WO2019131774A1 - 活性酸素産生抑制用組成物 - Google Patents
活性酸素産生抑制用組成物 Download PDFInfo
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- WO2019131774A1 WO2019131774A1 PCT/JP2018/047880 JP2018047880W WO2019131774A1 WO 2019131774 A1 WO2019131774 A1 WO 2019131774A1 JP 2018047880 W JP2018047880 W JP 2018047880W WO 2019131774 A1 WO2019131774 A1 WO 2019131774A1
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- composition
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- active oxygen
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- oxygen production
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- CRLGLUGVKCLBNA-YETGTWLTSA-N CCCC[C@@H](C(C)(C)[C@H](CC1)C[C@@H]2[C@]1(C)[C@](C)(CC[C@@]1([C@H]3CC(C)(C)CC1)C(O)=O)C3=CC2)OC(C)=O Chemical compound CCCC[C@@H](C(C)(C)[C@H](CC1)C[C@@H]2[C@]1(C)[C@](C)(CC[C@@]1([C@H]3CC(C)(C)CC1)C(O)=O)C3=CC2)OC(C)=O CRLGLUGVKCLBNA-YETGTWLTSA-N 0.000 description 1
- 0 C[C@](CC1)[C@](C)[*@]2C3=CC[C@]([C@@](C)(CC4)[C@@](CC5)C(C)(C)[C@]4OC(C)=O)[C@]5(C)[C@]3(C)CC[C@@]12C(O)=O Chemical compound C[C@](CC1)[C@](C)[*@]2C3=CC[C@]([C@@](C)(CC4)[C@@](CC5)C(C)(C)[C@]4OC(C)=O)[C@]5(C)[C@]3(C)CC[C@@]12C(O)=O 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
Definitions
- the present invention relates to a composition for suppressing active oxygen production.
- the invention also relates to a method of suppressing the production of active oxygen and the use of a triterpene acid having an acetyl group and / or a salt thereof for suppressing the production of active oxygen.
- the present invention also relates to a composition for suppressing or ameliorating cerebral dysfunction, a method for suppressing or ameliorating cerebral dysfunction and use of a triterpene acid having an acetyl group and / or a salt thereof for suppressing or ameliorating cerebral dysfunction. .
- Oxidative stress refers to a state in which the inside of a living body is in an oxidation state due to increased generation of active oxygen and decreased ability to remove active oxygen. Oxidative stress results in the oxidation of biomolecules such as proteins, DNA and lipids. Oxidation of these biomolecules is known to be involved in functional deterioration of various organs, leading to various diseases (Non-patent Document 1). Therefore, reducing oxidative stress is useful for the prevention, amelioration or treatment of various diseases.
- Reactive oxygen in the living body may be generated by electrons leaked from the mitochondrial electron transfer system or may be generated by an enzyme reaction.
- NADPH oxidase NADPH oxidase: hereinafter, also simply described as NOX
- NOX NADPH oxidase
- NOX is known as an enzyme that generates superoxide which is one of active oxygens. It is known that inhibiting NOX and suppressing the production of active oxygen has the effect of preventing, ameliorating or treating various conditions and diseases caused by active oxygen. For example, it has been reported that the suppression of the generation of superoxide by the inhibition of NOX suppresses the decrease in cognitive function (Non-patent Document 2).
- NOX activity is also known to increase with age, and is considered to be involved in acceleration of age-related diseases and aging phenomena. Suppressing NOX activity is thought to be useful for delaying various age-related diseases and aging phenomena.
- An object of the present invention is to provide a composition for suppressing active oxygen production, which has excellent action.
- an object of the present invention is to provide a composition for suppressing or ameliorating the brain function reduction having an excellent action.
- Inhibiting NOX is considered to be effective as a means for reducing the production of active oxygen and reducing oxidative stress in the body.
- the present inventors have found that triterpene acid having an acetyl group and / or a salt thereof can reduce oxidative stress by suppressing the production of active oxygen, and considered the present invention.
- the present invention relates to the following (1) to (21).
- a composition for suppressing active oxygen production which comprises a triterpene acid having an acetyl group and / or a salt thereof as an active ingredient.
- the composition for suppressing the production of active oxygen according to (1) which suppresses production of active oxygen by inhibiting NADPH oxidase (NOX).
- the triterpene acid having an acetyl group and / or a salt thereof is at least one selected from the group consisting of 3-acetylursolic acid, 3-acetyl oleanolic acid and salts thereof (1) or (2)
- composition for suppressing active oxygen production according to any one of (1) to (3) which is used for the prevention, amelioration or treatment of a condition or disease caused by oxidative stress.
- the composition for suppressing active oxygen production according to any one of (1) to (4) which is used for suppression or improvement of brain function reduction.
- the composition for suppressing active oxygen production according to (5) wherein the decrease in brain function is the decrease in brain function due to aging.
- the condition or disease caused by the oxidative stress or the brain function decline is at least one selected from the group consisting of forgetfulness, cognitive function decline, memory decline, poor judgment, dementia, and Alzheimer's disease
- the composition for active oxygen production suppression as described in (4) or (5) which is a state or a disease.
- Composition. The composition for suppressing active oxygen production according to any one of (1) to (8), which is an oral composition.
- a method for suppressing active oxygen production which comprises administering triterpene acid having an acetyl group and / or a salt thereof to a subject.
- a composition for suppressing or improving brain function deterioration which comprises a triterpene acid having an acetyl group and / or a salt thereof as an active ingredient.
