Composition for activating mitochondria

Abstract

Provided is a technique for enabling metabolism activation. More specifically, provided is a composition for activating mitochondria, the composition containing a specific component.

Description

Composition for activating mitochondria

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

[0002] It is known that various factors (e.g., high glucose load) increase intracellular oxidative stress and cause metabolic abnormalities. In particular, in diabetic patients and those at risk of developing diabetes, high glucose load is thought to cause metabolic abnormalities and lead to various symptoms, including those in the oral cavity.

[0003] For example, it has been reported that the metabolic function of periodontal tissues is impaired in diabetic states, and that activating the metabolic function of the gingiva of diabetic rats suppresses alveolar bone resorption.

[0004] J Clin Periodontol 2017; 44: 463-471. IADR / PER General Session 2018; Presentation ID 1622

[0005] The present inventors have searched for a means by which metabolism can be activated.

[0006] For example, even if oxidative stress in cells is increased, it is expected that metabolic disorders will be less likely to occur if metabolism can be activated. For this reason, a means capable of activating metabolism is considered to be useful.

[0007] The present inventors focused on the function of mitochondria, which play a major role in intracellular metabolism, particularly the ATP production capacity and / or oxygen consumption capacity of cells, and searched for materials that can improve the ATP production and oxygen consumption rate, or materials that can improve decreased ATP production and decreased oxygen consumption rate.

[0008] The present disclosure includes, for example, the subject matter described in the following sections:

[0009] Item 1-1. A composition for activating mitochondria, comprising at least one component selected from the group consisting of components listed in the table below.

[0010]

[0011] Item 1-2. The composition according to Item 1-1, wherein the mitochondria are mitochondria in periodontal ligament cells.

[0012] Item 1-3: The composition according to Item 1-1 or 1-2, wherein the mitochondrial activation is an increase in oxygen consumption in mitochondria.

[0013] Item 2-1. A composition for activating mitochondria, comprising at least one selected from the group consisting of pantothenic acid or a salt thereof, protamine or a salt thereof, and methionine or a salt thereof. Item 2-2. The composition according to Item 2-1, wherein the mitochondria are mitochondria in periodontal ligament cells. Item 2-3. The composition according to Item 2-1 or 2-2, wherein the mitochondrial activation is at least one selected from the group consisting of an increase in mitochondrial oxygen consumption, an improvement in mitochondrial ATP production capacity, and an increase in mitochondria. Item 2-4. The composition according to any one of Items 2-1 to 2-3, used for improving periodontal disease in diabetic patients. Item 2-5. A composition for improving symptoms of diabetes, prediabetes, or metabolic disorders due to aging, comprising at least one selected from the group consisting of pantothenic acid or a salt thereof, protamine or a salt thereof, and methionine or a salt thereof. Item 2-6. Item 2-5. The composition according to Item 2-5, wherein the symptoms of diabetes, prediabetes, or age-related metabolic disorders are obesity, renal dysfunction, retinopathy, neuropathy, cardiovascular disease, cerebral dysfunction, dementia, frailty, muscle weakness, or osteoporosis. Item 2-7. The composition according to any one of Items 2-1 to 2-6, which is an oral composition or an oral composition. Item 2-8. The composition according to any one of Items 2-1 to 2-6, which is a food composition. Item 2-9. The oral composition according to Item 2-7, which is an ointment, paste, paste, gel, liquid, spray, mouthwash, liquid dentifrice, toothpaste, or gum.

[0014] Item 3-1. A composition for activating mitochondria, comprising (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. Item 3-2. The composition according to Item 3-1, wherein the mitochondria are mitochondria in periodontal ligament cells. Item 3-3. A composition for improving periodontal disease, comprising (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. Item 3-4. The composition according to Item 3-3, used for improving periodontal disease in diabetic patients. Item 3-5. A composition for improving symptoms of metabolic disorders due to diabetes or aging, comprising (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. Item 3-6. Item 3-5. The composition according to item 3-5, wherein the symptom of diabetes or aging-related metabolic disorder is obesity, renal dysfunction, retinopathy, neuropathy, cardiovascular disease, cerebral dysfunction, dementia, frailty, muscle weakness, or osteoporosis. Item 3-7. The composition according to any one of items 3-1 to 3-6, which is an oral composition. Item 3-8. The composition according to item 3-7, which is a food composition.

[0015] Item 4-1. A composition for activating mitochondria, comprising (C) panthenol, and (D) at least one selected from the group consisting of cinnamon oil, and glutamic acid or a salt thereof. Item 4-2. The composition according to Item 4-1, wherein the mitochondria are mitochondria in periodontal ligament cells. Item 4-3. A composition for improving periodontal disease, comprising (C) panthenol, and (D) at least one selected from the group consisting of cinnamon oil, and glutamic acid or a salt thereof. Item 4-4. The composition according to Item 4-3, which is used to improve periodontal disease in diabetic patients. Item 4-5. The composition according to any one of Items 4-1 to 4-4, which is an oral composition.

[0016] Item A-1. A composition for mitochondrial activation comprising at least one member selected from the group consisting of panthenol, and pantothenic acid or a salt thereof, protamine or a salt thereof, and methionine or a salt thereof. Item A-2. The composition for mitochondrial activation according to Item A-1, comprising (A) pantothenic acid or a salt thereof, and (B) at least one member selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran. Item A-3. The composition for mitochondrial activation according to Item A-1, comprising (C) panthenol, and (D) at least one member selected from the group consisting of cinnamon oil, and glutamic acid or a salt thereof. Item A-4. The composition according to any one of Items A-1 to A-3, wherein the mitochondria are mitochondria in periodontal ligament cells.

[0017] Item B-1. A composition for improving periodontal disease, comprising panthenol, and at least one selected from the group consisting of pantothenic acid or a salt thereof, protamine or a salt thereof, and methionine or a salt thereof. Item B-2. The composition for improving periodontal disease according to Item B-1, comprising (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. Item B-3. The composition for improving periodontal disease according to Item B-1, comprising (C) panthenol, and (D) at least one selected from the group consisting of cinnamon oil and glutamic acid or a salt thereof. Item B-4. The composition according to any one of Items B-1 to B-3, used for improving periodontal disease in diabetic patients.

