Composition for activating mitochondria

Abstract

To provide a technique capable of inhibiting metabolic abnormalities resulting from a high glucose load.SOLUTION: A composition for activating mitochondria contains: (A) pantothenic acid or a salt thereof; and (B) at least one selected from a group consisting of methionine or salts thereof, protamine or salts thereof, ceramide, and rice bran.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to compositions for activating mitochondria, etc. [Background technology]

[0002] It is known that high glucose loading enhances oxidative stress in cells and causes metabolic abnormalities. In particular, it is believed that high glucose loading in diabetic patients and prediabetic subjects leads to metabolic abnormalities and various symptoms. These symptoms may include symptoms in the oral cavity.

[0003] For example, it has been reported that the metabolic function of periodontal tissues is impaired in a diabetic state, and that activating the metabolic function of the gingiva of diabetic rats suppresses alveolar bone resorption. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] J Clin Periodontol 2017; 44: 463-471. IADR / PER General Session 2018; Presentation ID 1622 Summary of the Invention [Problem to be solved by the invention]

[0005] The present inventors have searched for components capable of suppressing metabolic abnormalities caused by high glucose loading. [Means for solving the problem]

[0006] The present inventors have focused on the function of mitochondria, which plays an important role in intracellular metabolism, and have conducted research, particularly focusing on the ATP production capacity and oxygen consumption capacity of cells. They have searched for a material that can improve the decrease in ATP production and the decrease in oxygen consumption rate caused by high glucose loading, and have found that the combination of pantothenic acid or a salt thereof with a specific component can improve the decrease in ATP production and the decrease in oxygen consumption rate caused by high glucose loading, and have made further improvements.

[0007] The present disclosure includes, for example, the subject matter described in the following sections: Section 1. (A) pantothenic acid or a salt thereof, and (B) at least one selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran; A composition for activating mitochondria comprising: Section 2. The composition according to item 1, wherein the mitochondria are mitochondria in periodontal ligament cells. Section 3. (A) Pantothenic acid or its salts (B) at least one selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran; A composition for improving periodontal disease comprising: Section 4. Item 4. The composition according to item 3, which is used to improve periodontal disease in diabetic patients. Section 5. (A) Pantothenic acid or its salts (B) at least one selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran; A composition for improving symptoms due to metabolic disorders caused by diabetes or aging, comprising: Section 6. 6. The composition according to claim 5, wherein the symptoms of metabolic disorders due to diabetes or aging are obesity, renal dysfunction, retinopathy, neuropathy, cardiovascular disease, brain dysfunction, dementia, frailty, muscle weakness, or osteoporosis. Section 7. Item 7. The composition according to any one of Items 1 to 6, which is an oral composition. Section 8. Item 8. The composition according to item 7, which is a food composition. Effect of the Invention

[0008] It is possible to improve metabolic disorders caused by high glucose loading, particularly the decline in metabolic function involving mitochondria, and in particular the decline in ATP production and the decline in oxygen consumption rate caused by high glucose loading.

[0009] This may also make it possible to improve symptoms of periodontal disease, for example. [Brief description of the drawings]

[0010] [Figure 1a] This shows the rate of improvement in ATP decrease when high glucose-treated human periodontal ligament fibroblasts were treated with a combination of calcium pantothenate and protamine, methionine, rice bran, or ceramide. [Figure 1b] This shows the improvement rate of oxygen consumption rate (OCR) decrease when high glucose-treated human periodontal ligament fibroblasts were treated with calcium pantothenate in combination with protamine, methionine, rice bran, or ceramide. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Each embodiment included in the present disclosure will be described in more detail below. The present disclosure preferably includes compositions for mitochondrial activation and, in turn, compositions for improving periodontal disease, but is not limited thereto, and the present disclosure includes all that is disclosed in the present specification and that can be recognized by a person skilled in the art.

[0012] The composition included in the present disclosure contains (A) pantothenic acid or a salt thereof, and (B) at least one selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran. The composition may be referred to as the composition of the present disclosure. In addition, pantothenic acid or a salt thereof may be referred to as component (A), and at least one selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran may be referred to as component (B).

[0013] The salt of pantothenic acid is preferably an alkali metal salt or an alkaline earth metal salt, more specifically, more preferably a lithium salt, a sodium salt, a potassium salt, a calcium salt, a barium salt, or a magnesium salt, further preferably a sodium salt or a calcium salt, and particularly preferably a calcium salt. These salts may be used alone or in combination of two or more.