- the triterpene acid having an acetyl group and / or a salt thereof is at least one selected from the group consisting of 3-acetylursolic acid, 3-acetyl oleanolic acid and salts thereof (13) or (14)
- the composition for suppression or improvement of the brain function fall as described in 4.).
- the disease or condition caused by brain dysfunction is at least one condition or disease selected from the group consisting of forgetfulness, cognitive decline, memory decline, judgment loss, dementia, and Alzheimer's disease (13)
- the composition for suppressing or improving the brain function reduction according to (18), wherein the composition for oral use is a food or drink, a medicine or a quasi-drug.
- a method for suppressing or improving cerebral function deterioration which comprises administering triterpene acid having an acetyl group and / or a salt thereof to a subject.
- (21) Use of a triterpene acid having an acetyl group and / or a salt thereof for the suppression or improvement of brain dysfunction.
- the triterpene acid having an acetyl group and / or a salt thereof has a remarkable NOX inhibitory activity, and the inhibitory activity is significantly higher than that of a triterpene acid having no acetyl group, thereby suppressing the production of active oxygen
- the effect is very strong. Therefore, oxidative stress can be reduced more effectively. Therefore, the composition for suppressing active oxygen production of the present invention, which contains triterpene acid having an acetyl group and / or a salt thereof as an active ingredient, is useful for reducing oxidative stress.
- the composition for suppressing active oxygen production of the present invention is useful for suppressing or improving the decrease in brain function.
- the composition for suppressing or improving the brain function decrease of the present invention containing the triterpene acid having an acetyl group and / or the salt thereof as an active ingredient is useful for suppressing or improving the brain function decrease.
- FIG. 1 is a graph showing the light room latency (seconds) of the young control group, the old control group and the old Aronia ingested group in the acquisition trial and the regeneration trial.
- FIG. 2 is a graph showing the light room latency (seconds) of the ursolic acid intake group and the acetyl ursolic acid intake group in the acquisition trial and the regeneration trial.
- the composition for suppressing active oxygen production of the present invention is characterized by containing a triterpene acid having an acetyl group and / or a salt thereof as an active ingredient.
- the triterpene acid having an acetyl group and / or the salt thereof has the effect of suppressing the production of active oxygen. Therefore, oxidative stress can be effectively reduced. Therefore, the composition for suppressing active oxygen production of the present invention, which contains triterpene acid having an acetyl group and / or a salt thereof as an active ingredient, is useful for reducing oxidative stress.
- the composition for suppressing active oxygen production of the present invention can suppress the production of active oxygen by inhibiting NOX. This is due to the effect that the triterpene acid having an acetyl group and / or the salt thereof contained in the composition for suppressing active oxygen production of the present invention functions as an NOX inhibitor.
- oxidative stress due to active oxygen can be suppressed by taking the composition for suppressing active oxygen production of the present invention.
- triterpene acids and / or salts thereof having an acetyl group contained in the composition for suppressing active oxygen production of the present invention include acetyl ursolic acid, acetyl oleanolic acid, acetyl maslinic acid, acetyl asiatic acid, and acetyl betulin. And acids and their salts. Among these, at least one selected from the group consisting of 3-acetylursolic acid, 3-acetyloleanolic acid and a salt thereof in which an acetyl group is bonded to a hydroxyl group at the 3-position is preferable.
- the carboxyl group is not essential if it has an acetyl group, and may be at least one selected from the group consisting of ursan-type triterpenes having an acetyl group, oleanane-type triterpenes, and salts thereof. These compounds have high inhibitory activity on NOX.
- the salt of the triterpene acid having an acetyl group contained in the composition for suppressing active oxygen production of the present invention is not particularly limited, but is preferably orally ingestible.
- examples of such salts include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium; and ammonium salts.
- 3-acetylursolic acid is a compound having a structure represented by the following formula (1).
- 3-acetyl oleanolic acid is a compound having a structure represented by the following formula (2).
- the triterpene acid having an acetyl group and / or the salt thereof contained in the composition for suppressing active oxygen production of the present invention is not particularly limited depending on its origin or production method. For example, those derived from plants extracted from plants may be used, or those obtained by synthesis may be used. Moreover, a commercial item can also be used.
- a triterpene acid having a plant-derived acetyl group and / or a salt thereof is used, the origin thereof is Arona (Aronia), Rubus (Rubus) (Rubus), Rufa (Chaenomeles), Rosaceae Apple (Malus), Rosaceae (Pyrus), Asteraceae (Arctostaphylos), Azalea (Vaccinium), Myrtleidae (Syzygium), Gentianaceae (Swertia), Mokkoaceae Mockoku (Ternstroemia) Or at least one kind of plant selected from the group consisting of Alnus sativus (Ilex), Mucoraceae Ficus (Ficus), Moxaceae Olive (Olea) and Eucommia nematode (Eucommia) It is preferable. These plants contain a large amount of triterpene acid having an acetyl group and / or a salt thereof, and thus are suitable as a raw material of tri
- the triterpene acid and / or the salt thereof having an acetyl group contained in the composition for suppressing active oxygen production is 3-acetylursolic acid, 3-acetyl oleanolic acid or a salt thereof
- the origin thereof is Aronia genus (Aronia), Rosaceae raspberry genus (Rubus), Rosaceae Bokemon genus (Chaenomeles), Mokkomaceous genus Mokkoku (Ternstroemia), Alminaceae Mochincoma genus (Ilex), Culexaceae Ficus genus (Ficus), and Nematode techurus
- 3-acetyl ursolic acid, 3-acetyl oleanolic acid or a salt thereof is a plant of the Rosaceae family Aronia
- a plant of the Rosaceae family Alonia genus is Aronia arbutifolia (Aronia arbutifolia) And Aronia melanocarpa and Aronia x prunifolia.