[0018] Item C-1. A composition for improving symptoms of diabetes, prediabetes, or age-related metabolic disorders, comprising at least one member selected from the group consisting of panthenol, pantothenic acid or a salt thereof, protamine or a salt thereof, and methionine or a salt thereof. Item C-2. The composition according to Item C-1, comprising (A) pantothenic acid or a salt thereof, and (B) at least one member selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran. Item C-3. The composition for improving periodontal disease according to Item C-1, comprising (C) panthenol, and (D) at least one member selected from the group consisting of cinnamon oil and glutamic acid or a salt thereof. Item C-4. The composition according to any one of Items C-1 to C-3, wherein the symptom of diabetes, prediabetes, or metabolic disorder due to aging is obesity, renal dysfunction, retinopathy, neuropathy, cardiovascular disease, cerebral dysfunction, dementia, frailty, muscle weakness, or osteoporosis. Item C-5. The composition according to any one of Items A-1 to A-4, B-1 to B-4, and C-1 to C-4, which is an oral composition or an oral cavity composition. Item C-6. The composition according to any one of Items A-1 to A-4, B-1 to B-4, and C-1 to C-4, which is a food composition. Item C-7. The oral cavity composition according to Item C-5, which is an ointment, paste, paste, gel, liquid, spray, mouthwash, liquid dentifrice, toothpaste, or gum.

[0019] Item Ai. A compound for use in activating mitochondria, comprising at least one compound selected from the group consisting of panthenol, and pantothenic acid or a salt thereof, protamine or a salt thereof, and methionine or a salt thereof. Item A-ii. The compound for use in activating mitochondria according to Item Ai, wherein the compound is (A) pantothenic acid or a salt thereof, and (B) at least one compound selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran. Item A-iii. The compound for use in activating mitochondria according to Item Ai, wherein the compound is (C) panthenol, and (D) at least one compound selected from the group consisting of cinnamon oil and glutamic acid or a salt thereof. Item A-iv. The compound for use in activating mitochondria according to any of Items Ai to A-iii, wherein the mitochondria are mitochondria in periodontal ligament cells.

[0020] Item B-i. A compound for use in improving periodontal disease, comprising at least one compound selected from the group consisting of panthenol, and pantothenic acid or a salt thereof, protamine or a salt thereof, and methionine or a salt thereof. Item B-ii. The compound for use in improving periodontal disease according to Item B-i, wherein the compound is (A) pantothenic acid or a salt thereof, and (B) at least one compound selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran. Item B-iii. The compound for use in improving periodontal disease according to Item B-i, wherein the compound is (C) panthenol, and (D) at least one compound selected from the group consisting of cinnamon oil and glutamic acid or a salt thereof. Item B-iv. The compound for use in improving periodontal disease according to any of Items B-i to B-iii, wherein the periodontal disease is periodontal disease in a diabetic patient.

[0021] Item Ci. A compound for use in improving symptoms of diabetes, prediabetes, or metabolic disorders due to aging, comprising at least one compound selected from the group consisting of panthenol, and pantothenic acid or a salt thereof, protamine or a salt thereof, and methionine or a salt thereof. Item C-ii. A compound for use in improving symptoms of diabetes, prediabetes, or metabolic disorders due to aging, according to Item Ci, wherein the compound is (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. Item C-iii. A compound for use in improving symptoms of diabetes, prediabetes, or metabolic disorders due to aging, according to Item Ci, wherein the compound is (C) panthenol, and (D) at least one selected from the group consisting of cinnamon oil and glutamic acid or a salt thereof. Item C-iv.

[0013] Item C-i. A compound for use in improving symptoms of diabetes, prediabetes, or metabolic disorders due to aging, according to any one of Items C-i to C-iii, wherein the symptoms of diabetes, prediabetes, or metabolic disorders due to aging are obesity, renal dysfunction, retinopathy, neuropathy, cardiovascular disease, cerebral dysfunction, dementia, frailty, muscle weakness, or osteoporosis. Item C-v. An oral composition or oral composition containing a compound according to any one of Items A-i to A-iv, B-i to B-iv, and C-i to C-iv. Item C-vi. A food composition containing a compound according to any one of Items A-i to A-iv, B-i to B-iv, and C-i to C-iv. Item C-vii. The oral composition according to Item C-v, which is in the form of an ointment, paste, paste, gel, liquid, spray, mouthwash, liquid dentifrice, toothpaste, or gum.

[0022] It is possible to activate mitochondria and improve metabolic functions involving mitochondria (particularly, improve the ATP production capacity and / or oxygen consumption capacity of mitochondria). For example, even when oxidative stress in cells is increased, the improvement of metabolic functions can suppress the occurrence of metabolic disorders. Furthermore, although not particularly limited, it is possible to improve metabolic disorders caused by high glucose load, particularly a decrease in metabolic functions involving mitochondria. In particular, it can improve the decrease in ATP production and the decrease in oxygen consumption rate caused by high glucose load.

[0023] Furthermore, by improving the mitochondrial metabolism of cells in the oral cavity (e.g., gingival cells and periodontal ligament cells), it is possible to activate the metabolic function of cells in the oral cavity or suppress a decline in metabolic function, which is expected to make it possible to maintain oral health (e.g., prevent periodontal disease, improve the symptoms of periodontal disease, etc.).

