Composition for mitochondrial activation

Abstract

Methods capable of activating metabolism are provided. Specifically disclosed is a composition for activating mitochondria, which contains a specific component.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to a composition for activating mitochondria, etc. BACKGROUND

[0002] It is known that oxidative stress in cells is exacerbated due to various factors, for example, due to high glucose load, causing metabolic abnormalities. In particular, in diabetic patients, pre-diabetic populations, it is believed that high glucose load is applied, metabolism becomes abnormal, and various symptoms are caused. Symptoms in the oral cavity can also be included in this symptom.

[0003] For example, it has been reported that the metabolic function of periodontal tissue is impaired in a diabetic state, that the metabolic function of gingiva is activated in diabetic rats, and that alveolar bone resorption is inhibited.

[0004] PRIOR ART DOCUMENTS

[0005] NON-PATENT LITERATURE

[0006] Non-patent literature 1: J Clin Periodontol 2017; 44: 463-471. IADR / PER General Session 2018; Presentation ID 1622 SUMMARY

[0007] PROBLEMS TO BE SOLVED BY THE INVENTION

[0008] The present inventors have explored a means for activating metabolism.

[0009] SOLUTION TO THE PROBLEM

[0010] For example, if metabolism can be activated in the case where oxidative stress in cells is exacerbated, it can be expected that metabolic abnormalities will not easily occur. Therefore, it is believed that a means for activating metabolism is useful.

[0011] The present inventors have focused on the function of mitochondria, which plays a significant role in metabolism in cells, particularly ATP production ability and / or oxygen consumption ability in cells, and have explored a raw material that can increase the speed of ATP production, oxygen consumption, or a raw material that can improve the decrease in ATP production, the decrease in the speed of oxygen consumption.

[0012] The present disclosure includes, for example, the subject matter described in each of the following items.

[0013] Item 1-1.

[0014] A composition for activating mitochondria, comprising at least one selected from the group consisting of the components described in the table below.

[0015] [Table 1a]

[0016]

[0017] Item 1-2.

[0018] The composition according to item 1-1, wherein the mitochondria are mitochondria in periodontal ligament cells.

[0019] Item 1-3.

[0020] The composition according to item 1-1 or 1-2, wherein the mitochondrial activation is an increase in oxygen consumption in mitochondria.

[0021] Item 2-1.

[0022] A composition for mitochondrial activation, 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.

[0023] Item 2-2.

[0024] The composition according to item 2-1, wherein the mitochondria are mitochondria in periodontal ligament cells.

[0025] Item 2-3.

[0026] 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 oxygen consumption in mitochondria, an increase in ATP production ability in mitochondria, and an increase in mitochondria.

[0027] Item 2-4.

[0028] The composition according to any one of items 2-1 to 2-3, for use in improving periodontal disease in a diabetic patient.

[0029] Item 2-5.

[0030] A composition for improving a symptom caused by a metabolic disorder due to diabetes, prediabetes, or 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.

[0031] Item 2-6.

[0032] The composition according to item 2-5, wherein the symptom caused by a metabolic disorder due to diabetes, prediabetes, or aging is obesity, renal dysfunction, retinopathy, neurological disorder, cardiovascular disease, brain dysfunction, dementia, frailty, decreased muscle strength, or osteoporosis.

[0033] Item 2-7.

[0034] The composition according to any one of items 2-1 to 2-6, which is an oral composition or an oral cavity composition.

[0035] Item 2-8.

[0036] The composition according to any one of Items 2-1 to 2-6 is a food composition.

[0037] Item 2-9.

[0038] The oral composition according to Item 2-7 is an ointment, a paste, a skin cream, a gel, a liquid, a spray, a mouthwash, a liquid toothpaste, a paste toothpaste, or a chewing gum.

[0039] Item 3-1.

[0040] A composition for activating mitochondria, comprising:

[0041] (A) pantothenic acid or a salt thereof, and

[0042] (B) at least one selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, a ceramide, and rice bran.

[0043] Item 3-2.

[0044] The composition according to Item 3-1, wherein the mitochondria are mitochondria in periodontal membrane cells.

[0045] Item 3-3.

[0046] A composition for improving periodontal disease, comprising:

[0047] (A) pantothenic acid or a salt thereof

[0048] (B) at least one selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, a ceramide, and rice bran.

[0049] Item 3-4.

[0050] The composition according to Item 3-3, which is used for improving periodontal disease in a diabetic patient.

[0051] Item 3-5.

[0052] A composition for improving symptoms caused by metabolic disorder due to diabetes or aging, comprising:

[0053] (A) pantothenic acid or a salt thereof

[0054] (B) at least one selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, a ceramide, and rice bran.

[0055] Item 3-6.

[0056] The composition according to item 3-5, wherein the symptom caused by the metabolic disorder due to diabetes or aging is obesity, renal dysfunction, retinopathy, neurological disorder, cardiovascular disease, brain dysfunction, dementia, weakness, decrease in muscle strength, or osteoporosis.

[0057] Item 3-7.

[0058] The composition according to any one of items 3-1 to 3-6, which is an oral composition.

[0059] Item 3-8.

[0060] The composition according to item 3-7, which is a food composition.

[0061] Item 4-1.

[0062] A composition for activating mitochondria, comprising:

[0063] (C) ubiquinol, and

[0064] (D) at least one selected from the group consisting of cinnamon oil and glutamic acid or a salt thereof.

[0065] Item 4-2.

[0066] The composition according to item 4-1, wherein the mitochondria are mitochondria in periodontal ligament cells.

[0067] Item 4-3.

[0068] A composition for improving periodontal disease, comprising:

[0069] (C) ubiquinol, and

[0070] (D) at least one selected from the group consisting of cinnamon oil and glutamic acid or a salt thereof.

[0071] Item 4-4.

[0072] The composition according to item 4-3, which is for use in improving periodontal disease in a diabetic patient.

[0073] Item 4-5.

[0074] The composition according to any one of items 4-1 to 4-4, which is an oral composition.

[0075] Item A-1.

[0076] A composition for activating mitochondria, comprising at least one selected from the group consisting of:

[0077] ubiquinol,

[0078] pantothenic acid or a salt thereof,

[0079] Protamine or its salts, and

[0080] Methionine or its salts.

[0081] Item A-2.

[0082] The mitochondrial activation composition according to item A-1 contains:

[0083] (A) Pantothenic acid or its salts, and

[0084] (B) Select at least one of the following groups: methionine or its salt, protamine or its salt, ceramide, and rice bran.

[0085] Item A-3.

[0086] The mitochondrial activation composition according to item A-1 contains:

[0087] (C) Panthenol, and

[0088] (D) Select at least one of the following groups: cinnamon oil and glutamic acid or its salt.

[0089] Item A-4.

[0090] The composition according to any one of items A-1 to A-3, wherein the mitochondria are mitochondria in periodontal ligament cells.

[0091] Item B-1.

[0092] A composition for improving periodontal disease, comprising at least one of the following:

[0093] Panthenol,

[0094] Pantothenic acid or its salts,

[0095] Protamine or its salts, and

[0096] Methionine or its salts.

[0097] Item B-2.

[0098] The periodontal disease improvement composition according to item B-1 contains:

[0099] (A) Pantothenic acid or its salts, and

[0100] (B) Select at least one of the following groups: methionine or its salt, protamine or its salt, ceramide, and rice bran.