[0014] The salt of methionine is preferably an alkali metal salt or an alkaline earth metal salt, more specifically, lithium salt, sodium salt, potassium salt, calcium salt, barium salt, magnesium salt is more preferred, sodium salt or calcium salt is even more preferred, and calcium salt is particularly preferred. In addition, the salt of methionine is preferably a sulfate salt or a hydrochloride salt. These salts can be used alone or in combination of two or more.

[0015] The salt of protamine is preferably an alkali metal salt or an alkaline earth metal salt, more specifically, lithium salt, sodium salt, potassium salt, calcium salt, barium salt, magnesium salt is more preferred, sodium salt or calcium salt is even more preferred, and calcium salt is particularly preferred.Furthermore, the salt of protamine is preferably a sulfate salt or a hydrochloride salt, and more preferably a sulfate salt.These salts can be used alone or in combination of two or more kinds.

[0016] The origin of the ceramide is not particularly limited, and for example, ceramides extracted from animals and plants, ceramides produced by using microorganisms, or ceramides produced by chemical methods can be used. Among these, ceramides obtained by extraction from plants such as corn germ, wheat, rice, soybean, millet, spinach, etc., or microorganisms such as yeast, etc. are preferred.

[0017] The rice bran is not particularly limited, and known rice bran can be used. Known rice bran can be, for example, the pericarp, seed coat, episperm, starch layer, etc. of brown rice, which are by-produced when brown rice is polished to produce white rice. In addition, rice bran having an oil content of more than 2 mass% is preferable. Furthermore, rice bran extract obtained by squeezing rice bran or extracting it with water or alcohol (e.g., ethanol) can also be preferably used as the rice bran of the composition of the present disclosure.

[0018] The content ratio of the (A) component to the (B) component is not particularly limited as long as the effect is not impaired, and for example, it is preferably about 0.1 to 10 parts by mass of the (B) component per 1 part by mass of the (A) component. The upper or lower limit of the range (0.1 to 10) may be, for example, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, or 9. For example, the range is more preferably about 0.2 to 5 parts by mass or about 0.2 to 3 parts by mass.

[0019] The content of the (A) component in the composition of the present disclosure is not particularly limited as long as the effect is not impaired, and may be, for example, 0.001 to 20 mass% based on the total amount of the composition. The upper or lower limit of the range may be, for example, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 7.5, 10, or 15. For example, the range is preferably 0.01 to 5 mass%.

[0020] The content of the (B) component in the composition of the present disclosure is not particularly limited as long as the effect is not impaired, and may be, for example, 0.001 to 20 mass% based on the total amount of the composition. The upper or lower limit of the range may be, for example, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 7.5, 10, or 15. For example, the range is preferably 0.01 to 5 mass%.

[0021] When methionine or a salt thereof is contained in the composition of the present disclosure, its content is preferably within the range of the content of component (B) described above, more preferably 0.001 to 0.5% by mass, and even more preferably 0.01 to 0.1% by mass, relative to the total amount of the composition.

[0022] Furthermore, when protamine or a salt thereof is contained in the composition of the present disclosure, its content is preferably within the content range of the above-mentioned component (B), more preferably 0.001 to 0.5% by mass, and even more preferably 0.005 to 0.1% by mass, relative to the total amount of the composition.

[0023] Furthermore, when the composition of the present disclosure contains ceramide, its content is preferably within the content range of the above-mentioned component (B), more preferably 0.001 to 0.5% by mass, and even more preferably 0.01 to 0.1% by mass, relative to the total amount of the composition.

[0024] Furthermore, when rice bran is contained in the composition of the present disclosure, its content is preferably within the range of the content of component (B) described above, more preferably 0.001 to 0.5 mass%, and even more preferably 0.01 to 0.1 mass%, relative to the total amount of the composition.

[0025] The composition of the present disclosure can be suitably used as, for example, an oral composition or an oral composition. In addition, when used as an oral composition, it can be more preferably used as an oral pharmaceutical composition or a food composition. These compositions can be produced according to a conventional method. If necessary, other components may be used in combination.