[0024] 1 shows the improvement rate of ATP decrease when high-glucose-treated human periodontal ligament fibroblasts are treated with calcium pantothenate. 2 shows the improvement rate of ATP decrease when high-glucose-treated human periodontal ligament fibroblasts are treated with protamine sulfate. 3 shows the improvement rate of ATP decrease when high-glucose-treated human periodontal ligament fibroblasts are treated with methionine. 4 shows the improvement rate of oxygen consumption rate (OCR) decrease when high-glucose-treated human periodontal ligament fibroblasts are treated with calcium pantothenate. 5 shows the improvement rate of oxygen consumption rate (OCR) decrease when high-glucose-treated human periodontal ligament fibroblasts are treated with protamine sulfate. 6 shows the improvement rate of oxygen consumption rate (OCR) decrease when high-glucose-treated human periodontal ligament fibroblasts are treated with methionine. 7 shows the OCR values ​​(relative values) when human periodontal ligament fibroblasts are treated with various test substances. 8 shows the relative values ​​when the steady-state OCR value without test substance treatment is set to 1. The figure shows the copy number of mitochondrial DNA (mtDNA) relative to nuclear DNA (nDNA) when high-glucose-treated human periodontal ligament fibroblasts are treated with various test substances. The figure shows the improvement rate of ATP decrease when high-glucose-treated human periodontal ligament fibroblasts are treated with a combination of calcium pantothenate and protamine, methionine, rice bran, or ceramide. The figure shows the improvement rate of oxygen consumption rate (OCR) decrease when high-glucose-treated human periodontal ligament fibroblasts are treated with a combination of calcium pantothenate and protamine, methionine, rice bran, or ceramide. The figure shows the improvement rate of ATP decrease when high-glucose-treated human periodontal ligament fibroblasts are treated with a combination of panthenol and cinnamon oil or sodium glutamate. The figure shows the improvement rate of oxygen consumption rate (OCR) decrease when high-glucose-treated human periodontal ligament fibroblasts are treated with a combination of panthenol and cinnamon oil or sodium glutamate.

[0025] Each embodiment of the present disclosure will be described in more detail below. The present disclosure preferably includes, but is not limited to, compositions for activating mitochondria, and the present disclosure includes all of the compositions disclosed herein and recognizable by a person skilled in the art.

[0026] The composition for mitochondrial activation encompassed by the present disclosure contains specific components capable of activating mitochondria. Such compositions may be referred to as compositions of the present disclosure. Furthermore, such specific components may be referred to as components of the present disclosure. In one aspect, the composition of the present disclosure contains the specific components listed in the following table, either alone or in combination of two or more.

[0027]

[0028] These ingredients can be purchased commercially. The extract is preferably an extract made from water, alcohol, or a hydroalcohol. The alcohol is preferably ethanol and / or butylene glycol. The extract may be in the form of a dry substance or a liquid.

[0029] These components can be broadly classified into compounds and extracts of living organisms (for example, whole or part of animals or plants).

[0030] Examples of compounds include inositol, reduced palatinose, isoleucine, cholecalciferol, glycyrrhizinic acid or a salt thereof, allantoin, alanine, protamine or a salt thereof, cinnamaldehyde, paramylon, cyclodextrin (particularly γ-cyclodextrin), arginine, ceramide, methionine, glutamic acid or a salt thereof, etc. As the salt of glycyrrhizinic acid, an alkali metal salt is preferred, and a sodium salt or a potassium salt is more preferred. More specifically, dipotassium glycyrrhizinate and trisodium glycyrrhizinate are preferred. As the salt of protamine, hydrochloride and sulfate are preferred, and sulfate is more preferred. As the salt of glutamic acid, an alkali metal salt is preferred, and a sodium salt or a potassium salt is more preferred.

[0031] As the extract of the organism, it is preferable to use an extract of a part that is usually used as an extract for external use or as food.

[0032] The chamomile extract is not particularly limited as long as it is an extract of chamomile, and for example, extracts obtained from the stems, leaves, or flowers can be used, and among these, extracted oils (e.g., essential oils) can be particularly preferably used.

[0033] The Cistanche extract is preferably an extract of the fleshy stem of Cistanche, which is a parasitic plant of the Orobanchaceae family and is used as a herbal medicine.

[0034] Olive leaf extract is an extract of olive leaves and is an ingredient used in supplements and topical preparations.

[0035] As the eucommia extract, eucommia leaf extract is particularly preferred, as it is widely used as a supplement.

[0036] Arnica flower extract is an extract obtained from the flowers (and roots) of Arnica montana, and is an ingredient used as an external preparation, etc. Arnica is a plant of the Asteraceae family.

[0037] Honeysuckle leaf extract is an extract of honeysuckle leaves. Peony root extract is an extract of peony root. Panax ginseng root extract is an extract of ginseng root.

[0038] The ginger extract is preferably a ginger rhizome extract, which can be used in external preparations and foods to promote blood circulation.

[0039] Placenta extract is an extract obtained from the placenta of mammals (particularly cows, pigs, horses, etc.) and is used in cosmetics and other products.

[0040] Lamium extract is an extract of the whole plant and / or flowers of Lamium, a plant of the Lamiaceae family, and is used in cosmetics and the like.

[0041] The melilot extract is an extract of the whole plant of the legume Melilotus nigra (also known as Melilot) and is used in foods and other applications.

[0042] Willow extract is an extract of the bark and / or shoots of the willow tree, and is used in supplements and the like.

[0043] Wild grape extract is an extract of wild grapes (mainly fruit (especially seeds), stems, leaves, etc.) and is used in foods, etc.

[0044] Valeriana root extract is an extract of the roots of Valeriana officinalis L. and is used in supplements, etc.

[0045] Fennel extract is an extract of the fruit of the Umbelliferae plant, and is used in cosmetics and other products.

[0046] Devil's claw extract is an extract of the root (tuber) of devil's claw and is used in supplements, etc.

[0047] St. John's wort extract is an extract of the flowers, stems, or leaves of St. John's wort, and is used as an external preparation.

[0048] Senega extract is an extract of senega root and is used as an antitussive and expectorant.

[0049] Rice bran extract is an extract of rice bran.

[0050] Fermented black garlic extract is an extract of fermented black garlic obtained by fermenting garlic (bulbs) for a certain period of time, and is used in supplements, etc.

[0051] Purple brown rice extract is an extract of ancient reddish-purple brown rice such as red rice and black rice, and is used in supplements, etc.

[0052] Wild thyme extract is an extract of the whole plant (especially the leaves and stems) of wild thyme, and is used in external preparations and the like.

[0053] Turmeric rhizome extract is an extract of turmeric rhizome.

[0054] Panax notoginseng extract is an extract of Panax notoginseng root and is used in supplements.