[0101] Item B-3.

[0102] The periodontal disease improvement composition according to item B-1 contains:

[0103] (C) panthenol, and

[0104] (D) at least one selected from the group consisting of cinnamon oil and glutamic acid or a salt thereof.

[0105] Item B-4.

[0106] The composition according to any one of Items B-1 to B-3 for improving periodontal disease in a diabetic patient.

[0107] Item C-1.

[0108] A composition for improving symptoms caused by metabolic disorder due to diabetes, prediabetes, or aging, comprising at least one selected from the group consisting of:

[0109] panthenol,

[0110] pantothenic acid or a salt thereof,

[0111] protamine or a salt thereof, and

[0112] methionine or a salt thereof.

[0113] Item C-2.

[0114] The composition according to Item C-1, comprising:

[0115] (A) pantothenic acid or a salt thereof, and

[0116] (B) at least one selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran.

[0117] Item C-3.

[0118] The periodontal disease-improving composition according to Item C-1, comprising:

[0119] (C) panthenol, and

[0120] (D) at least one selected from the group consisting of cinnamon oil and glutamic acid or a salt thereof.

[0121] Item C-4.

[0122] The composition according to any one of Items C-1 to C-3, wherein the symptoms caused by metabolic disorder due to diabetes, prediabetes, or aging are obesity, renal dysfunction, retinopathy, neurological disorder, cardiovascular disease, brain dysfunction, dementia, frailty, decreased muscle strength, or osteoporosis.

[0123] Item C-5.

[0124] The composition according to any one of items A-1 to A-4, B-1 to B-4 and C-1 to C-4 is a food composition.

[0125] Item C-6.

[0126] The composition according to any one of items A-1 to A-4, B-1 to B-4 and C-1 to C-4 is a food composition.

[0127] Item C-7.

[0128] The oral composition according to item C-5 is an ointment, a paste, a skin cream, a gel, a liquid, a spray, a mouthwash, a liquid toothpaste, a paste toothpaste, or a chewing gum.

[0129] Item A-i.

[0130] A compound for use in activation of mitochondria, which is at least one compound selected from the group consisting of:

[0131] panthenol,

[0132] pantothenic acid or a salt thereof,

[0133] protamine or a salt thereof, and

[0134] methionine or a salt thereof.

[0135] Item A-ii.

[0136] The compound for use in activation of mitochondria according to item A-i, wherein the above compound is:

[0137] (A) pantothenic acid or a salt thereof, and

[0138] (B) at least one selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, a ceramide, and rice bran.

[0139] Item A-iii.

[0140] The compound for use in activation of mitochondria according to item A-i, wherein the above compound:

[0141] (C) panthenol, and

[0142] (D) at least one selected from the group consisting of cinnamon oil and glutamic acid or a salt thereof.

[0143] Item A-iv.

[0144] The compound for use in activation of mitochondria according to any one of items A-i to A-iii, wherein the above mitochondria are mitochondria in periodontal ligament cells.

[0145] Item B-i.

[0146] A compound for use in the improvement of periodontal disease, which is at least one compound selected from the group consisting of:

[0147] ubiquinol,

[0148] pantothenic acid or a salt thereof,

[0149] protamine or a salt thereof, and

[0150] methionine or a salt thereof.

[0151] Item B-ii.

[0152] The compound for use in the improvement of periodontal disease according to item B-i, wherein the above compound is:

[0153] (A) pantothenic acid or a salt thereof, and

[0154] (B) at least one selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran.

[0155] Item B-iii.

[0156] The compound for use in the improvement of periodontal disease according to item B-i, wherein the above compound is:

[0157] (C) ubiquinol, and

[0158] (D) at least one selected from the group consisting of cinnamon oil and glutamic acid or a salt thereof.

[0159] Item B-iv.

[0160] The compound for use in the improvement of periodontal disease according to any one of items B-i to B-iii, wherein the above periodontal disease is periodontal disease of a diabetic patient.

[0161] Item C-i.

[0162] A compound for use in the improvement of symptoms caused by metabolic disorders due to diabetes, prediabetes, or aging, which is at least one compound selected from the group consisting of:

[0163] ubiquinol,

[0164] pantothenic acid or a salt thereof,

[0165] protamine or a salt thereof, and

[0166] methionine or a salt thereof.

[0167] Item C-ii.

[0168] The compound for use in the improvement of a symptom caused by a metabolic disorder caused by diabetes, prediabetes, or aging according to item C-i, wherein the above compound is:

[0169] (A) pantothenic acid or a salt thereof, and

[0170] (B) at least one selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran.

[0171] Item C-iii.

[0172] The compound for use in the improvement of a symptom caused by a metabolic disorder caused by diabetes, prediabetes, or aging according to item C-i, wherein the above compound is:

[0173] (C) panthenol, and

[0174] (D) at least one selected from the group consisting of cinnamon oil and glutamic acid or a salt thereof.

[0175] Item C-iv.

[0176] The compound for use in the improvement of a symptom caused by a metabolic disorder caused by diabetes, prediabetes, or aging according to any one of items C-i to C-iii, wherein the symptom caused by a metabolic disorder caused by diabetes, prediabetes, or aging is obesity, renal dysfunction, retinopathy, neurological disorder, cardiovascular disease, brain dysfunction, dementia, frailty, decrease in muscle strength, or osteoporosis.

[0177] Item C-v.

[0178] An oral or oral care composition containing the compound according to any one of items A-i to A-iv, B-i to B-iv, and C-i to C-iv.

[0179] Item C-vi.

[0180] A food composition containing the compound according to any one of items A-i to A-iv, B-i to B-iv, and C-i to C-iv.

[0181] Item C-vii.

[0182] The oral care composition according to item C-v, which is an ointment, a paste, a skin cream, a gel, a liquid, a spray, a mouthwash, a liquid toothpaste, a paste toothpaste, or a chewing gum.

[0183] Effects of the Invention

[0184] It is capable of activating mitochondria, improving mitochondria-related metabolic function (particularly improving the ATP production capacity and / or oxygen consumption capacity of mitochondria). For example, by improving metabolic function, it is possible to inhibit the occurrence of metabolic abnormalities when oxidative stress is high in cells.

[0185] In addition, although not particularly limited, it is possible to improve metabolic abnormalities, particularly a decrease in mitochondria-related metabolic function, which occur due to high glucose loading. In particular, it is possible to improve a decrease in ATP production and a decrease in oxygen consumption rate, which occur due to high glucose loading.

[0186] In addition, by improving the mitochondrial metabolism of cells in the oral cavity (for example, gingival cells, periodontal ligament cells), it is possible to activate the metabolic function of cells in the oral cavity or inhibit a decrease in the metabolic function of the cells, and thus it is also possible to expect to maintain the health of the oral cavity (for example, prevent periodontal disease, improve periodontal disease symptoms, and the like). BRIEF DESCRIPTION OF DRAWINGS

[0187] Figure 1a The ATP decrease improvement rate when pantothenic acid calcium is applied to human periodontal ligament fibroblasts subjected to high glucose treatment is shown.

[0188] Figure 1b The ATP decrease improvement rate when protamine sulfate is applied to human periodontal ligament fibroblasts subjected to high glucose treatment is shown.

[0189] Figure 1c The ATP decrease improvement rate when methionine is applied to human periodontal ligament fibroblasts subjected to high glucose treatment is shown.