[0026] When used as a food composition, other ingredients include, for example, bases, carriers, additives that are acceptable from the viewpoint of food hygiene, and other ingredients and materials that can be used as foods. The form of the food composition is not particularly limited, and examples include processed foods, health foods (nutritional supplements, nutritional functional foods, foods for the sick, foods for specified health uses, functional products, etc.), supplements, foods for the sick (hospital food, sick food, nursing food, etc.). These can be prepared by conventional methods. In particular, when preparing a food composition as a health food (nutritional supplements, nutritional functional foods, foods for the sick, foods for specified health uses, functional products, etc.) or supplements, it is preferable to prepare it in the form of, for example, granules, capsules, tablets (including chewable agents, etc.), beverages (drink powders, drinks, smoothies, etc.) so that it is easy to take continuously, and among them, capsules, tablets, tablets, drink powders, drinks, jellies, and gummies are preferable from the viewpoint of ease of intake, but are not particularly limited thereto. When the food composition is used as a food additive composition, the form of the composition may be, for example, liquid, powder, flake, granule, paste, etc. More specifically, the food composition may be, for example, seasoning (soy sauce, sauce, ketchup, dressing, etc.), flake (furikake), barbecue sauce, spice, roux paste (curry roux paste, etc.), etc.

[0027] When used as an oral composition, it can be in the form (dosage form) of, for example, an ointment, paste, gel, liquid, spray, mouthwash, liquid dentifrice, toothpaste, gum, etc.

[0028] As other components, components that are known to be blended in oral compositions can be used.

[0029] For example, the surfactant may be a nonionic surfactant, an anionic surfactant, or an amphoteric surfactant.Specifically, for example, nonionic surfactants include sugar fatty acid esters such as sucrose fatty acid esters, maltose fatty acid esters, and lactose fatty acid esters; fatty acid alkanolamides; glycerin fatty acid esters; sorbitan fatty acid esters; fatty acid monoglycerides; polyoxyethylene alkyl ethers with a polyoxyethylene addition coefficient of 8 to 10 and an alkyl group with 13 to 15 carbon atoms; polyoxyethylene alkylphenyl ethers with a polyoxyethylene addition coefficient of 10 to 18 and an alkyl group with 9 carbon atoms; diethyl sebacate; polyoxyethylene hydrogenated castor oil; fatty acid polyoxyethylene sorbitan; etc. Examples of anionic surfactants include sulfate ester salts such as sodium lauryl sulfate and polyoxyethylene lauryl ether sodium sulfate; sulfosuccinates such as sodium lauryl sulfosuccinate and polyoxyethylene lauryl ether sodium sulfosuccinate; acylamino acid salts such as sodium cocoyl sarcosine and sodium lauroyl methyl alanine; and sodium cocoyl methyl taurine. Examples of amphoteric surfactants include acetate betaine type surfactants such as lauryl dimethylamino acetate betaine and coconut oil fatty acid amidopropyl dimethylamino acetate betaine; imidazoline type surfactants such as N-cocoyl-N-carboxymethyl-N-hydroxyethyl ethylenediamine sodium; and amino acid type surfactants such as N-lauryl diaminoethyl glycine. These surfactants can be blended alone or in combination of two or more. The blending amount is usually 0.1 to 5% by mass based on the total amount of the composition.

[0030] In addition, as the flavoring agent, for example, menthol, carboxylic acid, anethole, eugenol, methyl salicylate, limonene, ocimene, n-decyl alcohol, citronellol, α-terpineol, methyl acetate, citronenyl acetate, methyl eugenol, cineole, linalool, ethyl linalool, thymol, spearmint oil, peppermint oil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil, perilla oil, wintergreen oil, clove oil, eucalyptus oil, pimento oil, d-camphor, d-borneol, fennel oil, cinnamon oil, cinnamaldehyde, peppermint oil, vanillin, etc. can be used. These can be blended alone or in combination of two or more kinds, for example, in an amount of 0.001 to 1.5% by mass based on the total amount of the composition.

[0031] In addition, examples of sweeteners that can be used include saccharin sodium, acesulfame potassium, stevioside, neohesperidyl dihydrochalcone, perillartine, thaumatin, aspartyl phenylalanyl methyl ester, p-methoxycinnamic aldehyde, etc. These can be blended in an amount of, for example, 0.01 to 1% by mass based on the total amount of the composition. Furthermore, as a wetting agent, sorbitol, ethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, polypropylene glycol, xylitol, maltitol, lactitol, polyoxyethylene glycol, etc. can be blended alone or in combination of two or more kinds.

[0032] As preservatives, parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben, sodium benzoate, phenoxyethanol, alkyldiaminoethylglycine hydrochloride, and the like can be added.