[0055] Although not particularly limited, in another embodiment, among these components, the components described in the following table are particularly preferred.

[0056]

[0057] The content of the components of the present disclosure in the composition of this embodiment of the present disclosure is not particularly limited as long as the effects are not impaired, and may be, for example, about 0.01 to 99.99% by mass.

[0058] In yet another aspect, the composition of the present disclosure contains, as the components of the present disclosure, one type alone or two or more types in combination of panthenol, pantothenic acid or a salt thereof, protamine or a salt thereof, and methionine or a salt thereof.

[0059] The salt of pantothenic acid is preferably an alkali metal salt or an alkaline earth metal salt, more specifically, lithium salt, sodium salt, potassium salt, calcium salt, barium salt, or magnesium salt is more preferred, sodium salt or calcium salt is even more preferred, and calcium salt is particularly preferred. These salts may be used alone or in combination of two or more.

[0060] The protamine salt is preferably an alkali metal salt or an alkaline earth metal salt, more specifically, lithium salt, sodium salt, potassium salt, calcium salt, barium salt, or magnesium salt is more preferred, sodium salt or calcium salt is even more preferred, and calcium salt is particularly preferred. Furthermore, preferred examples of the protamine salt include sulfate salt and hydrochloride salt, with sulfate salt being particularly preferred. These salts can be used alone or in combination of two or more.

[0061] As the salt of methionine, an alkali metal salt or an alkaline earth metal salt is preferred, more specifically, a lithium salt, a sodium salt, a potassium salt, a calcium salt, a barium salt, or a magnesium salt is more preferred, a sodium salt or a calcium salt is even more preferred, and a calcium salt is particularly preferred. Other preferred salts of methionine include sulfate and hydrochloride. These salts can be used alone or in combination of two or more. The content of the components of the present disclosure in the composition of this embodiment of the present disclosure is not particularly limited as long as the effects are not impaired. For example, the content can be about 0.01 to 99.99% by mass.

[0062] In another aspect, the composition of the present disclosure contains, as components of the present disclosure, (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. Furthermore, 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). The pantothenic acid salt, protamine salt, and methionine salt are as described above.

[0063] The origin of the ceramide is not particularly limited, and for example, ceramides extracted from animals and plants, ceramides produced 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, and spinach, or microorganisms such as yeast, are preferred.

[0064] The rice bran is not particularly limited, and known rice bran can be used. Examples of known rice bran include the pericarp, seed coat, episperm, and starch layer of brown rice, which are by-products produced when brown rice is polished to produce white rice. Furthermore, rice bran with an oil content of more than 2% by mass is preferred. Furthermore, rice bran extracts obtained by squeezing rice bran or extracting it with water or alcohol (e.g., ethanol) can also be preferably used as the rice bran in the composition of the present disclosure.

[0065] The content ratio of component (A) to component (B) is not particularly limited as long as the effect is not impaired, and for example, about 0.1 to 10 parts by mass of component (B) per 1 part by mass of component (A) is preferred. The upper or lower limit of this 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.

[0066] The content of component (A) in the composition of this embodiment 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% relative to the total amount of the composition. The upper or lower limit of this 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%.

[0067] The content of component (B) in the composition of this embodiment 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% relative to the total amount of the composition. The upper or lower limit of this 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%.

[0068] When methionine or a salt thereof is contained in the composition of the present disclosure in this aspect, the content thereof 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.

[0069] Furthermore, when protamine or a salt thereof is contained in the composition of the present disclosure in this aspect, its content is preferably within the content range of the component (B) described above, 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.

[0070] Furthermore, when the composition of the present disclosure according to this aspect contains a ceramide, the content thereof 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.

[0071] Furthermore, when rice bran is contained in the composition of the present disclosure in this aspect, the content thereof 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.

[0072] In another aspect, the composition of the present disclosure contains, as components of the present disclosure, (C) panthenol and (D) at least one selected from the group consisting of cinnamon oil and glutamic acid or a salt thereof. This composition may be referred to as the composition of the present disclosure. Furthermore, panthenol may be referred to as component (C), and at least one selected from the group consisting of cinnamon oil and glutamic acid or a salt thereof may be referred to as component (D).

[0073] The salt of glutamic acid is preferably an alkali metal salt or an alkaline earth metal salt, more specifically, lithium salt, sodium salt, potassium salt, calcium salt, barium salt, or magnesium salt is more preferred, sodium salt or potassium salt is even more preferred, and sodium salt is particularly preferred. Furthermore, the salt of glutamic acid is preferably a sulfate salt or a hydrochloride salt, and hydrochloride salt is particularly preferred. These salts can be used alone or in combination of two or more.

[0074] The content ratio of component (C) to component (D) is not particularly limited as long as the effect is not impaired, and for example, about 0.1 to 10 parts by mass of component (D) per 1 part by mass of component (C) is preferred. The upper or lower limit of this 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.

[0075] The content of component (C) in the composition of this embodiment of the present disclosure is not particularly limited as long as the effect is not impaired, and may be, for example, 0.1 to 0.5 mass% relative to the total amount of the composition. The upper or lower limit of this range may be, for example, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, or 0.45. For example, the range is preferably 0.15 to 0.45 mass% or 0.2 to 0.4 mass%.

[0076] The content of component (D) in the composition of this embodiment of the present disclosure is not particularly limited as long as the effect is not impaired, and may be, for example, 0.001 to 1.3 mass% relative to the total amount of the composition. The upper or lower limit of this range may be, for example, 0.005, 0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 0.7, 1, or 1.2. For example, the range is preferably 0.005 to 1 mass% or 0.01 to 0.7 mass%.

[0077] When cinnamon oil is contained in the composition of the present disclosure in this aspect, its content is preferably within the content range of the component (D) described above, and particularly, is preferably 0.001 to 1 mass %, more preferably 0.002 to 0.5 mass %, and even more preferably 0.01 to 0.1 mass %, relative to the total amount of the composition.

[0078] Furthermore, when glutamic acid or a salt thereof is contained in the composition of the present disclosure in this aspect, its content is preferably within the content range of the component (B) described above, more preferably 0.01 to 0.3 mass%, and even more preferably 0.02 to 0.2 mass%, relative to the total amount of the composition.