- Aronia melanocarpa Aronia melanocarpa (Aronia melanocarpa) is also referred to as Chokeberry or Black Chokeberry, as another name.
- triterpene acid which has an acetyl group from a plant, for example, after extracting the raw material containing triterpene acid which has an acetyl group with water-containing ethanol and concentrating an extract, it can obtain by performing column refinement
- composition for suppressing active oxygen production of the present invention may contain any component in addition to the triterpene acid having an acetyl group and / or a salt thereof as long as the effect is not impaired.
- optional components include, for example, physiologically active components such as vitamins, minerals, hormones, proteins, amino acids, carbohydrates, polyunsaturated fatty acids, triglycerides containing the fatty acids in constituent fatty acids, nutritional components, etc.
- Emulsifiers, tonicifiers (tonicity agents), buffers, solubilizers, preservatives, stabilizers, etc. which are compounded in formulation.
- the composition for suppressing active oxygen production of the present invention is preferably used for the prevention, amelioration or treatment of a condition or disease caused by oxidative stress.
- the composition for suppressing active oxygen production of the present invention contains, as an active ingredient, a triterpene acid having an acetyl group and / or a salt thereof.
- triterpene acids having an acetyl group and / or salts thereof can inhibit NOX. Therefore, production of active oxygen can be suppressed, and oxidative stress caused by active oxygen can be suppressed. Therefore, the composition for suppressing active oxygen production of the present invention is useful for preventing, ameliorating or treating a condition or disease caused by oxidative stress.
- preventing a condition or disease refers to enhancing a subject's resistance to the condition or disease, or preventing the onset of the condition or disease.
- “ameliorating or treating a condition or disease” refers to recovering the subject from the condition or disease, reducing the severity of the condition or disease, preventing progression of the condition or disease. Point to
- Conditions or diseases caused by oxidative stress include, for example, nerve cell disorders, intracerebral inflammation, allergic diseases (atopic dermatitis, allergic rhinitis (hay fever), allergic conjunctivitis, allergic gastroenteritis, bronchial asthma, children Asthma, food allergy, drug allergy, urticaria etc.), Parkinson's disease, cerebral infarction, cataract, epilepsy, spinal cord injury, arteriosclerosis, retinopathy of prematurity, chronic renal dysfunction, renal disorder, pancreatitis, myocardial infarction, adult respiratory distress Syndrome, pulmonary emphysema, collagen disease such as rheumatoid arthritis, vasculitis, edema, diabetic complication, ultraviolet disorder, alpine disease, porphyrinemia, burn, frostbite, contact dermatitis, multiple organ failure, disseminated intravascular coagulation (DIC) conditions or diseases such as cancer, aging, fatigue, chronic fatigue syndrome and the like.
- allergic diseases
- composition for suppressing active oxygen production of the present invention is preferably used for the prevention, amelioration or treatment of a condition or disease caused by these oxidative stress.
- nerve cell disorder for example, nerve cell disorder of the brain may be mentioned, and forgetfulness, cognitive function decline, memory decline, concentration decline, attentiveness decline, judgment decline, spatial cognition decline, nerve activity decline And conditions or diseases such as neurotransmission dysfunction, cognitive flexibility, executive dysfunction, information processing speed, depression, dementia, Alzheimer's disease and the like.
- the composition for suppressing active oxygen production according to the present invention is a group or group consisting of forgetfulness, cognitive function decline, memory decline, judgment decline, dementia, and Alzheimer's disease as a condition or disease caused by oxidative stress. Useful for at least one condition or disease selected.
- composition for suppressing active oxygen production of the present invention is suitably used for the prevention, amelioration or treatment of brain dysfunction due to nerve cell injury in the brain, and forgetfulness, cognitive decline, memory decline, judgment ability It is more preferred to use for the prevention, amelioration or treatment of at least one condition or disease selected from the group consisting of depression, dementia and Alzheimer's disease.
- the composition for suppressing active oxygen production of the present invention is preferably used for suppressing or improving the decrease in brain function.
- a condition or disease caused by brain function decline forgetfulness, cognitive function decline, memory decline, concentration decline, attentiveness decline, judgment decline, spatial cognition decline, neuroactivity decline, neurotransmission decline, cognitive softness It includes conditions or diseases such as hypogonadism, executive function depression, information processing speed reduction, depression-like symptoms, dementia, and Alzheimer's disease and the like.
- the composition for suppressing active oxygen production according to the present invention is a group consisting of forgetfulness, cognitive function decline, memory decline, judgment decline, dementia and Alzheimer's disease as a condition or disease caused by brain function decline.
- suppression or improvement of brain function decrease refers to maintaining brain function, suppressing and / or preventing progression of brain function decrease, or improving brain function decrease.
- the decrease in brain function is the decrease in brain function associated with the aging of the subject.
- the composition for suppressing active oxygen production according to the present invention can suppress the production of active oxygen and can suppress oxidative stress caused by active oxygen, thereby suppressing the decline in brain function associated with aging. Or because it is considered to be useful for improvement.
- the composition for suppressing active oxygen production of the present invention may be an oral composition or an external composition.
- the composition for suppressing active oxygen production of the present invention may be used as food and drink, external preparation, medicine or quasi-drug.
- the composition for suppressing active oxygen production of the present invention is preferably a composition for oral use, for example, food and drink, medicine (oral medicine) or quasi drug (oral quasi drug) Is more preferred.