[0190] Figure 2a The oxygen consumption rate (OCR) decrease improvement rate when pantothenic acid calcium is applied to human periodontal ligament fibroblasts subjected to high glucose treatment is shown.

[0191] Figure 2b The oxygen consumption rate (OCR) decrease improvement rate when protamine sulfate is applied to human periodontal ligament fibroblasts subjected to high glucose treatment is shown.

[0192] Figure 2c The oxygen consumption rate (OCR) decrease improvement rate when methionine is applied to human periodontal ligament fibroblasts subjected to high glucose treatment is shown.

[0193] Figure 3 The OCR value (relative value) when human periodontal ligament fibroblasts are treated with various test substances is shown. The OCR value (relative value) is a relative numerical value when the steady-state OCR value before treatment with the test substance is set to 1.

[0194] Figure 4 The copy number of mitochondrial DNA (mtDNA) of human periodontal ligament fibroblasts subjected to high glucose treatment is shown, relative to nuclear DNA (nDNA), when treated with various test substances.

[0195] Figure 5a The ATP decrease improvement rate when human periodontal ligament fibroblasts subjected to high glucose treatment are treated with calcium pantothenate in combination with protamine, methionine, rice bran, or ceramide is shown.

[0196] Figure 5b The oxygen consumption rate (OCR) decrease improvement rate when human periodontal ligament fibroblasts subjected to high glucose treatment are treated with calcium pantothenate in combination with protamine, methionine, rice bran, or ceramide is shown.

[0197] Figure 6a The ATP decrease improvement rate when human periodontal ligament fibroblasts subjected to high glucose treatment are treated with panthenol in combination with cinnamon oil or sodium glutamate is shown.

[0198] Figure 6b The oxygen consumption rate (OCR) decrease improvement rate when human periodontal ligament fibroblasts subjected to high glucose treatment are treated with panthenol in combination with cinnamon oil or sodium glutamate is shown. DETAILED DESCRIPTION

[0199] Hereinafter, each embodiment included in the present disclosure is described in further detail. The present disclosure preferably includes a composition for activating mitochondria and the like, but is of course not limited thereto, and the present disclosure includes all solutions that can be recognized by those skilled in the art disclosed in the present specification.

[0200] The composition for activating mitochondria included in the present disclosure contains a specific component capable of activating mitochondria. This composition is sometimes referred to as the composition of the present disclosure. In addition, this specific component is sometimes referred to as the component of the present disclosure.

[0201] In one mode, the composition of the present disclosure contains one or two or more of the specific components described in the following table, alone or in combination.

[0202] [Table 1b]

[0203]

[0204]

[0205] These components can also be used by purchasing commercially available products. The extract is preferably an extract of water, alcohol, or an aqueous alcohol. As the alcohol, ethanol and / or butanediol are preferred. In addition, the extract can be a dry product or a liquid.

[0206] These components can be roughly classified into compounds and extracts of organisms (e.g., whole or a part of animals or plants).

[0207] As the compounds, inositol, paratoluenesulfonic acid, isoleucine, cholecalciferol, glycyrrhizin or a salt thereof, allantoin, alanine, protamine or a salt thereof, cinnamaldehyde, paramylum, cyclodextrin (particularly γ-cyclodextrin), arginine, ceramide, methionine, glutamic acid or a salt thereof, and the like can be exemplified. As the salt of glycyrrhizin, an alkali metal salt is preferred, and a sodium salt or a potassium salt is more preferred. More specifically, dipotassium glycyrrhinate, trisodium glycyrrhinate are preferred. In addition, as the salt of protamine, a hydrochloride, a sulfate, and the like are preferred, and a sulfate is more preferred. In addition, as the salt of glutamic acid, an alkali metal salt is preferred, and a sodium salt or a potassium salt is more preferred.

[0208] As the extract of organisms, an extract of a part usually used as an extract in external use or food is preferably used.

[0209] As the extract of motherwort, there is no particular limitation as long as it is an extract of motherwort (chamomile), and an extract obtained from a stem, a leaf, a flower, and the like can be used, of which an essential oil (e.g., an essential oil) and the like can be particularly preferably used.

[0210] As the extract of Cistanche, an extract of a succulent stem of Cistanche is preferably used. Note that the extract of Cistanche is a parasitic plant of the family Orobanchaceae, and the extract thereof is used as a crude drug.

[0211] The extract of olive leaves is an extract of leaves of an olive tree, and is a component used as a supplement, an external agent, and the like.

[0212] As the extract of Eucommia ulmoides, an extract of a leaf of Eucommia ulmoides is particularly preferred. The extract of a leaf of Eucommia ulmoides is widely used as a supplement, and the like.

[0213] As the extract of Arnica montana flowers, an extract obtained from flowers (and roots) of Arnica montana is a component used as an external agent, and the like. Note that Arnica montana is a plant of the family Asteraceae.

[0214] The extract of leaves of Lonicera japonica is an extract of leaves of Lonicera japonica. The extract of roots of Paeonia japonica is an extract of roots of Paeonia japonica. The extract of roots of Panax ginseng is an extract of roots of Panax ginseng.

[0215] The extract of ginger is preferably an extract of rhizomes of ginger. It is expected to promote blood circulation and the like, and can be used as an external agent, a food, and the like.

[0216] The (animal) placental protein is an extract obtained from a placenta of a mammal (particularly a cow, a pig, a horse, and the like), and is used in cosmetics, and the like.

[0217] Shortstem wild sesame extract is an extract of the whole plant and / or flower of Shortstem wild sesame (Sesamum prostratum), and is used in cosmetics and the like.

[0218] Lucerne extract is an extract of the whole plant of Lucerne (also called sweet clover) (Medicago sativa), and is used in foods and the like.

[0219] Willow extract is an extract of the bark and / or new shoots of willow, and is used in supplements and the like.

[0220] Ampelopsis extract is an extract of Ampelopsis (mainly an extract of the fruit (particularly the seed), stem, leaf, and the like), and is used in foods and the like.

[0221] Valerian root extract is an extract of the root of Valeriana officinalis L., and is used in supplements and the like.

[0222] Anise fruit extract is an extract of the fruit of Pimpinella anisum of the Umbelliferae family, and is used in cosmetics and the like.

[0223] Kanna extract is an extract of the root (tuber) of Sceletium tortuosum, and is used in supplements and the like.

[0224] Small-leaf privet extract is an extract of the flower, stem, or leaf of Small-leaf privet (Ligustrum sinense), and is used in external agents and the like.

[0225] Jujube root extract is an extract of the root of Jujube (Ziziphus jujuba), and is used in antitussive and expectorant drugs and the like.

[0226] Rice bran extract is an extract of rice bran.

[0227] Fermented black garlic bulb extract is an extract of fermented black garlic obtained by fermenting garlic (bulb) for a certain period of time, and is used in supplements and the like.

[0228] Purple brown rice extract is an extract of brown rice that is red-purple, such as red rice and black rice, which are ancient rice, and is used in supplements and the like.

[0229] European thyme extract is an extract of the whole plant (particularly the leaf and stem) of Thymus vulgaris, and is used in external agents and the like.

[0230] Turmeric rhizome extract is an extract of the rhizome of Curcuma longa.

[0231] Panax notoginseng extract is an extract of Panax notoginseng (root), and is used in supplements and the like.