[0079] The intake form of the composition of the present disclosure is not particularly limited, but is preferably oral ingestion or topical application to the oral mucosa. That is, the composition of the present disclosure is preferably an oral composition or an oral composition. Oral ingestion of the composition of the present disclosure can activate mitochondria in cells (particularly cells in the oral cavity) and improve mitochondrial-related metabolic function (particularly, improve mitochondrial oxygen consumption capacity). The composition of the present disclosure is preferably, for example, an oral pharmaceutical composition, a food composition (including a beverage composition and a food additive composition), or an oral composition.

[0080] The composition of the present disclosure may contain the above-mentioned components and may further contain other components. The other components may be appropriately selected depending on the field in which the composition is used. For example, a pharmaceutically or food hygienically acceptable carrier may be used.

[0081] When used as a pharmaceutical composition, other components include pharmaceutically acceptable bases, carriers, and / or additives (e.g., solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants, lubricants, etc.) The form of the pharmaceutical composition is not particularly limited, and examples include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, creams, and poultices.

[0082] When used as a food composition, other ingredients include bases, carriers, and additives that are acceptable in terms of food hygiene, as well as other ingredients and materials that can be used as foods. The form of the food composition is also 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, and foods for the sick (hospital meals, sick meals, or nursing care meals, etc.). These can be prepared by conventional methods. In particular, when preparing food compositions as health foods (nutritional supplements, nutritional functional foods, foods for the sick, foods for specified health uses, functional products, etc.) or supplements, they are preferably prepared in the form of granules, capsules, tablets (including chewable tablets, etc.), beverages (drink powders, energy drinks, smoothies, etc.) to facilitate continuous intake. Among these, capsules, tablets, tablets, drink powders, energy drinks, jellies, and gummies are preferred for ease of intake, but are not particularly limited thereto. When the food composition is used as a food additive composition, the form thereof may be, for example, liquid, powder, flake, granule, or paste.

[0083] 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.

[0084] Furthermore, as other components, components that are known to be incorporated into oral compositions can be used.

[0085] For example, the surfactant may be a nonionic surfactant, an anionic surfactant, or an amphoteric surfactant. Specific examples of 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 having a polyoxyethylene addition coefficient of 8 to 10 and an alkyl group having 13 to 15 carbon atoms; polyoxyethylene alkylphenyl ethers having a polyoxyethylene addition coefficient of 10 to 18 and an alkyl group having 9 carbon atoms; diethyl sebacate; polyoxyethylene hydrogenated castor oil; and fatty acid polyoxyethylene sorbitan. 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 sarcosinate and sodium lauroyl methyl alanine; and sodium cocoyl methyl taurate. Examples of zwitterionic surfactants include acetate betaine surfactants such as lauryl dimethylamino acetate betaine and coconut oil fatty acid amidopropyl dimethylamino acetate betaine; imidazoline surfactants such as N-cocoyl-N-carboxymethyl-N-hydroxyethylethylenediamine sodium; and amino acid surfactants such as N-lauryl diaminoethylglycine. These surfactants can be blended alone or in combination of two or more. The blending amount is typically 0.1 to 5% by mass based on the total amount of the composition.

[0086] Furthermore, as flavoring agents, for example, fragrances such as 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, peppermint oil, vanillin, etc. can be used alone or in combination of two or more thereof, in an amount of, for example, 0.001 to 1.5% by mass based on the total amount of the composition.

[0087] Furthermore, sweeteners that can be used include, for example, saccharin sodium, acesulfame potassium, stevioside, neohesperidyl dihydrochalcone, perillartine, thaumatin, aspartyl phenylalanyl methyl ester, and p-methoxycinnamic aldehyde, which can be blended in an amount of, for example, 0.01 to 1% by mass based on the total amount of the composition.

[0088] Furthermore, as a wetting agent, sorbitol, ethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, polypropylene glycol, xylitol, maltitol, lactite, polyoxyethylene glycol, etc. may be blended alone or in combination of two or more kinds.

[0089] As preservatives, parabens such as methylparaben, ethylparaben, propylparaben, and butylparaben, sodium benzoate, phenoxyethanol, alkyldiaminoethylglycine hydrochloride, and the like can be added.

[0090] As colorants, legal pigments such as Blue No. 1, Yellow No. 4, Red No. 202, and Green No. 3, mineral pigments such as ultramarine, enhanced ultramarine, and Prussian blue, titanium oxide, and the like may be blended.

[0091] The pH adjuster may be citric acid, phosphoric acid, malic acid, pyrophosphoric acid, lactic acid, tartaric acid, glycerophosphoric acid, acetic acid, nitric acid, or chemically acceptable salts thereof, or sodium hydroxide. These may be added alone or in combination of two or more so that the pH of the composition falls within the range of 4 to 8, preferably 5 to 7. The amount of pH adjuster added may be, for example, 0.01 to 2% by weight.

[0092] Medicinal ingredients include vitamin E compounds such as dl-α-tocopherol acetate, tocopherol succinate, and tocopherol nicotinate, amphoteric disinfectants such as dodecyldiaminoethylglycine, nonionic disinfectants such as triclosan, isopropylmethylphenol, and hinokitiol, anionic disinfectants such as sodium lauroyl sarcosinate, cationic disinfectants such as cetylpyridinium chloride, chlorhexidine hydrochloride, benzalkonium chloride, and benzethonium chloride, dextranase, amylase, protease, mutanase, lysozyme, and lytic enzymes (Retec Enzyme). and the like, alkali metal monofluorophosphates such as sodium monofluorophosphate and potassium monofluorophosphate, fluorides such as sodium fluoride and stannous fluoride, tranexamic acid, epsilon aminocaproic acid, aluminum chlorohydroxyl allantoin, dihydrocholesterol, glycyrrhetinic acid, copper chlorophyllin sodium, glycerophosphate, chlorophyll, sodium chloride, callopeptide, carbazochrome, hinokitiol, potassium nitrate, palatinit, and the like can be blended alone or in combination of two or more.

