be administered, and also can be administered as the composition containing it.For example, above-mentioned composition of the present invention can also be used.

[0038] The present invention also includes the use of ergothioneine or a salt thereof for producing a vasodilator composition. The present invention also includes use of ergothioneine or a salt thereof for producing a composition for preventing or improving hypertension. The present invention also provides ergothioneine or a salt thereof for preventing or improving hypertension.

[0039] In this specification, numerical ranges expressed with lower and upper limits, i.e., "lower limit to upper limit," include both lower and upper limits. For example, a range expressed with "1 to 2" means from 1 to 2, inclusive. In this specification, upper and lower limits may be used as ranges based on any combination. Example

[0040] Hereinafter, the present invention will be described in further detail with reference to examples, but the scope of the present invention is not limited thereto.

[0041] <Example 1> (Evaluation of substrate binding inhibition activity of ATP-sensitive potassium channels) To evaluate the molecular target of L-ergothioneine, an in vitro assay targeting ATP-sensitive potassium (KATP) channels was conducted. The in vitro assay was commissioned by Eurofins Panlabs and performed as follows.

[0042] 400 μg of rat cerebral cortical membrane fraction (containing KATP channels, manufactured by Eurofins Cerep) was dissolved in 50 mM Tris-HCl buffer (pH 7.4) and 0.1 nM [ 3 [3H]Glyburide and L-ergothioneine (L-ergothioneine concentration: 100 μM or 1000 μM) were incubated together at 22°C for 60 minutes. Glyburide is a KATP channel inhibitor. Nonspecific binding was determined in the presence of 1 μM gliburide (without L-ergothioneine). When gliburide was present in excess, [3H]gliburide could not bind to the KATP channel, and the radioactivity detected at this time was nonspecific binding. The membrane fraction was washed and filtered through a filter membrane, and the substrate binding inhibition activity of L-ergothioneine was evaluated using radioactivity as an indicator. [ 3 The more [H] glibenclamide is present, the stronger the radioactivity of the membrane fraction.

[0043] Figure 1 This is a graph showing the evaluation of the substrate binding inhibitory activity of L-ergothioneine on ATP-sensitive potassium channels. The concentration (μM) on the horizontal axis represents the concentration of L-ergothioneine. The substrate of KATP channel is in conjunction with hindering activity (%) and is sought according to the following steps.The radioactivity of membrane fraction in the reaction solution (control group) not containing L-ergothioneine is made as 100%, based on the radioactivity of membrane fraction in the reaction solution with L-ergothioneine, seek the relative activity (%) relative to control group when adding L-ergothioneine (100 μM or 1000 μM).When L-ergothioneine hinders the combination of glibenclamide and KATP channel, the radioactivity of membrane fraction reduces.Therefore, by deducting the relative activity (%) when L-ergothioneine adds from the radioactivity (100%) of the membrane fraction of contrast, seek the substrate for KATP channel and in conjunction with hindering activity (%).

[0044] L-ergothioneine exhibits binding inhibition activity against the substrate glibenclamide at KATP channels. Since vasodilation is known to occur due to the opening of KATP channels, it is speculated that L-ergothioneine exhibits vasodilation via KATP channels.

[0045] <Example 2> (Evaluation of blood pressure in humans) For the purpose of evaluating the effect of a supplement formulated with ergothioneine on human blood pressure, a placebo-controlled, randomized, double-blind, parallel intergroup comparative trial was conducted in which healthy men and women aged 60 and above and below 65 years (9 in the tested food group and 10 in the control food group, a total of 19) were selected to take a capsule formulated with 8 mg of ergothioneine (tested food) or a capsule not formulated with ergothioneine (control food) once a day for 12 weeks.