[0232] Although not particularly limited, in another mode, particularly preferred are the ingredients among these ingredients that are listed in the following table.

[0233] [Table 2]

[0234]

[0235] The content of the component of the present disclosure in the composition of the present disclosure in this mode is not particularly limited as long as it is within a range not impairing the effects. For example, about 0.01 to 99.99 mass% can be cited.

[0236] In another mode, the composition of the present disclosure contains, as the component of the present disclosure, alone one or a combination of two or more of panthenol, pantothenic acid or a salt thereof, protamine or a salt thereof, and methionine or a salt thereof.

[0237] As the salt of pantothenic acid, 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 or a barium salt, a magnesium salt is more preferred, further a sodium salt or a calcium salt is preferred, and a calcium salt is particularly preferred. These salts can be used alone or in combination of two or more.

[0238] As the salt of protamine, 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 or a barium salt, a magnesium salt is more preferred, further a sodium salt or a calcium salt is preferred, and a calcium salt is particularly preferred. In addition, as the salt of protamine, a sulfate salt, a hydrochloride salt is also preferred, and a sulfate salt is particularly preferred. These salts can be used alone or in combination of two or more.

[0239] 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 or a barium salt, a magnesium salt is more preferred, further a sodium salt or a calcium salt is preferred, and a calcium salt is particularly preferred. In addition, as the salt of methionine, a sulfate salt, a hydrochloride salt is also preferred. These salts can be used alone or in combination of two or more.

[0240] The content of the component of the present disclosure in the composition of the present disclosure in this mode is not particularly limited as long as it is within a range not impairing the effects. For example, about 0.01 to 99.99 mass% can be cited.

[0241] In another mode, the composition of 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. In addition, pantothenic acid or a salt thereof is sometimes referred to as a (A) component, and at least one selected from the group consisting of methionine or a salt thereof, protamine or a salt thereof, ceramide, and rice bran is sometimes referred to as a (B) component.

[0242] As the salt of pantothenic acid, the salt of protamine, and the salt of methionine, the above-described is cited.

[0243] As the ceramide, the origin is not particularly limited, and for example, ceramides extracted from plants and animals, ceramides produced by microorganisms, or ceramides produced by chemical methods can be used. Among them, ceramides extracted from plants such as corn germ, wheat, rice, soybean, millet, and spinach, or microorganisms such as yeast are preferable.

[0244] As the rice bran, there is no particular limitation, and known rice bran can be used. As the known rice bran, for example, rice bran produced as a byproduct when brown rice is milled to produce white rice, such as the pericarp, seed coat, aleurone, starch layer, and the like of brown rice can be used. In addition, as the rice bran, rice bran having an oil content of more than 2% by mass is preferable. In addition, rice bran extract obtained by pressing or water or alcohol (for example, ethanol) extraction of rice bran is also preferably used as the rice bran of the composition of the present disclosure.

[0245] As the content ratio of the (A) component to the (B) component, there is no particular limitation as long as the effect is not impaired, and for example, 0.1 to 10 parts by mass or so of the (B) component is preferable to 1 part by mass of the (A) component. The upper limit or the lower limit of this range (0.1 to 10) can 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, this range is more preferably 0.2 to 5 parts by mass or so or 0.2 to 3 parts by mass or so.

[0246] In addition, as the content of the (A) component in the composition of the present disclosure of this mode, there is no particular limitation as long as the effect is not impaired, and for example, 0.001 to 20% by mass to the total amount of the composition can be exemplified. The upper limit or the lower limit of this range can 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, this range is preferably 0.01 to 5% by mass.

[0247] In addition, as the content of the (B) component in the composition of the present disclosure of this mode, there is no particular limitation as long as the effect is not impaired, and for example, 0.001 to 20% by mass to the total amount of the composition can be exemplified. The upper limit or the lower limit of this range can 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, this range is preferably 0.01 to 5% by mass.

[0248] Note that, when the composition of the present disclosure of this mode contains methionine or a salt thereof, as the content thereof, the content range of the above-mentioned (B) component is preferable, and more preferably 0.001 to 0.5% by mass to the total amount of the composition, and further preferably 0.01 to 0.1% by mass.

[0249] In addition, when the composition of the present disclosure contains protamine or a salt thereof in this way, as the content thereof, the content range of the above-mentioned (B) component is preferable, and more preferably 0.001 to 0.5% by mass, and further preferably 0.005 to 0.1% by mass, relative to the total amount of the composition.

[0250] In addition, when the composition of the present disclosure contains ceramide in this way, as the content thereof, the content range of the above-mentioned (B) component is preferable, and more preferably 0.001 to 0.5% by mass, and further preferably 0.01 to 0.1% by mass, relative to the total amount of the composition.

[0251] In addition, when the composition of the present disclosure contains ceramide in this way, as the content thereof, the content range of the above-mentioned (B) component is preferable, and more preferably 0.001 to 0.5% by mass, and further preferably 0.01 to 0.1% by mass, relative to the total amount of the composition.

[0252] In addition, in another way, the composition of the present disclosure contains (C) panthenol, and (D) at least one selected from the group consisting of cinnamon oil and glutamic acid or a salt thereof, as components of the present disclosure. This composition is sometimes referred to as the composition of the present disclosure. In addition, panthenol is sometimes referred to as the (C) component, and at least one selected from the group consisting of cinnamon oil and glutamic acid or a salt thereof is sometimes referred to as the (D) component.

[0253] As the salt of glutamic acid, an alkali metal salt or an alkaline earth metal salt is preferable, and more specifically, a lithium salt, a sodium salt, a potassium salt, a calcium salt or a barium salt, a magnesium salt is more preferable, and further preferably a sodium salt or a potassium salt, and particularly preferably a sodium salt. In addition, as the salt of glutamic acid, a sulfate salt, a hydrochloride salt is also preferable, and particularly preferably a hydrochloride salt. These salts can be used alone or in combination of two or more.

[0254] As the content ratio of the (C) component and the (D) component, there is no particular limitation as long as the effect is not impaired, and for example, relative to 1 part by mass of the (C) component, the (D) component is preferably around 0.1 to 10 parts by mass. The upper limit or the lower limit of this range (0.1 to 10) can 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, this range is more preferably around 0.2 to 5 parts by mass or around 0.2 to 3 parts by mass.

[0255] In addition, the content of the (C) component in the composition of the present disclosure in this mode is not particularly limited as long as it is within a range that does not impair the effects, and for example, 0.1 to 0.5% by mass with respect to the total amount of the composition can be cited. The upper limit or the lower limit of this range can 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% by mass or 0.2 to 0.4% by mass.

[0256] In addition, the content of the (D) component in the composition of the present disclosure in this mode is not particularly limited as long as it is within a range that does not impair the effects, and for example, 0.001 to 1.3% by mass with respect to the total amount of the composition can be cited. The upper limit or the lower limit of this range can 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% by mass or 0.01 to 0.7% by mass.

[0257] Note that, in the composition of the present disclosure in this mode, when cinnamomum oil is contained, as the content thereof, the content range of the above-described (D) component is preferable, and with respect to the total amount of the composition, 0.001 to 1% by mass is preferable, 0.002 to 0.5% by mass is more preferable, and 0.01 to 0.1% by mass is further preferable.