[0093] Furthermore, it is also possible to add alcohols, silicone, apatite, white petrolatum, paraffin, liquid paraffin, microcrystalline wax, squalane, plastibase, etc. as bases.

[0094] The composition of the present disclosure can be preferably used for activating mitochondria in cells. More specifically, the composition of the present disclosure can preferably improve the decrease in oxygen consumption rate caused by, for example, high glucose or oxidative stress. Therefore, it can also be preferably used to improve metabolic abnormalities in cells derived from diabetic patients or prediabetic humans. For example, because the metabolic function of periodontal tissues is impaired in diabetic states, which is thought to accelerate the progression of periodontal disease in diabetic patients, the composition can be preferably used particularly for improving metabolic abnormalities in cells in periodontal tissues (e.g., periodontal ligament cells), and thereby for inhibiting and / or improving the progression of periodontal disease. Furthermore, the composition not only improves mitochondrial metabolism in oral cells (e.g., gingival cells and periodontal ligament cells), but also activates the metabolic function of various cells or inhibits the decline of metabolic function. Therefore, the composition of the present disclosure can be used not only for inhibiting and / or improving the progression of periodontal disease, but also for improving the metabolic function of other tissues impaired, for example, by diabetes, prediabetes, or aging. For example, it can be used to inhibit and / or improve obesity, renal dysfunction, retinopathy, neuropathy, cardiovascular disease, cerebral dysfunction, dementia, frailty, muscle weakness, and osteoporosis.

[0095] The subjects for which the composition of the present disclosure is to be ingested or applied are not particularly limited, and for example, healthy individuals can be preferred. Furthermore, from the viewpoint of achieving favorable effects, subjects with metabolic disorders (particularly subjects with reduced mitochondrial metabolism due to, for example, increased intracellular oxidative stress) are preferred, and more specifically, subjects with metabolic disorders due to, for example, high glucose load are more preferred. Furthermore, as described above, improving the mitochondrial metabolism of oral cells (e.g., gingival cells and periodontal ligament cells) can activate the metabolic function of oral cells or suppress the decline in metabolic function, which is expected to maintain oral health (e.g., prevent periodontal disease). Therefore, subjects with gingival inflammation or periodontal disease are also preferred.

[0096] The timing of ingestion or application of the composition of the present disclosure is not particularly limited, but it can be, for example, ingested or applied before or after a meal (for example, within about 0.5 or 1 hour after a meal). The meal preferably contains carbohydrates (especially carbohydrates that can be converted to glucose when absorbed into the body) and lipids. It can also be preferably used, for example, during or after periodontal disease treatment to prevent recurrence.

[0097] Furthermore, although not particularly limited, cells in the oral cavity are preferred as cells whose metabolic disorders can be suppressed by ingestion or application of the composition of the present disclosure, and among these, gingival cells and periodontal ligament cells (particularly gingival fibroblasts and periodontal ligament fibroblasts) are preferred. Periodontal ligament cells are known to be strongly involved in immune responses, inflammatory responses, and alveolar bone resorption in periodontal disease, and are therefore most preferred.

[0098] It should be noted that in this specification, the term "comprising" includes "consisting essentially of" and "consisting of." Furthermore, the present disclosure encompasses any and all combinations of the constituent elements described in this specification.

[0099] Furthermore, the various characteristics (properties, structures, functions, etc.) described in each embodiment of the present disclosure above may be combined in any way to identify the subject matter encompassed by the present disclosure, i.e., the present disclosure encompasses all subject matter consisting of any combination of the combinable characteristics described herein.

[0100] Hereinafter, the embodiments of the present disclosure will be described in more detail with reference to examples, but the embodiments of the present disclosure are not limited to the following examples. (1) Consideration of Various Components

[0101] Human periodontal ligament fibroblasts (HPDLF) were treated with a test sample, and the oxygen consumption rate (OCR) of the cells was measured. More specifically, this was done as follows.

[0102] 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 a concentration of 2 × 10 ５ The cells were seeded onto a 96-well plate at a density of 100 μL / well and cultured overnight, after which they were treated with each test substance (sample: final concentration 1 μg / mL) for 24 hours.

[0103] OCR measurements were performed as follows. 100 μL of oxygen probe reaction solution, which exhibits increased phosphorescence intensity when the oxygen concentration in the culture medium decreased, was added to each well. Then, a drop of mineral oil was added to each well to prevent oxygen from entering from the air. Phosphorescence intensity was measured using a Cytation 5 plate reader (BioTek Instruments), and the cellular OCR was calculated using the Stern-Volmer equation. The OCR value (relative value) for each test substance is expressed as a numerical value relative to the steady-state OCR value without administration, which is set to 1. In other words, since the steady-state OCR value without administration is set to 1, if the OCR value doubles due to administration of a test substance, the OCR value is 2.

[0104] The type and amount of each sample and the results obtained are shown in Table 3.

[0105] (2) Examination of specific ingredients

[0106] Human periodontal ligament fibroblasts (HPDLF) were treated with a test sample, and the intracellular ATP concentration and oxygen consumption rate (OCR) of the cells were measured. More specifically, the procedure was as follows.

[0107] The test substances (samples) used were calcium pantothenate, protamine sulfate, and methionine. Each test substance was dissolved in the medium used in the test and used as a solution.

[0108] Measurement of intracellular ATP in periodontal ligament fibroblasts. Intracellular ATP was measured using the Luminescent ATP detection assay kit (ab113849; Abcam). Human periodontal ligament fibroblasts (HPDLF) were cultured at a concentration of 0.12 × 10 ５ Cells were seeded onto 48-well plates at a density of 100 μL / well and cultured for 48 hours. After pre-treatment with each test substance (sample) for 24 hours, they were subsequently cultured for an additional 72 hours in the presence of 50 mM D-glucose (Sigma-Aldrich). Controls were treated in the same manner with 50 mM L-glucose. Then, 50 μL of cell lysis solution was added for 5 minutes to lyse the cells and stabilize ATP. D-luciferase reagent was then 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 (%) for each sample was calculated using the following formula:

[0109]

[0110] That is, the ATP decrease improvement rate (%) is 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.