- composition for active oxygen production suppression of this invention may be a composition for raw materials used as raw materials, such as these food-drinks, external preparation, a pharmaceutical, or a quasi-drug.
- food and drink is a general term for solids, fluids and liquids, and mixtures thereof, which can be taken orally.
- Examples of food and drink include food for specified health use, food for functional indication, nutritive function food, nutritional supplement food, health food, functional food, food for infants, food for elderly people and the like.
- Foods for specified health use are those who take in food for the purpose of specific health in the diet after receiving the permission under Article 26 paragraph 1 of the Health Promotion Act or the approval under Article 29 paragraph 1 of the law It means a food that indicates that the purpose of the health can be expected by ingestion.
- Functionally labeled food refers to food that displays scientifically based functionality at the employer's responsibility, based on food labeling standards Article 2 (1) (x). Information on the basis of safety and functionality before sales is said to have been sent to the Secretary General of the Consumer Agency.
- the nutritive function food is a food that can be used for supplementation / supplementation when there is a tendency that the nutritional components necessary for one day are insufficient.
- the form of food-drinks is not specifically limited, It can be set as various forms.
- supplements for example, oral solid preparations such as tablets, coated tablets, fine granules, granules, powders, pills, capsules (including soft capsules and hard capsules), dry syrups, chewables, etc .; It can also be in the form of various preparations of liquid preparations for oral use such as syrups.
- conventional coated forms may be used, for example, sugar-coated tablets, gelatin capsules, enteric-coated agents, film-coating agents, etc.
- the tablets can also be multi-layered tablets such as double tablets.
- the composition for suppressing active oxygen production according to the present invention when used as a food or drink, the food or drink includes a stevia extract, a sweetener such as acesulfame potassium or sucralol, a sugar such as sucrose, malic acid or citric acid anhydride Etc., dietary fibers such as indigestible dextrin, flavors and colorants may be included.
- a stevia extract such as acesulfame potassium or sucralol
- a sugar such as sucrose, malic acid or citric acid anhydride Etc.
- dietary fibers such as indigestible dextrin, flavors and colorants may be included.
- the composition for suppressing active oxygen production of the present invention is used as an external preparation, it is preferably used as a composition for external use on the skin.
- the composition for suppressing active oxygen production according to the present invention is a tape, an ointment, a face wash (face wash cosmetic), a lotion, a pack, a massage cream, a milky lotion, an emulsion, a cream , Skin care cosmetics such as essence (beauty liquid), soaps, liquid detergents, bath additives, sunscreen creams, sun oils, deodorant sprays, body care cosmetics such as body lotions, body creams, hand creams etc. it can.
- the cosmetic may further contain a carrier and an excipient that can be used for the cosmetic.
- the route of administration of the drug or quasi-drug may be either oral or parenteral administration, preferably oral administration.
- parenteral administration include administration by transdermal, topical, nasal, sublingual, pulmonary, enteral, transmucosal, injection and the like.
- the dosage form of the preparation for oral administration includes liquid, tablets, powders, pills, fine granules, granules, dragees, capsules, suspensions, emulsions, syrups, extracts, emulsions, microcapsules , Troches, lozenges, buccal agents, chewable agents and the like.
- the dosage form of the preparation for parenteral administration includes aerosols, injections, drops, inhalants, infusions, suppositories, transdermal absorption agents, nasal drops, eye drops, patches, creams, gels And lotions.
- the composition for suppressing the generation of active oxygen of the present invention may be used alone, and other pharmaceuticals or quasi-drugs You may use together.
- the composition for suppressing active oxygen production of the present invention is used as a drug or quasi drug
- the drug or quasi drug comprises a pharmaceutically acceptable carrier, excipient, buffer, binder. And at least one additive selected from the group consisting of disintegrants, lubricants, antioxidants, and colorants.
- composition for suppressing active oxygen production of the present invention may be used in the form of an agent, as one example, but is not limited to this form.
- the agent may be used as it is as a composition for suppressing active oxygen production or may be used as a composition for suppressing active oxygen production containing the agent.
- the content of the triterpene acid having an acetyl group and / or the salt thereof is not particularly limited, and may be set according to the form.
- the content is preferably 0.01% by weight or more, more preferably 0.1 to 99% by weight, and still more preferably 1 to 70% by weight.
- the content is the total of two or more triterpene acids having an acetyl group and / or salts thereof if they are contained.
- the daily intake amount of triterpene acid having an acetyl group and / or a salt thereof is 0.01 to 200 mg, The concentration is more preferably 1 to 100 mg, and in one aspect, 8 to 17 mg. In the case where two or more types of triterpene acids having an acetyl group and / or salts thereof are ingested with respect to the above intake amount, the total of them.
- the amount of triterpene acid and / or salt thereof having an acetyl group per day is 0.01 to It is preferably 200 mg and more preferably 0.1 to 100 mg. Also, this amount may be used at one time or may be divided and used several times. When two or more kinds of triterpene acids having an acetyl group and / or a salt thereof are used, the total amount of them is used.
- composition for suppressing the generation of active oxygen is expected to enhance the effect of suppressing the generation of active oxygen by continuously taking (administering) the composition.
- the composition for suppressing active oxygen production of the present invention is one which is continuously ingested.
- the composition for suppressing active oxygen production is preferably continuously taken for at least two weeks or more. More preferably, it is taken continuously for 12 weeks or more.
- composition for suppressing active oxygen production of the present invention As a subject to which the composition for suppressing active oxygen production of the present invention is to be ingested or administered, a human or non-human mammal is preferable. Moreover, the object which wants or requires suppression of active oxygen is mentioned as a target made to take in or administer the composition for active oxygen production suppression of this invention. In one aspect, a subject who wants or needs prevention, amelioration or treatment of the above-mentioned condition or disease caused by oxidative stress can be mentioned.