[0258] In addition, in the composition of the present disclosure in this mode, when glutamic acid or a salt thereof is contained, as the content thereof, the content range of the above-described (B) component is preferable, and with respect to the total amount of the composition, 0.01 to 0.3% by mass is more preferable, and 0.02 to 0.2% by mass is further preferable.

[0259] The mode of ingestion of the composition of the present disclosure is not particularly limited, and oral ingestion or topical application to the oral mucosa is preferable. That is, the composition of the present disclosure is preferably an oral composition, an oral cavity composition. By orally ingesting the composition of the present disclosure, in cells, particularly cells in the oral cavity, mitochondria can be activated, and mitochondrial-related metabolic functions can be improved (particularly, the oxygen consumption capacity of mitochondria can be improved). The composition of the present disclosure is, for example, preferably an oral pharmaceutical composition, a food composition (including a beverage composition and a food additive composition), an oral cavity composition.

[0260] The composition of the present disclosure contains the above-described components, and can further contain other components. The other components can be appropriately selected depending on the field in which the composition is used. For example, a pharmaceutically or food hygienically acceptable carrier can be used.

[0261] In the case of use as a pharmaceutical composition, as other components, pharmaceutically acceptable bases, carriers and / or additives (for example, solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants, lubricants, etc.) and the like can be exemplified. In addition, the form of the pharmaceutical composition is not particularly limited, and tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, creams, cataplasms and the like can be exemplified.

[0262] In the case of use as a food composition, as other components, food hygienically acceptable bases, carriers, additives, other components / materials usable as foods and the like can be exemplified. In addition, the form of the food composition is not particularly limited, and for example, processed foods, health foods (nutritional supplementary foods, nutritional functional foods, foods for patients, foods for specified health use, functional labeled goods and the like), supplements, foods for patients (hospital diets, patient diets or nursing foods and the like) and the like can be exemplified. They can be prepared by conventional methods. In particular, in the case of preparation of the food composition as a health food (nutritional supplementary food, nutritional functional food, food for patients, food for specified health use, functional labeled good and the like) or a supplement, in order to make it easy to take continuously, for example, preparation in the form of granules, capsules, tablets (including chewable tablets and the like), beverages (beverage powders, drinkable agents, slushes and the like) and the like is preferred, and from the aspect of ease of taking, the form of capsules, compressed tablets, tablets, beverage powders, drinkable agents, jellies, gummies is preferred, but is not particularly limited to these. Note that, in the food composition, in the case of use as a food additive composition, as its form, for example, the form of liquid, powder, sheet, granule, paste can be exemplified.

[0263] In the case of use as an oral composition, for example, it can be prepared in the form (dose form) of ointments, pastes, skin ointments, gels, liquids, sprays, mouthwashes, liquid toothpastes, paste toothpastes, chewing gums and the like.

[0264] In addition, as other components, publicly known components compatible with the oral composition can be used.

[0265] For example, as the surfactant, a nonionic surfactant, an anionic surfactant, or an amphoteric surfactant can be used. Specifically, for example, as the nonionic surfactant, sugar fatty acid esters such as sucrose fatty acid ester, maltose fatty acid ester, and lactose fatty acid ester; fatty acid alkanolamide; glycerin fatty acid ester; sorbitan fatty acid ester; fatty acid monoglyceride; polyoxyethylene alkyl ether having a polyoxyethylene addition factor of 8 to 10 and an alkyl group having a carbon number of 13 to 15; polyoxyethylene alkyl phenyl ether having a polyoxyethylene addition factor of 10 to 18 and an alkyl group having a carbon number of 9; diethyl sebacate; polyoxyethylene hydrogenated castor oil; and fatty acid polyoxyethylene sorbitan can be exemplified. As the anionic surfactant, sulfate salts such as sodium lauryl sulfate and sodium polyoxyethylene lauryl ether sulfate; sulfosuccinate salts such as sodium lauryl sulfosuccinate and sodium polyoxyethylene lauryl ether sulfosuccinate; acyl amino acid salts such as sodium cocoyl sarcosinate and sodium lauroyl methyl alaninate; and sodium cocoyl methyl taurate can be exemplified. As the amphoteric surfactant, betaine-type surfactants such as lauryl dimethyl aminoacetic acid betaine and coconut oil fatty acid amide propyl dimethyl aminoacetic acid betaine; imidazoline-type surfactants such as sodium N-cocoyl-N-carboxymethyl-N-hydroxyethyl ethylenediamine; and amino acid-type surfactants such as N-lauryl diaminomethyl glycine can be exemplified. These surfactants can be used alone or in combination of two or more. The amount of the surfactant used is usually 0.1 to 5% by mass relative to the total amount of the composition.

[0266] In addition, as the flavoring agent, for example, menthol, carboxylic acid, anethole, eugenol, methyl salicylate, limonene, ocimene, n-decanol, citronellal, a-terpineol, methyl acetate, citronellyl acetate, eugenol methyl ether, eucalyptol, linalool, ethyl linalool, thymol, spearmint leaf oil, peppermint oil, lemon peel oil, lime oil, clary sage oil, rosemary leaf oil, cinnamon oil, perilla oil, wintergreen oil, clove oil, bluegum oil, pimento oil, d-camphor, d-limonene, anise oil, cinnamon oil, peppermint oil, vanillin, and the like can be used. These can be used alone or in combination of two or more, and can be used, for example, in an amount of 0.001 to 1.5% by mass relative to the total amount of the composition.

[0267] In addition, as the sweetening agent, for example, sodium saccharin, acesulfame potassium, stevioside, neohesperidin dihydrochalcone, perillartine, thaumatin, aspartame, and p-methoxy cinnamaldehyde can be used. These can be used, for example, in an amount of 0.01 to 1% by mass relative to the total amount of the composition.

[0268] Further, as the wetting agent, sorbitol, ethylene glycol, propylene glycol, glycerin, 1,3-butanediol, polypropylene glycol, xylitol, maltitol, lactitol, and polyoxyethylene glycol can be used alone or in combination of two or more.

[0269] As the preservative, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, and the like can be used in combination with p-hydroxybenzoic acid esters, sodium benzoate, phenoxyethanol, alkyl diaminethyl glycine hydrochloride, and the like.

[0270] As the colorant, blue No. 1, yellow No. 4, red No. 202, green No. 3, and the like can be used in combination with legal pigments, mineral pigments such as ultramarine blue, intensified ultramarine blue, and Prussian blue, and titanium oxide.

[0271] As the 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, and the like can be used in combination with two or more of these in a manner such that the pH of the composition is in the range of 4 to 8, preferably 5 to 7. The amount of the pH adjuster can be, for example, 0.01 to 2% by weight.

[0272] As the pharmaceutical ingredient, dl-α-tocopherol acetate, tocopherol succinate, or tocopherol nicotinate, and the like vitamin E, dodecyl diaminethyl glycine, and the like amphoteric bactericide, triclosan, isopropyl methyl phenol, hinokitiol, and the like nonionic bactericide, sodium lauroyl sarcosinate, and the like anionic bactericide, cetylpyridinium chloride, chlorhexidine hydrochloride, benzalkonium chloride, benzethonium chloride, and the like cationic bactericide, dextranase, amylase, protease, mutanase, lysozyme, and the like enzymes, sodium monofluorophosphate, potassium monofluorophosphate, and the like alkali monofluorophosphate, sodium fluoride, stannous fluoride, and the like fluoride, tranexamic acid, ε-aminocaproic acid, aluminum chlorohydroxyl allantoin, dihydrocholesterol, glycyrrhetinic acid, copper sodium chlorophyllin, glycerophosphate, chlorophyll, sodium chloride, caropeptide, carbaxel, hinokitiol, potassium nitrate, paratin sugar, and the like can be used in combination with two or more of these.