[0111] The results are shown in Figures 1a to 1c. In the figures, pantothenic acid refers to calcium pantothenate, and protamine refers to protamine sulfate. When concentrations are indicated in the figures, they refer to the concentrations of each test substance in the culture medium. The same applies to the following figures.

[0112] 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 a concentration of 2 × 10 ５ Cells were seeded into 96-well plates at a density of 100 μL / well and cultured overnight. After pre-treatment with each test substance (sample) for 24 hours, they were subsequently cultured for an additional 24 hours in the presence of 100 mM D-glucose (Sigma-Aldrich). Controls were treated in the same manner with 100 mM L-glucose. 100 μL of oxygen probe reaction solution, which exhibits increased phosphorescence intensity when the oxygen concentration in the culture medium decreases, was added to each well. Mineral oil droplets were then added to each well to prevent oxygen from entering from the air. 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 (%) for each sample was calculated using the following formula:

[0113]

[0114] That is, the OCR decline improvement rate (%) is 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 D-glucose was treated from the OCR value when only L-glucose was treated.

[0115] The results are shown in Figures 2a-2c.

[0116] Measurement of oxygen consumption rate (OCR) in periodontal ligament fibroblasts (without high glucose load) OCR was measured using an Extracellular OCR plate assay kit (E297, DOJINDO). Human periodontal ligament fibroblasts (HPDLF) were cultured at a concentration of 2 × 10 ５The cells were seeded onto a 96-well plate at a density of 100 μL / well and cultured overnight, after which they were treated with each test substance (sample: final concentration 1 μg / mL) for 24 hours.

[0117] OCR measurements were performed as follows. 100 μL of oxygen probe reaction solution, which exhibits increased phosphorescence intensity when the oxygen concentration in the culture medium decreased, was added to each well. Then, a drop of mineral oil was added to each well to prevent oxygen from entering from the air. Phosphorescence intensity was measured using a Cytation 5 plate reader (BioTek Instruments), and the cellular OCR was calculated using the Stern-Volmer equation. The OCR value (relative value) for each test substance is expressed as a numerical value relative to the steady-state OCR value without administration, which is set to 1. In other words, since the steady-state OCR value without administration is set to 1, if the OCR value doubles due to administration of a test substance, the OCR value is 2.

[0118] The results are shown in Figure 3. The uncoupler FCCP was used as a positive control at a final concentration of 2 μM. FCPP stands for carbonyl cyanide-p-trifluoromethoxyphenylhydrazone. Medium alone was used as a control.

[0119] Method for measuring mitochondrial DNA in periodontal ligament fibroblasts Human periodontal ligament fibroblasts (HPDLF) were cultured at a concentration of 0.9 x 10 ５Two days later, the cells were treated with each test substance (sample: final concentration 1 μg / mL) for 24 hours, and then cultured for 3 days in the presence of 50 mM D-glucose (Sigma-Aldrich, USA). Controls were treated in the same manner with 50 mM L-glucose. DNA was isolated using a NucleoSpin Tissue extraction kit (Takara, Japan). Quantitative PCR of the isolated DNA was performed using TB Green Fast qPCR Mix (Takara, Japan) on an ABI7500fast (Thermo Fisher Scientific), and the copy number of mitochondrial DNA (mtDNA) was calculated relative to that of nuclear DNA (nDNA).

[0120] The results are shown in Figure 4. In this figure, HG indicates that only 50 mM D-glucose was applied (no test substance was applied), and control indicates that only 50 mM L-glucose was applied (no test substance was applied).

[0121] An increase in the relative copy number of mtDNA to nDNA is thought to mean an increase in mitochondria, and therefore an improvement in metabolic functions related to mitochondria. (3) Combination study of specific ingredients 1

[0122] Human periodontal ligament fibroblasts (HPDLF) were treated with a test sample and high glucose, and then the intracellular ATP concentration and oxygen consumption rate (OCR) of the cells were measured. More specifically, the procedure was as follows.

[0123] Measurement of intracellular ATP in periodontal ligament fibroblasts. Intracellular ATP was measured using the Luminescent ATP detection assay kit (ab113849; Abcam). Human periodontal ligament fibroblasts (HPDLF) were cultured at a concentration of 0.12 × 10 ５Cells were seeded onto 48-well plates at a density of 100 μL / well and cultured for 48 hours. After pre-treatment with each test substance (sample) for 24 hours, they were subsequently cultured for an additional 72 hours in the presence of 50 mM D-glucose (Sigma-Aldrich). Controls were treated in the same manner with 50 mM L-glucose. Then, 50 μL of cell lysis solution was added for 5 minutes to lyse the cells and stabilize ATP. D-luciferase reagent was then 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 (%) for each sample was calculated using the following formula:

[0124]

[0125] That is, the ATP decrease improvement rate (%) is 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.

[0126] 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 a concentration of 2 × 10 ５Cells were seeded into 96-well plates at a density of 100 μL / well and cultured overnight. After pre-treatment with each test substance (sample) for 24 hours, they were subsequently cultured for an additional 24 hours in the presence of 100 mM D-glucose (Sigma-Aldrich). Controls were treated in the same manner with 100 mM L-glucose. 100 μL of oxygen probe reaction solution, which exhibits increased phosphorescence intensity when the oxygen concentration in the culture medium decreases, was added to each well. Mineral oil droplets were then added to each well to prevent oxygen from entering from the air. 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 (%) for each sample was calculated using the following formula:

[0127]

[0128] That is, the OCR decline improvement rate (%) is 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 D-glucose was treated from the OCR value when only L-glucose was treated.

[0129] The type and amount of each sample, as well as the results obtained, are shown in Tables 4a and 4b. All samples were used as aqueous solutions. In these tables, "pantothene" refers to calcium pantothenate. "ALA" refers to 5-aminolevulinic acid. Commercially available rice-derived ceramide was used as "ceramide." Commercially available rice bran water extract was used as "rice bran."

[0130] The concentrations of all the sample aqueous solutions are shown in % (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).