- composition for suppressing the generation of active oxygen of the present invention may be labeled as preventing, ameliorating or treating a condition or disease caused by oxidative stress or brain function deterioration.
- a condition or disease caused by oxidative stress or brain function deterioration.
- the display of may be attached.
- the present invention also encompasses the following methods and uses. That is, the active oxygen production suppression method which administers triterpene acid and / or its salt which has an acetyl group to a subject is also one of the present invention. In addition, the use of a triterpene acid having an acetyl group and / or a salt thereof for suppressing the production of active oxygen is also one of the present invention.
- the intake (dosage amount), administration subject, and preferred embodiments thereof are the same as in the case of the composition for suppressing active oxygen production.
- the above methods and uses may be therapeutic methods and uses, and may be non-therapeutic methods and uses. "Non-therapeutic" is a concept that does not include medical practice, i.e. surgery, treatment or diagnosis.
- the present invention provides a composition for suppressing or improving brain dysfunction, a method for suppressing or improving brain dysfunction, and a triterpene acid having an acetyl group for suppressing or improving brain dysfunction and / or the like It also includes the use of salt. That is, a composition for suppressing or improving brain function deterioration comprising triterpene acid having an acetyl group and / or a salt thereof as an active ingredient is also one of the present invention.
- the triterpene acid having an acetyl group and / or the salt thereof in the composition for suppressing or improving the brain function deterioration and the triterpene acid having an acetyl group and / or a salt thereof used in the composition for suppressing active oxygen production of the present invention Similar ones can be used. Among them, at least one selected from the group consisting of 3-acetyl ursolic acid, 3-acetyl oleanolic acid and a salt thereof in which an acetyl group is bonded to a hydroxyl group at position 3 is preferable.
- the composition for suppressing or improving cerebral function decline according to the present invention is at least one condition selected from the group consisting of forgetfulness, cognitive function decline, memory decline, judgment decline, dementia, and Alzheimer's disease. Or it is useful for diseases, and among these, it is useful for suppressing or improving cognitive function, particularly memory function decline.
- composition for suppressing or improving the brain function deterioration of the present invention may contain any component in addition to the triterpene acid having an acetyl group and / or a salt thereof as long as the effect is not impaired.
- the same components as optional components contained in the composition for suppressing active oxygen production of the present invention can be used.
- the composition for suppressing or improving the brain function reduction of the present invention may be a composition for oral use or a composition for the same as the composition for suppressing active oxygen production of the present invention, and it may be food, drink, external use It may be used as a medicine, medicine or quasi drug.
- the method for producing the composition is not particularly limited. It can be the same.
- composition for suppressing or improving the brain function reduction of the present invention may be used in the form of an agent as one example, but is not limited to the present form.
- the agent may be used as it is as a composition for suppressing or improving brain function decrease, or may be used as a composition for suppressing or improving brain function decrease including the agent.
- the composition for suppressing or improving the brain function decrease of the present invention is a raw material composition, triterpene acid having an acetyl group in the same blending amount as the raw material composition in the composition for active oxygen production suppression of the present invention And / or their salts can be included.
- the intake amount of triterpene acid and / or its salt having an acetyl group per day intake (administration)
- Methods and intake (administration) subjects can be the same as in the case of the composition for suppressing active oxygen production.
- composition for suppressing or improving the brain function decrease can be used to suppress or improve the brain function decrease due to aging.
- composition for suppressing or improving the brain function decrease of the present invention may have an indication indicating that it is for the prevention, amelioration or treatment of a condition or disease caused by the brain function decrease.
- a condition or disease caused by the brain function decrease.
- the display of may be attached.
- a method for suppressing or improving cerebral function deterioration which comprises administering triterpene acid having an acetyl group and / or a salt thereof to a subject is also one of the present invention.
- the decrease in brain function may be a decrease in brain function due to aging.
- the use of a triterpene acid having an acetyl group and / or a salt thereof for suppressing or improving brain dysfunction is also one of the present invention.
- the decrease in brain function may be a decrease in brain function due to aging.
- the intake (dosage amount), administration subject, and preferred embodiments thereof are the same as in the case of the composition for suppressing active oxygen production.
- the above methods and uses may be therapeutic methods and uses, and may be non-therapeutic methods and uses. "Non-therapeutic" is a concept that does not include medical practice, i.e. surgery, treatment or diagnosis.
- Example 1 Measurement of NOX inhibitory activity using a preparation (1) Preparation of differentiated HL-60 cells Human myeloid leukemia cells HL-60 cells repeat proliferation in an undifferentiated state, but are added to mature granulocytes by adding DMSO (dimethyl sulfoxide) or retinoic acid. It is known that NOX, which is an indicator of differentiation, as well as proliferative capacity is expressed intracellularly. This NOX can be used as an index for evaluating NOX inhibitory activity.
- DMSO dimethyl sulfoxide
- HL-60 cells were differentiated into NOX expressing granulocytes by the following method.
- undifferentiated HL-60 cells cultured in RPMI 1640 medium containing 10% FBS were suspended at 5 ⁇ 10 5 cells / mL in RPMI 1640 medium containing 10% FBS containing 1% DMSO. Thereafter, the suspension was divided into 15 mL aliquots in petri dishes with an inner diameter of 10 cm, and cultured in a CO 2 incubator (37 ° C.) for 3 days. Thereafter, RPMI 1640 medium containing 10% FBS containing 10 mL of 1% DMSO was added to each petri dish and cultured for further 3 days.