[0273] In addition, as the base, alcohols, silicon, apatite, white vaseline, paraffin, liquid paraffin, microcrystalline wax, squalane, Plastibase, and the like can be added.

[0274] The composition of the present disclosure can be preferably used for activation of mitochondria in cells. More specifically, the composition of the present disclosure can, for example, preferably improve the decrease in oxygen consumption rate resulting from high glucose, oxidative stress load. Thus, it can also be preferably used for improving metabolic abnormalities in cells derived from a diabetic patient, a prediabetic patient. For example, the metabolic function of periodontal tissues is impaired in a diabetic state, which is considered to exacerbate the progression of periodontal disease in diabetic patients, and thus can be particularly preferably used for improving metabolic abnormalities of cells (e.g., periodontal ligament cells) in periodontal tissues, and in turn can be preferably used for inhibiting and / or improving the progression of periodontal disease. In addition, not only the metabolism of mitochondria in cells in the oral cavity (e.g., gingival cells, periodontal ligament cells) can be improved, but also the metabolic function of various cells can be activated or the decrease in metabolic function can be inhibited, and thus 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, for example, a diabetic state, a prediabetic state, or the metabolic function of other tissues that are impaired due to aging. For example, it can be used for inhibition and / or improvement of obesity, renal dysfunction, retinopathy, neurological disorders, cardiovascular diseases, brain dysfunction, dementia, frailty, decreased muscle strength, osteoporosis.

[0275] The subject of intake or application of the composition of the present disclosure is not particularly limited, and for example, it can be preferably ingested or applied by a healthy person. In addition, from the viewpoint that the effect can be preferably exerted, a subject that develops metabolic abnormalities (particularly, for example, a subject in which oxidative stress in cells is exacerbated, or a subject in which the metabolism of mitochondria is decreased), and more specifically, more preferably, for example, a subject that develops metabolic abnormalities caused by high glucose load. In addition, as described above, by improving the metabolism of mitochondria in cells in the oral cavity (e.g., gingival cells, periodontal ligament cells), the metabolic function of cells in the oral cavity can be activated or the decrease in metabolic function can be inhibited, and thus maintaining oral health (e.g., preventing periodontal disease) can be expected, and thus a subject in which gingivitis or periodontal disease occurs is also preferable.

[0276] In addition, the period of intake or application of the composition of the present disclosure is not particularly limited, and for example, it can be ingested or applied before or after ingestion of food (e.g., within 0.5 or 1 hour before or after a meal). The meal more preferably contains a saccharide (particularly, a saccharide that can be absorbed as glucose in the body) or a lipid. In addition, for example, it can be preferably used in or after periodontal disease treatment.

[0277] In addition, although not particularly limited, as a cell in which metabolic abnormalities can be inhibited by intake or application of the composition of the present disclosure, cells in the oral cavity are preferable, and among them, gingival cells, periodontal ligament cells (particularly, gingival fibroblasts, periodontal ligament fibroblasts) are preferable. Periodontal ligament cells are known to strongly participate in immune responses, inflammatory reactions, alveolar bone resorption in periodontal disease, and are the most preferable.

[0278] It should be noted that in the present specification, "comprising" also includes "consisting essentially of" and "consisting of." In addition, the present disclosure includes any combination of all the components described in the present specification.

[0279] In addition, various characteristics (properties, structures, functions, etc.) explained with respect to each embodiment of the present disclosure described above can be arbitrarily combined in determining the subject matter encompassed by the present disclosure. That is, the present disclosure includes all the subject matter constituted by all the combinations of each characteristic capable of being combined described in the present specification.

[0280] Embodiments

[0281] Hereinafter, the embodiments of the present disclosure will be described more specifically by showing examples, but the embodiments of the present disclosure are not limited to the following examples.

[0282] (1) Research on various components

[0283] After the test sample application treatment on human periodontal ligament fibroblasts (HPDLF), the oxygen consumption rate (OCR) in the cells was measured. More specifically, the following was performed.

[0284] Measurement of oxygen consumption rate (OCR) in periodontal ligament fibroblasts

[0285] OCR was measured using an Extracellular OCR plate assay kit (E297, DOJINDO). Human periodontal ligament fibroblasts (HPDLF) were seeded at a density of 2 x 10 5 cells / 100 μL / well in a 96-well plate and cultured overnight. Thereafter, each test substance (sample: final concentration 1 μg / mL) was treated for 24 hours.

[0286] The determination of OCR was performed as follows. Oxygen probe reaction solution 100 μL having a property that the intensity of phosphorescence increases when the oxygen concentration in the culture solution decreases was added to each well. Thereafter, in order to prevent the inflow of oxygen in the air, mineral oil droplets were added to each well. The intensity of phosphorescence was determined using a Cytation 5 enzyme marker (BioTek Instruments), and the OCR of the cells was calculated by the Stern-Volmer equation. The OCR value (relative value) of each test substance was shown in the form of a value when the steady-state OCR value when no substance was administered was set to 1. That is, since the steady-state OCR value when no substance was administered was set to 1, when the OCR value was doubled due to the administration of the test substance, the OCR value was 2.

[0287] The kind, the amount of use, and the obtained results of each sample are shown in Table 3.

[0288] [Table 3]

[0289]

[0290]

[0291] (2) Study of specific components

[0292] For human periodontal ligament fibroblasts (HPDLF), after the test sample application treatment, the intracellular ATP concentration and the oxygen consumption rate (OCR) in the cells were determined. More specifically, this was performed as follows.

[0293] Note that, as the test substance (sample), calcium pantothenate, protamine sulfate, and methionine were used. Each test substance was dissolved in the culture medium used in the test to prepare a solution for use.

[0294] Measurement of intracellular ATP in periodontal ligament fibroblasts

[0295] The intracellular ATP was determined using a Luminescent ATP detection assay kit (ab113849; Abeam). Human periodontal ligament fibroblasts (HPDLF) were seeded at 0.12 x 10 5The cells were seeded at a density of 1 cell / 100 μL / well in a 48-well plate and incubated for 48 hours. After that, each test substance (sample) was subjected to 24-hour pre-treatment, followed by further incubation for 72 hours in the presence of 50 mM of D-glucose (Sigma Aldrich). For the control, the same treatment was performed using 50 mM of L-glucose. After that, the cells were lysed by adding 50 μL of cell lysis solution for 5 minutes to stabilize ATP. Then, D-luciferase reagent was added, and incubation was performed for 10 minutes under light shielding. Chemiluminescence caused by luciferase was measured using a Cytation 5 microplate reader (BioTek Instruments), and the ATP concentration (μM) was determined using a standard curve. The ATP decrease improvement rate (%) of each sample was calculated using the following formula.

[0296] [Table 1]

[0297]

[0298] That is, the ATP decrease improvement rate (%) represents the ratio (%) obtained by dividing the value obtained by subtracting the ATP value when only D-glucose treatment was performed from the ATP value when D-glucose treatment was performed after sample treatment, by the value obtained by subtracting the ATP value when only D-glucose treatment was performed from the ATP value when only L-glucose treatment was performed.