[0131]

[0132]

[0133] As shown in Table 4a, when calcium pantothenate was used in combination with protamine, methionine, rice bran, or ceramide, excellent values ​​were observed for both the rate of improvement in ATP decrease and the rate of improvement in OCR decrease.

[0134] The results shown in Table 4a are also shown in the form of graphs. Specifically, the results relating to the improvement rate of ATP decrease in Table 4a are shown in Figure 5a, and the results relating to the improvement rate of OCR decrease in Table 4b are shown in Figure 5b. (4) Study 2 of combinations of specific components

[0135] Human periodontal ligament fibroblasts (HPDLF) were treated with a test sample and high glucose, and then the intracellular ATP concentration and oxygen consumption rate (OCR) of the cells were measured. More specifically, the procedure was as follows.

[0136] Measurement of intracellular ATP in periodontal ligament fibroblasts. Intracellular ATP was measured using the Luminescent ATP detection assay kit (ab113849; Abcam). Human periodontal ligament fibroblasts (HPDLF) were cultured at a concentration of 0.12 × 10 ５ Cells were seeded onto 48-well plates at a density of 100 μL / well and cultured for 48 hours. After pre-treatment with each test substance (sample) for 24 hours, they were subsequently cultured for an additional 72 hours in the presence of 50 mM D-glucose (Sigma-Aldrich). Controls were treated in the same manner with 50 mM L-glucose. Then, 50 μL of cell lysis solution was added for 5 minutes to lyse the cells and stabilize ATP. D-luciferase reagent was then 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 (%) for each sample was calculated using the following formula:

[0137]

[0138] That is, the ATP decrease improvement rate (%) is 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.

[0139] 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 a concentration of 2 × 10 ５ Cells were seeded into 96-well plates at a density of 100 μL / well and cultured overnight. After pre-treatment with each test substance (sample) for 24 hours, they were subsequently cultured for an additional 24 hours in the presence of 100 mM D-glucose (Sigma-Aldrich). Controls were treated in the same manner with 100 mM L-glucose. 100 μL of oxygen probe reaction solution, which exhibits increased phosphorescence intensity when the oxygen concentration in the culture medium decreases, was added to each well. Mineral oil droplets were then added to each well to prevent oxygen from entering from the air. 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 (%) for each sample was calculated using the following formula:

[0140]

[0141] That is, the OCR decline improvement rate (%) is 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 D-glucose was treated from the OCR value when only L-glucose was treated.

[0142] The type and amount of each sample, as well as the results obtained, are shown in Table 5. All samples were used as aqueous solutions. The "cinnamon oil" used was cinnamon oil that complies with the Japanese Pharmacopoeia regulations.

[0143] The concentrations of all the sample aqueous solutions are shown in % (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).

[0144]

[0145] As shown in Table 5, when panthenol was used in combination with cinnamon oil, or glutamic acid or a salt thereof, excellent values ​​were observed for both the rate of improvement in ATP decrease and the rate of improvement in OCR decrease.

[0146] The results shown in Table 5 are also shown in the form of graphs. Specifically, the results relating to the improvement rate of ATP decrease in Table 5 are shown in FIG. 6a, and the results relating to the improvement rate of OCR decrease in Table 5 are shown in FIG. 6b. In the figures, "glutamine" refers to "sodium L-glutamate."

Claims

1. A compound for use in improving periodontal disease, comprising at least one compound selected from the group consisting of panthenol, pantothenic acid or a salt thereof, protamine or a salt thereof, and methionine or a salt thereof.

2. The compound for use in improving periodontal disease according to claim 1, wherein the compound is at least one selected from the group consisting of: (A) pantothenic acid or a salt thereof, and (B) methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran.

3. The compound for use in improving periodontal disease according to claim 1, wherein the compound is at least one selected from the group consisting of (C) panthenol, and (D) cinnamon oil, and glutamic acid or a salt thereof.

4. A compound for use in improving periodontal disease according to any one of claims 1 to 3, wherein the periodontal disease is periodontal disease in diabetic patients.

5. A compound for use in activating mitochondria, comprising at least one compound selected from the group consisting of panthenol, pantothenic acid or a salt thereof, protamine or a salt thereof, and methionine or a salt thereof.

6. The compound for use in activating mitochondria according to claim 5, wherein the compound is at least one selected from the group consisting of: (A) pantothenic acid or a salt thereof, and (B) methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran.

7. The compound for use in activating mitochondria according to claim 5, wherein the compound is at least one selected from the group consisting of (C) panthenol, and (D) cinnamon oil, and glutamic acid or a salt thereof.

8. A compound for use in activating mitochondria according to any one of claims 5 to 7, wherein the mitochondria are mitochondria in periodontal ligament cells.

9. A compound for use in improving symptoms due to diabetes, prediabetes, or metabolic disorders due to aging, comprising at least one compound selected from the group consisting of panthenol, pantothenic acid or a salt thereof, protamine or a salt thereof, and methionine or a salt thereof.

10. The compound for use in improving symptoms due to diabetes, prediabetes, or metabolic disorders due to aging according to claim 9, wherein the compound is at least one selected from the group consisting of: (A) pantothenic acid or a salt thereof, and (B) methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran.

11. The compound for use in improving symptoms due to diabetes, prediabetes, or metabolic disorders due to aging according to claim 9, wherein the compound is at least one selected from the group consisting of: (C) panthenol, and (D) cinnamon oil, and glutamic acid or a salt thereof.

12. The compound for use in improving a symptom of diabetes, prediabetes, or metabolic disorder due to aging according to any one of claims 9 to 11, wherein the symptom of diabetes, prediabetes, or metabolic disorder due to aging is obesity, renal dysfunction, retinopathy, neuropathy, cardiovascular disease, brain dysfunction, dementia, frailty, muscle weakness, or osteoporosis.

13. An oral or buccal composition comprising a compound according to any one of claims 1 to 12.

14. A food composition comprising a compound according to any one of claims 1 to 12.

15. The oral composition according to claim 13, which is an ointment, paste, gel, liquid, spray, mouthwash, liquid dentifrice, toothpaste, or gum.

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