- HL-60 cells were differentiated into granulocytes expressing NOX. The differentiated HL-60 cells were used for measurement of NOX inhibitory activity described later.
- test sample solution group of 3-acetyl oleanolic acid 3-acetyl oleanolic acid is dissolved in DMSO so that the concentration of 3-acetyl oleanolic acid is 2.5 mg / mL, and DMSO is used here.
- DMSO is used here
- test sample solution group of ursolic acid Ursolic acid is dissolved in DMSO so that the concentration of ursolic acid is 5 mg / mL, and a 2-fold dilution series of solution is prepared from this using DMSO. Further, each solution was diluted with D-MEM medium to prepare test sample solution groups of ursolic acid at final concentrations of 50, 25, 12.5, 6.3, 3.1, and 1.6 ⁇ M.
- test sample solution group of oleanolic acid Oleanolic acid is dissolved in DMSO so that the concentration of oleanolic acid is 5 mg / mL, and a 2-fold dilution series solution is prepared from this using DMSO. Further, each solution was added to D-MEM medium to prepare test sample solution groups of oleanolic acid at final concentrations of 50, 25, 12.5, 6.3, 3.1, and 1.6 ⁇ M.
- WST-1 (2- (4-Iodophenyl) -3- (4-nitrophenly) -5- (2,4-disulfophenyl) to a concentration of 0.8 mg / mL -2H-tetrazolium, monosodium salt) was dissolved in D-MEM medium to prepare a WST-1 solution.
- WST-1 reacts with superoxide to form yellow formazan. Since yellow formazan absorbs light at a wavelength of 450 nm, the amount of formation of yellow formazan can be measured by measuring the absorbance at a wavelength of 450 nm. Further, since the amount of formation of yellow formazan is proportional to the amount of superoxide at the time of reaction, the amount of superoxide can be measured by measuring the amount of formation of yellow formazan.
- PMA Phorbol 12-Myristate 13-acetate
- the differentiated HL-60 cells were collected by centrifugation and suspended in D-MEM medium not containing FBS and phenol red to a concentration of 5 ⁇ 10 6 cells / mL. Next, 25 ⁇ L of the above cell suspension was poured into a 96-well microplate per well. Next, 25 ⁇ L of the WST-1 solution prepared as described above was added to the wells.
- each solution of the test sample solution group of 3-acetylursolic acid prepared, each solution of the test sample solution group of 3-acetyloleanolic acid, each solution of the test sample solution group of ursolic acid, test sample solution group of oleanolic acid Or 25 ⁇ l of DMEM medium was added to the wells. The cell suspension was stirred after each solution was added. Thereafter, 25 ⁇ L of the prepared PMA solution was added (final concentration of PMA in culture medium: 1 ⁇ M) to activate NOX, and a reaction was performed at 37 ° C. for 60 minutes.
- 3-acetylursolic acid and 3-acetyl oleanolic acid have the same NOx inhibitory activity as VAS 2870 (described above) known as an NOx inhibitor, and further have an acetyl group. It was found to have high NOX inhibitory activity as compared to not ursolic acid and oleanolic acid. From this, it was shown that 3-acetylursolic acid and 3-acetyl oleanolic acid are useful as active ingredients of the composition for suppressing active oxygen production. In addition, it became clear that the acetylation of triterpenes can enhance the NOX inhibitory activity.
- Example 2 Measurement of NOX inhibitory activity using plant extract>
- Preparation of Alonia Extract The pressed pods of the Rosaceae family Aronia melanocarpa were lyophilized and then crushed. The crushed material was extracted with aqueous ethanol, filtered and concentrated under reduced pressure to obtain an extract powder. The extract powder was dissolved in water and extracted with ethyl acetate five times. The ethyl acetate transition was subjected to Diaion HP-20 and eluted with different concentrations of aqueous ethanol. The ethanol eluate was subjected to Silica gel 60N, and eluted with hexane / ethyl acetate mixtures of different concentrations. The eluates were successively confirmed by thin layer chromatography, and the eluates having the same spot pattern were combined to form one fraction. This gave several fractions.
- the compound was determined by comparing the retention time of the peak in the chromatogram of each fraction with the retention time of each standard.
- the retention time of each compound under the above analysis conditions was: oleanolic acid, 11.42 min; ursolic acid, 11.94 min; 3-acetyl oleanolic acid, 16.77 min; 3-acetylursolic acid, 17.53 min.
- the fraction containing ursolic acid and oleanolic acid is defined as the triterpene acid fraction without acetyl group (fraction 1), and the fraction containing 3-acetylursolic acid and 3-acetyl oleanolic acid is acetylated. It was set as the triterpene acid fraction (fraction 2) which has group.
- the IC 50 of fraction 1 was 80 ⁇ g / mL, and the IC 50 of fraction 2 was 4 ⁇ g / mL. Furthermore, using the formula of (i), the inhibitory activity ratio of the triterpene acid having an acetyl group in fraction 2 to the triterpene acid without an acetyl group in fraction 1 was calculated. The results are shown in Table 2.
- triterpene acids having an acetyl group in fraction 2 were found to have higher NOX inhibitory activity compared to triterpene acids without an acetyl group in fraction 1.