[0299] The results are shown in Figures 1a-1c Note that in the figure, pantothenate indicates calcium pantothenate, and protamine indicates protamine sulfate. In addition, the concentration is indicated in the figure, and the concentration indicates the concentration of each test substance in the culture solution. The same applies to the following figures.

[0300] Measurement of oxygen consumption rate (OCR) in periodontal ligament fibroblasts

[0301] OCR was measured using an Extracellular OCR plate assay kit (E297, DOJINDO). Human periodontal ligament fibroblasts (HPDLF) were seeded at a density of 2 x 10 5The cells were seeded at a density of 2 x 10 5 cells / 100 μL / well in a 96-well plate and incubated overnight. Thereafter, each test substance (sample) was subjected to 24-hour pre-treatment, followed by further incubation for 24 hours in the presence of 100 mM D-glucose (Sigma Aldrich). For the control, the same treatment was performed using 100 mM L-glucose. An oxygen probe reagent having a property of increasing phosphorescence intensity when the oxygen concentration in the culture solution decreases was added to each well at 100 μL. Thereafter, in order to prevent the inflow of oxygen in the air, mineral oil droplets were added to each well. The phosphorescence intensity was measured using a Cytation 5 microplate reader (BioTek Instruments), and the OCR of the cells was calculated by the Stern-Volmer equation. The OCR improvement rate (%) by each sample was calculated by the following formula.

[0302] [Numeral 2]

[0303]

[0304] That is, the OCR decrease improvement rate (%) represents the proportion (%) obtained by dividing the value obtained by subtracting the OCR value when only D-glucose treatment is performed from the OCR value when sample treatment followed by D-glucose treatment is performed, by the value obtained by subtracting the OCR value when only D-glucose treatment is performed from the OCR value when only L-glucose treatment is performed.

[0305] The results are shown in Figures 2a-2c .

[0306] Measurement of oxygen consumption rate (OCR) in periodontal ligament fibroblasts (without high glucose load)

[0307] OCR was measured using an Extracellular OCR plate assay kit (E297, DOJINDO). Human periodontal ligament fibroblasts (HPDLF) were seeded at a density of 2 x 10 5 cells / 100 μL / well in a 96-well plate and incubated overnight. Thereafter, each test substance (sample: final concentration 1 μg / mL) was subjected to 24-hour treatment.

[0308] The determination of OCR was performed as follows. Oxygen probe reaction solution 100 μL having a property that the intensity of phosphorescence increases when the oxygen concentration in the culture solution decreases was added to each well. Thereafter, in order to prevent the inflow of oxygen in the air, mineral oil droplets were added to each well. The intensity of phosphorescence was determined using a Cytation 5 enzyme marker (BioTek Instruments), and the OCR of the cells was calculated by the Stern-Volmer equation. The OCR value (relative value) of each test substance was shown in the form of a value when the steady-state OCR value when no substance was administered was set to 1. That is, since the steady-state OCR value when no substance was administered was set to 1, when the OCR value was doubled due to the administration of the test substance, the OCR value was 2.

[0309] The results are shown in Figure 3 . As a positive object substance, the uncoupling agent FCCP was used at a final concentration of 2 μM. Note that FCPP is carbonyl cyanide-p-trifluoromethoxyphenylhydrazone. In addition, as a control, only the culture medium was used.

[0310] Method for mitochondrial DNA measurement in periodontal ligament fibroblasts

[0311] Human Periodontal Ligament Fibroblast (HPDLF) was seeded at a density of 0.9 x 10 5 cells / well in a 12-well plate, and after 2 days, each test substance (sample: final concentration 1 μg / mL) was disposed of for 24 hours, and thereafter, incubated for 3 days in the presence of 50 mM of D-glucose (Sigma Aldrich, USA). As a control, the same disposition was performed using 50 mM of L-glucose. DNA was isolated using NucleoSpin Tissue extraction kit (Takara, Japan). Quantitative PCR of the isolated DNA was performed using TB Green Fast qPCR Mix (Takara, Japan), and the copy number of mitochondrial DNA (mtDNA) was calculated relatively to nuclear DNA (nDNA).

[0312] The results are shown in Figure 4 . In this figure, HG indicates that only 50 mM of D-glucose was applied (no test substance was applied). In addition, Control indicates that only 50 mM of L-glucose was applied (no test substance was applied).

[0313] It is considered that the increase in the relative copy number of mtDNA relative to nDNA means an increase in mitochondria, and further, an increase in mitochondrial-related metabolic function.

[0314] (3) Combination study of specific components 1

[0315] After the test sample application treatment and high glucose treatment of human periodontal ligament fibroblasts (HPDLF), the intracellular ATP concentration and the oxygen consumption rate (OCR) in the cells were measured. More specifically, the following was performed.

[0316] Measurement of intracellular ATP in periodontal ligament fibroblasts

[0317] The intracellular ATP was measured using a Luminescent ATP detection assay kit (ab113849; Abeam). Human periodontal ligament fibroblasts (HPDLF) were seeded at a density of 0.12 x 10 5 cells / 100 μL / well in a 48-well plate and cultured for 48 hours. After that, 24-hour pre-treatment with each test substance (sample) was performed, followed by further culture for 72 hours in the presence of 50 mM D-glucose (Sigma Aldrich). For the control, the same treatment was performed using 50 mM L-glucose. After that, the cells were lysed by adding 50 μL of cell lysis solution for 5 minutes to stabilize the ATP. Further, D-luciferase reagent was added, and incubation was performed for 10 minutes under light shielding. Chemiluminescence due to luciferase was measured using a Cytation 5 microplate reader (BioTek Instruments), and the ATP concentration (μM) was measured using a standard curve. The ATP decrease improvement rate (%) of each sample was calculated using the following formula.

[0318] [Num. 3]

[0319]

[0320] That is, the ATP decrease improvement rate (%) represents the ratio (%) obtained by dividing the value obtained by subtracting the ATP value when only D-glucose treatment is performed from the ATP value when D-glucose treatment is performed after sample treatment by the value obtained by subtracting the ATP value when only D-glucose treatment is performed from the ATP value when only L-glucose treatment is performed.

[0321] Measurement of oxygen consumption rate (OCR) in periodontal ligament fibroblasts

[0322] OCR was measured using an Extracellular OCR plate assay kit (E297, DOJINDO). Human periodontal ligament fibroblasts (HPDLF) were sampled at a concentration of 2 × 10⁻⁶. 5 Cells were seeded at a density of 100 μL / well in 96-well plates and cultured overnight. Afterward, each sample was pretreated for 24 hours, followed by a further 24-hour culture in the presence of 100 mM D-glucose (Sigma Aldrich). For the control, the same treatment was performed with 100 mM L-glucose. 100 μL of an oxygen probe reaction solution, which exhibits the property of increasing phosphorescence intensity as the oxygen concentration in the culture medium decreases, was added to each well. Subsequently, to prevent the influx of atmospheric oxygen, mineral oil droplets were added to each well. Phosphorescence intensity was measured using a Cytation 5 microplate 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.

[0323] [Number 4]

[0324]

[0325] That is, the OCR reduction improvement rate (%) represents the percentage obtained by subtracting the OCR value of D-glucose treatment alone from the OCR value of D-glucose treatment alone after sample treatment, and dividing the result by subtracting the OCR value of D-glucose treatment alone from the OCR value of L-glucose treatment alone.