[0046] First, before the start of the test (before the start of ingestion of the test food or control food), the blood pressure of the subject is evaluated. In addition, 12 weeks after ingestion of the test food or control food, the blood pressure of the subject is measured again (12th week examination). In principle, blood pressure is measured on the upper arm on the opposite side of the dominant hand. For the measurement, after staying quiet for more than 10 minutes after arriving at the hospital, the blood pressure is measured three times continuously at the seat, and the median value of the three measured values ​​is used as the measured value on the evaluation day. Blood pressure is measured by a nurse or examination technician under the supervision of a doctor using a medical electronic blood pressure monitor AVE-1500PASESA (Shisei Datum Co., Ltd.).

[0047] (Food for evaluation) Two types of food were used for evaluation, and they were indistinguishable in appearance, flavor, etc. Food tested: Capsules containing the substance tested (8 mg of L-ergothioneine) Control food: capsules that do not contain the substance being tested The raw materials of each evaluation food included dextrin, calcium stearate, and hydroxypropyl methylcellulose in addition to the test substance. A control food was made using the same raw materials as the test food, except that the test substance (L-ergothioneine) was not added.

[0048] The average value of the blood pressure (mmHg) of the 9 subjects in the tested food group was used as the blood pressure of the tested food group. The average value of the blood pressure (mmHg) of the 10 subjects in the control food group was used as the blood pressure of the control food group. In addition, for each group, the change in blood pressure (Δ blood pressure (mmHg)) was calculated by subtracting the blood pressure at the time of the examination before the start of the test from the blood pressure at the time of the examination at the 12th week. The change in blood pressure (Δ blood pressure (mmHg)) at the time of the examination before the start of the test was set to 0. As blood pressure, both diastolic blood pressure and systolic blood pressure were measured, and Δ diastolic blood pressure (mmHg) and Δ systolic blood pressure (mmHg) were calculated as the change in blood pressure, respectively.

[0049] Figure 2 The graph shows the changes in diastolic blood pressure in the test food group and the control food group. A two-sample t-test was used to test for significant differences between the groups (**: p < 0.01, relative to the control food group). The results showed that diastolic blood pressure was significantly lower in the test food group. Figure 2 In the table, black squares (■) represent the tested food group, and white squares (□) represent the control food group. "0W" on the horizontal axis represents the time of inspection before the start of the experiment, and "12W" represents the time of inspection at the 12th week.

[0050] Figure 3 The following is a graph showing changes in systolic blood pressure in the test food group and the control food group. A two-sample t-test was used to test for significant differences between the groups (**: p < 0.01, relative to the control food group). The results showed that the increase in systolic blood pressure was suppressed in the test food group compared to the control food group. Figure 3 In the table, black squares (■) represent the tested food group, and white squares (□) represent the control food group. "0W" on the horizontal axis represents the time of inspection before the start of the experiment, and "12W" represents the time of inspection at the 12th week.

[0051] It is inferred from the results of Examples 1 and 2 that L-ergothioneine dilates blood vessels through KATP channels, showing a blood pressure improving effect (preventive or improving effect on hypertension).

Claims

1. A vasodilator composition, characterized in that: Contains ergothioneine or its salt as an active ingredient.

2. The composition according to claim 1, characterized in that Used for the prevention or improvement of hypertension.

3. The composition according to claim 1 or 2, characterized in that Dilates blood vessels through ATP-sensitive potassium channels.

4. The composition according to claim 1 or 2, characterized in that It is a composition for oral use.

5. The composition according to claim 4, characterized in that For food and drink.

6. The composition according to claim 1 or 2, characterized in that The product is labeled with at least one function selected from the group consisting of "dilate blood vessels and maintain blood flow", "promote blood circulation", "prevent or improve hypertension", "prevent or improve shoulder stiffness", "prevent or improve headaches", "prevent or improve chills", "prevent decreased cerebral circulation" and "improve cerebral circulation".

7. A method for dilating blood vessels, characterized in that: Ergothioneine or a salt thereof is administered to the subject.

8. An application, characterized in that: Ergothioneine or its salts are used to dilate blood vessels.

Images