- ⁇ Reference example 1 Brain function evaluation using aging promotion model> The brain function depression inhibitory effect of the Alonia extract was evaluated using the extract powder obtained in Example 2. Senescent Accelerated Model Prone 10 (SAMP10) mice, one of accelerated aging models, are known to show early age-related brain dysfunction and to evaluate the effects on age-related decline in brain function it can. Therefore, using this animal, the brain function improving effect of Alonia extract was examined. A series of animal experiments were conducted based on a plan approved by the head of the organization after reviewing the in-house animal experiment committee in compliance with the Animal Welfare Management Act and other related laws and regulations.
- SAMP10 Senescent Accelerated Model Prone 10
- Brain function evaluation test (passive avoidance test) Brain function was assessed using a passive avoidance test (step-through test).
- the passive avoidance response is a learning behavior that escapes from unpleasant stimuli, and the passive avoidance test is known as a system that can evaluate brain functions such as memory function.
- (1-1) 30 seconds after the acquisition trial mouse is placed in the bright room (width 9 cm, depth 11.5 cm, height 15 cm) of the step-through type passive avoidance reaction apparatus (manufactured by Muromachi Kikai) The door of a dark room (14 cm wide, 17.5 cm deep, 15 cm high) was opened and the time (light latencies) until the mouse entered the dark room was measured.
- Example 3 Comparison of Ursolic Acid and Acetyl Ursolic Acid Using Aging Acceleration Model
- the brain function improving effects of ursolic acid and acetyl ursolic acid contained in Alonia were compared by recovery of light room latency.
- SAMP10 mice were purchased at 14 weeks of age and acclimated to 8 months of age, then randomly divided into 2 groups and AIN-93M diet containing 0.006% ursolic acid or AIN- containing 0.002% acetyl ursolic acid
- ursolic acid and acetyl ursolic acid have an inhibitory effect on brain function decline with aging, and triterpenic acid having an acetyl group has suppressive effect on brain function decline with aging as compared to triterpene acids having no acetyl group.
- triterpenic acid having an acetyl group has suppressive effect on brain function decline with aging as compared to triterpene acids having no acetyl group.
- composition for suppressing active oxygen production of the present invention is useful in the field of food and drink, in the field of medicine, and the like.
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Abstract
Description
そのため、酸化ストレスを低下させることは種々の疾患の予防、改善又は治療に有用である。
NOXを阻害し、活性酸素の産生を抑制することにより、活性酸素が原因となる様々な状態や疾患の予防、改善、又は治療効果があることが知られている。例えば、NOXの阻害によるスーパーオキシドの発生抑制は、認知機能の低下を抑制するという報告がある(非特許文献2)。
本発明者らは、アセチル基を有するトリテルペン酸及び/又はその塩が、活性酸素の産生を抑制することで酸化ストレスを低減することができることを見出し、本発明に想到した。
(1)アセチル基を有するトリテルペン酸及び/又はその塩を有効成分として含む活性酸素産生抑制用組成物。
(2)NADPHオキシダーゼ(NOX)を阻害することにより活性酸素の産生を抑制する(1)に記載の活性酸素産生抑制用組成物。
(3)上記アセチル基を有するトリテルペン酸及び/又はその塩が、3-アセチルウルソル酸、3-アセチルオレアノール酸及びこれらの塩からなる群から選択される少なくとも1種である(1)又は(2)に記載の活性酸素産生抑制用組成物。
(4)酸化ストレスに起因する状態又は疾患の予防、改善、若しくは、治療のために使用される(1)~(3)のいずれかに記載の活性酸素産生抑制用組成物。