[0326] The types, amounts, and results of each sample are shown in Tables 4a and 4b. All samples were used in aqueous solution form. It should be noted that in these tables, "pantothenate" refers to calcium pantothenate. Additionally, "ALA" refers to 5-aminolevulinic acid. Furthermore, commercially available rice-derived ceramides were used as "ceramides." Additionally, commercially available rice bran aqueous extracts were used as "rice bran."

[0327] It should be noted that the concentration of any sample aqueous solution is expressed as % (w / v), but since it is basically the same as the value of % (w / w) (% (w / w) is slightly larger), it can also be interpreted as % (w / w) (i.e., mass %).

[0328] [Table 4a]

[0329]

[0330] [Table 4b]

[0331]

[0332] As shown in Table 4a, it was found that both the ATP decrease improvement rate and the OCR decrease improvement rate showed excellent values when pantothenic acid calcium was used in combination with protamine, methionine, rice bran, or ceramide.

[0333] The results shown in Table 4a are graphed in the figure. Specifically, the results of the ATP decrease improvement rate of Table 4a are shown in Figure 5a , and the results of the OCR decrease improvement rate of Table 4b are shown in Figure 5b .

[0334] (4) Combination study 2 of specific components

[0335] After applying the test sample application treatment and high glucose treatment to human periodontal ligament fibroblasts (HPDLF), the intracellular ATP concentration and the oxygen consumption rate (OCR) in the cells were measured. More specifically, this was performed as follows.

[0336] Measurement of intracellular ATP in periodontal ligament fibroblasts

[0337] The intracellular ATP was measured using a Luminescent ATP detection assay kit (ab113849; Abeam). Human periodontal ligament fibroblasts (HPDLF) were seeded at a density of 0.12 x 10 5 cells / 100 μL / well in a 48-well plate and cultured for 48 hours. After that, 24 hours of pre-treatment with each test substance (sample) was performed, followed by further culture for 72 hours in the presence of 50 mM D-glucose (Sigma Aldrich). For the control, the same treatment was performed using 50 mM L-glucose. After that, the cells were lysed by adding 50 μL of cell lysis solution for 5 minutes to stabilize the ATP. D-luciferase reagent was further added, and incubated for 10 minutes in the dark. Chemiluminescence due to luciferase was measured using a Cytation 5 microplate reader (BioTek Instruments), and the ATP concentration (μM) was measured using a standard curve. The ATP decrease improvement rate (%) of each sample was calculated using the following formula.

[0338] [Table 5]

[0339]

[0340] That is, the OCR decrease improvement rate (%) represents the proportion (%) obtained by dividing the value obtained by subtracting the OCR value when only D-glucose treatment is performed from the OCR value when D-glucose treatment is performed after sample treatment from the value obtained by subtracting the OCR value when only D-glucose treatment is performed from the OCR value when only L-glucose treatment is performed.

[0341] Measurement of oxygen consumption rate (OCR) in periodontal ligament fibroblasts

[0342] OCR was measured using an Extracellular OCR plate assay kit (E297, DOJINDO). Human periodontal ligament fibroblasts (HPDLF) were seeded at a density of 2 x 10 5 cells / 100 μL / well in a 96-well plate and incubated overnight. Thereafter, after 24 hours of pre-treatment with each test substance (sample), further incubation was performed in the presence of 100 mM D-glucose (Sigma Aldrich) for 24 hours. For the control, the same treatment was performed using 100 mM L-glucose. An oxygen probe reagent having a property that the intensity of phosphorescence increases when the oxygen concentration in the culture solution decreases was added at 100 μL to each well. Thereafter, in order to prevent the inflow of oxygen in the air, mineral oil droplets were added to each well. The intensity of phosphorescence was measured using a Cytation 5 microplate reader (BioTek Instruments), and the OCR of the cells was calculated by the Stern-Volmer equation. The OCR improvement rate (%) brought about by each sample was calculated by the following formula.

[0343] [Numeral 6]

[0344]

[0345] That is, the OCR decrease improvement rate (%) represents the proportion (%) obtained by dividing the value obtained by subtracting the OCR value when only D-glucose treatment is performed from the OCR value when D-glucose treatment is performed after sample treatment from the value obtained by subtracting the OCR value when only D-glucose treatment is performed from the OCR value when only L-glucose treatment is performed.

[0346] The kind, the amount of use, and the obtained results of each sample are shown in Table 5. Each sample was used in the form of an aqueous solution. Note that "cinnamon oil" indicates the use of Japanese Pharmacopoeia standard cinnamon oil.

[0347] Note that the concentration of each sample aqueous solution is expressed in % (w / v), but since it is approximately the same as the value of % (w / w) (slightly larger than % (w / w)), it can also be interpreted as % (w / w) (i.e., mass %).

[0348] [Table 5]

[0349]

[0350] As shown in Table 5, it is known that when ubiquinol is used in combination with cinnamon oil or glutamic acid or a salt thereof, both the ATP decrease improvement rate and the OCR decrease improvement rate show excellent values.

[0351] The results shown in Table 5 are also shown in figures. Specifically, the results of the ATP decrease improvement rate of Table 5 are shown in Figure 6a , and the results of the OCR decrease improvement rate of Table 5 are shown in Figure 6b . Note that in this figure, "glutamate" means "sodium L-glutamate".

Claims

1. A compound for use in the improvement of periodontal disease, which is at least one compound selected from the group consisting of: ubiquinol, pantothenic acid or a salt thereof, protamine or a salt thereof, and methionine or a salt thereof.

2. The compound for use in the amelioration of periodontal disease according to claim 1, 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.

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

4. The compound for use in the amelioration of periodontal disease according to any one of claims 1 to 3, wherein, The periodontal disease is periodontal disease of a diabetic patient.

5. A compound for use in the activation of mitochondria, which is at least one compound selected from the group consisting of: ubiquinol, pantothenic acid or a salt thereof, protamine or a salt thereof, and methionine or a salt thereof.

6. The compound for use in the activation of mitochondria according to claim 5, 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.

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

8. The compound for use in the activation of mitochondria according to any one of claims 5 to 7, wherein, The mitochondria are mitochondria in periodontal membrane cells.

9. A compound for use in the improvement of a symptom caused by metabolic disorder due to diabetes, prediabetes, or aging, which is at least one compound selected from the group consisting of: ubiquinol, pantothenic acid or a salt thereof, protamine or a salt thereof, and methionine or a salt thereof.

10. The compound for use in the amelioration of symptoms brought about by metabolic disorders caused by diabetes, prediabetes, or aging according to claim 9, 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.

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

12. The compound for use in amelioration of symptoms brought about by metabolic disorders caused by diabetes, prediabetes, or aging according to any one of claims 9 to 11, wherein, The symptom caused by metabolic disorder due to diabetes, prediabetes, or aging is obesity, renal dysfunction, retinopathy, neurological disorder, cardiovascular disease, brain dysfunction, dementia, frailty, decrease in muscle strength, or osteoporosis.

13. An oral or oral cavity composition containing the compound according to any one of claims 1 to 12.

14. A food composition containing the compound according to any one of claims 1 to 12.

15. The oral cavity composition according to claim 13, which is an ointment, a paste, a skin cream, a gel, a liquid, a spray, a mouthwash, a liquid toothpaste, a paste toothpaste, or a chewing gum.

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