[0033] As coloring agents, legal pigments such as Blue No. 1, Yellow No. 4, Red No. 202, Green No. 3, mineral pigments such as ultramarine, enhanced ultramarine, and Prussian blue, titanium oxide, etc. may be blended.

[0034] As a pH adjuster, citric acid, phosphoric acid, malic acid, pyrophosphoric acid, lactic acid, tartaric acid, glycerophosphoric acid, acetic acid, nitric acid, or chemically possible salts thereof, sodium hydroxide, etc. may be blended. These may be blended alone or in combination of two or more kinds so that the pH of the composition is in the range of 4 to 8, preferably 5 to 7. The blending amount of the pH adjuster may be, for example, 0.01 to 2% by weight.

[0035] The active ingredients include vitamin E such as dl-α-tocopherol acetate, tocopherol succinate, or tocopherol nicotinate, amphoteric bactericides such as dodecyldiaminoethylglycine, nonionic bactericides such as triclosan, isopropylmethylphenol, and hinokitiol, anionic bactericides such as sodium lauroyl sarcosine, cationic bactericides such as cetylpyridinium chloride, chlorhexidine hydrochloride, benzalkonium chloride, and benzethonium chloride, enzymes such as dextranase, amylase, protease, mutanase, lysozyme, and lytic enzymes (retic enzymes), and monophosphate bactericides such as glyceryl phosphate bactericides. Alkali metal monofluorophosphates such as sodium fluorophosphate and potassium monofluorophosphate, fluorides such as sodium fluoride and stannous fluoride, tranexamic acid, epsilon aminocaproic acid, aluminum chlorohydroxyl allantoin, dihydrocholesterol, glycyrrhetinic acid, glycyrrhizic acid, copper chlorophyllin sodium, glycerophosphate, chlorophyll, sodium chloride, callopeptide, allantoin, carbazochrome, hinokitiol, potassium nitrate, palatinit, etc. can be blended alone or in combination of two or more.

[0036] Furthermore, it is also possible to add, as a base, alcohols, silicone, apatite, white petrolatum, paraffin, liquid paraffin, microcrystalline wax, squalane, plastibase, and the like.

[0037] The composition of the present disclosure can be preferably used for activating mitochondria in cells (especially in cells loaded with high glucose). More specifically, the composition of the present disclosure can preferably improve the decrease in ATP production and the decrease in oxygen consumption rate caused by high glucose loading. Therefore, the composition can be preferably used to improve metabolic abnormalities, especially in cells loaded with high glucose (e.g., cells derived from humans with diabetes or prediabetes). For example, the metabolic function of periodontal tissues is impaired in a diabetic state, which is thought to promote the progression of periodontal disease in diabetic patients, and therefore the composition can be preferably used to improve metabolic abnormalities in cells in periodontal tissues (e.g., periodontal ligament cells), and thus to inhibit and / or improve the progression of periodontal disease. In addition, the composition of the present disclosure can be used not only to inhibit and / or improve the progression of periodontal disease, but also to improve the metabolic function of other tissues that are impaired by, for example, diabetes or prediabetes, or aging. For example, the composition can be used to inhibit and / or improve obesity, renal dysfunction, retinopathy, neuropathy, cardiovascular disease, brain dysfunction, dementia, frailty, muscle weakness, and osteoporosis.

[0038] In addition, in this specification, the term "comprising" includes "consisting essentially of" and "consisting of." In addition, the present disclosure includes any combination of the constituent elements described in this specification.

[0039] In addition, the various characteristics (properties, structures, functions, etc.) described in each embodiment of the present disclosure above may be combined in any way to specify the subject matter included in the present disclosure. In other words, the present disclosure includes all subject matter consisting of all combinations of each combinable characteristic described in this specification. EXAMPLES

[0040] Hereinafter, the embodiments of the present disclosure will be described more specifically with reference to examples, but the embodiments of the present disclosure are not limited to the following examples.

[0041] Human periodontal ligament fibroblasts (HPDLF) were treated with the test sample and with high glucose, and the intracellular ATP concentration and the oxygen consumption rate (OCR) in the cells were measured. More specifically, the procedure was as follows.

[0042] Measurement of intracellular ATP in periodontal ligament fibroblasts Intracellular ATP was measured using a Luminescent ATP detection assay kit (ab113849; Abcam). Human periodontal ligament fibroblasts (HPDLF) were cultured at 0.12 × 10 5 The cells were seeded in a 48-well plate at a density of 100μL / well and cultured for 48 hours. After pretreatment with each test substance (sample) for 24 hours, the cells were further cultured in the presence of 50mM D-glucose (Sigma Aldrich) for 72 hours. The control was treated in the same way with 50mM L-glucose. Then, 50μL of cell lysis solution was added for 5 minutes to lyse the cells and stabilize ATP. D-luciferase reagent was added and incubated for 10 minutes in the dark. Chemiluminescence from the luciferase reaction was measured using a Cytation 5 plate reader (BioTek Instruments), and ATP concentration (μM) was measured using a standard curve. The ATP reduction improvement rate (%) of each sample was calculated using the following formula:

[0043]

number

[0044] In other words, the ATP decrease improvement rate (%) indicates the percentage obtained by subtracting the ATP value when only D-glucose was treated from the ATP value when D-glucose was treated after sample treatment, divided by the ATP value when only L-glucose was treated from the ATP value when only D-glucose was treated.

[0045] Measurement of oxygen consumption rate (OCR) in periodontal ligament fibroblasts OCR was measured using an extracellular OCR plate assay kit (E297, DOJINDO). Human periodontal ligament fibroblasts (HPDLF) were cultured at 2 × 10 5 The cells were seeded in a 96-well plate at a density of 100 cells / 100 μL / well and cultured overnight. After pretreatment with each test substance (sample) for 24 hours, the cells were cultured for another 24 hours in the presence of 100 mM D-glucose (Sigma Aldrich). As a control, the cells were treated in the same way with 100 mM L-glucose. 100 μL of oxygen probe reaction solution, which has the property of increasing phosphorescence intensity when the oxygen concentration in the culture medium decreases, was added to each well. Then, a drop of mineral oil was added to each well to prevent the inflow of oxygen from the air. The phosphorescence intensity was measured using a Cytation 5 plate reader (BioTek Instruments), and the OCR of the cells was calculated using the Stern-Volmer equation. The OCR improvement rate (%) of each sample was calculated using the following formula:

[0046]

number

[0047] In other words, the OCR decline improvement rate (%) indicates the percentage obtained by subtracting the OCR value when only D-glucose was treated from the OCR value when D-glucose was treated after sample treatment, divided by the OCR value when only L-glucose was treated from the OCR value when only D-glucose was treated.

[0048] The type and amount of each sample, as well as the results obtained, are shown in Tables 1 and 2. All samples were used as aqueous solutions. In these tables, "pantothenic" refers to calcium pantothenate, and "ALA" refers to 5-aminolevulinic acid. Commercially available rice-derived ceramide was used as "ceramide," and a commercially available rice bran water extract was used as "rice bran."

[0049] In addition, the concentrations of all the sample aqueous solutions are shown as % (w / v), but since this is almost the same as the % (w / w) value (the % (w / w) is only slightly larger), it is acceptable to interpret it as % (w / w) (i.e., % by mass).

[0050] [Table 1]

[0051] [Table 2]

[0052] As shown in Table 1, it was found that when calcium pantothenate was used in combination with protamine, methionine, rice bran, or ceramide, excellent values ​​were shown for both the ATP decrease improvement rate and the OCR decrease improvement rate.

[0053] The results shown in Table 1 are also shown in graph form in Figure 1. Specifically, the results relating to the improvement rate of ATP decrease in Table 1 are shown in Figure 1a, and the results relating to the improvement rate of OCR decrease in Table 1 are shown in Figure 1b.

Claims

1. (A) pantothenic acid or a salt thereof, and (B) at least one selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran; A composition for activating mitochondria comprising:

2. The composition according to claim 1 , wherein the mitochondria are mitochondria in periodontal ligament cells.

3. (A) Pantothenic acid or its salt (B) at least one selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran; A composition for improving periodontal disease comprising:

4. The composition according to claim 3, which is used to improve periodontal disease in diabetic patients.

5. (A) Pantothenic acid or its salt (B) at least one selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran; A composition for improving symptoms due to metabolic disorders caused by diabetes or aging, comprising:

6. The composition according to claim 5, wherein the symptoms caused by metabolic disorders due to diabetes or aging are obesity, renal dysfunction, retinopathy, neuropathy, cardiovascular disease, brain dysfunction, dementia, frailty, muscle weakness, or osteoporosis.

7. The composition according to any one of claims 1 to 6, which is an oral composition.

8. The composition of claim 7 which is a food composition.

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