(5)脳機能低下の抑制又は改善のために使用される(1)~(4)のいずれかに記載の活性酸素産生抑制用組成物。
(6)上記脳機能低下が、加齢による脳機能低下である(5)に記載の活性酸素産生抑制用組成物。
(7)上記酸化ストレス若しくは上記脳機能低下に起因する状態又は疾患が、もの忘れ、認知機能低下、記憶力低下、判断力低下、認知症、及び、アルツハイマー病からなる群から選択される少なくとも1つの状態又は疾患である(4)又は(5)に記載の活性酸素産生抑制用組成物。
(8)酸化ストレス若しくは脳機能低下に起因する状態又は疾患の予防、改善、若しくは、治療用である旨の表示を付した、(1)~(7)のいずれかに記載の活性酸素産生抑制用組成物。
(9)経口用組成物である(1)~(8)のいずれかに記載の活性酸素産生抑制用組成物。
(10)上記経口用組成物が、飲食品、医薬品又は医薬部外品である(9)に記載の活性酸素産生抑制用組成物。
(11)アセチル基を有するトリテルペン酸及び/又はその塩を対象に投与する、活性酸素産生抑制方法。
(12)活性酸素の産生を抑制するための、アセチル基を有するトリテルペン酸及び/又はその塩の使用。
(13)アセチル基を有するトリテルペン酸及び/又はその塩を有効成分として含む脳機能低下の抑制又は改善用組成物。
(14)加齢による脳機能低下の抑制又は改善のために使用される(13)に記載の脳機能低下の抑制又は改善用組成物。
(15)前記アセチル基を有するトリテルペン酸及び/又はその塩が、3-アセチルウルソル酸、3-アセチルオレアノール酸及びこれらの塩からなる群から選択される少なくとも1種である(13)又は(14)に記載の脳機能低下の抑制又は改善用組成物。
(16)脳機能低下に起因する疾患又は状態が、もの忘れ、認知機能低下、記憶力低下、判断力低下、認知症、及び、アルツハイマー病からなる群から選択される少なくとも1つの状態又は疾患である(13)~(15)のいずれかに記載の脳機能低下の抑制又は改善用組成物。
(17)脳機能低下に起因する状態又は疾患の予防、改善、若しくは、治療用である旨の表示を付した、(13)~(16)のいずれか一項に記載の脳機能低下の抑制又は改善用組成物。
(18)経口用組成物である(13)~(17)のいずれかに記載の脳機能低下の抑制又は改善用組成物。
(19)前記経口用組成物が、飲食品、医薬品又は医薬部外品である(18)に記載の脳機能低下の抑制又は改善用組成物。
(20)アセチル基を有するトリテルペン酸及び/又はその塩を対象に投与する脳機能低下の抑制又は改善方法。
(21)脳機能低下の抑制又は改善のための、アセチル基を有するトリテルペン酸及び/又はその塩の使用。
また、アセチル基を有するトリテルペン酸及び/又はその塩を有効成分として含む本発明の脳機能低下の抑制又は改善用組成物は、脳機能低下の抑制又は改善のために有用である。
本発明の活性酸素産生抑制用組成物は、アセチル基を有するトリテルペン酸及び/又はその塩を有効成分として含むことを特徴とする。
アセチル基を有するトリテルペン酸及び/又はその塩は、活性酸素の産生を抑制する効果を有する。そのため、効果的に酸化ストレスを低減することができる。従って、アセチル基を有するトリテルペン酸及び/又はその塩を有効成分として含む本発明の活性酸素産生抑制用組成物は、酸化ストレスを低減するために有用である。
これは、本発明の活性酸素産生抑制用組成物に含まれるアセチル基を有するトリテルペン酸及び/又はその塩がNOXの阻害剤として機能する効果によるものである。
これらの化合物は、NOXに対して高い阻害活性を有する。
植物由来のアセチル基を有するトリテルペン酸及び/又はその塩を用いる場合、その由来は、バラ科アロニア属(Aronia)、バラ科キイチゴ属(Rubus)、バラ科ボケ属(Chaenomeles)、バラ科リンゴ属(Malus)、バラ科ナシ属(Pyrus)、ツツジ科クマコケモモ属(Arctostaphylos)、ツツジ科スノキ属(Vaccinium)、フトモモ科フトモモ属(Syzygium)、リンドウ科センブリ属(Swertia)、モッコク科モッコク属(Ternstroemia)、モチノキ科モチノキ属(Ilex)、クワ科イチジク属(Ficus)、モクセイ科オリーブ属(Olea)及びトチュウ科トチュウ属(Eucommia)からなる群から選択される少なくとも1種の植物であることが好ましい。
これらの植物はアセチル基を有するトリテルペン酸及び/又はその塩を多く含むので、アセチル基を有するトリテルペン酸及び/又はその塩の原料として適している。
なお、アロニア・メラノカルパ(Aronia melanocarpa)は、別名称として、チョークベリー(Chokeberry)や、ブラックチョークベリー(Black Chokeberry)とも呼ばれる。アセチル基を有するトリテルペン酸を植物から抽出する場合、例えば、アセチル基を有するトリテルペン酸を含む原料を含水エタノールで抽出し、抽出液を濃縮したのち、カラム精製を行うことで得ることができる。
本発明の活性酸素産生抑制用組成物は、酸化ストレスに起因する状態又は疾患の予防、改善、若しくは、治療のために使用することが好ましい。
本発明の活性酸素産生抑制用組成物は、アセチル基を有するトリテルペン酸及び/又はその塩を有効成分として含む。
上記の通り、アセチル基を有するトリテルペン酸及び/又はその塩は、NOXを阻害することができる。そのため、活性酸素の産生を抑制することができ、活性酸素に起因する酸化ストレスを抑制することができる。
従って、本発明の活性酸素産生抑制用組成物は、酸化ストレスに起因する状態又は疾患を予防、改善、若しくは、治療するために有用である。
また、本明細書で「状態又は疾患を改善若しくは治療する」とは、対象を状態又は疾患から回復させること、状態又は疾患の重篤度を軽減すること、状態又は疾患の進行を防止することを指す。
また、本発明の活性酸素産生抑制用組成物は、脳の神経細胞障害による脳機能障害の予防、改善、又は治療のために好適に使用され、もの忘れ、認知機能低下、記憶力低下、判断力低下、認知症、及び、アルツハイマー病からなる群から選択される少なくとも1つの状態又は疾患の予防、改善、若しくは、治療のために使用することがより好ましい。
脳機能低下に起因する状態又は疾患として、もの忘れ、認知機能低下、記憶力低下、集中力低下、注意力低下、判断力低下、空間認識力低下、神経活動性低下、神経伝達機能低下、認知柔軟性低下、実行機能低下、情報処理速度低下、鬱様症状、認知症、及び、アルツハイマー病等のような状態又は疾患が挙げられる。なかでも、本発明の活性酸素産生抑制用組成物は、脳機能低下に起因する状態又は疾患として、もの忘れ、認知機能低下、記憶力低下、判断力低下、認知症、及び、アルツハイマー病からなる群から選択される少なくとも1つの状態または疾患に有用である。
なお、本明細書で「脳機能低下の抑制又は改善」とは、脳機能を維持すること、脳機能低下の進行を抑制及び/又は防止すること、又は、脳機能低下を改善することを指す。
また、脳機能低下は、対象の加齢に伴う脳機能低下であることが好ましい。上記のように加齢に伴い、NOX活性が上昇することから生体内で活性酸素が増加する。
本発明の活性酸素産生抑制用組成物は、活性酸素の産生を抑制することができ、活性酸素に起因する酸化ストレスを抑制することができるため、これにより、加齢に伴う脳機能低下の抑制又は改善に有用であると考えられるためである。
また、本発明の活性酸素産生抑制用組成物は、飲食品、外用剤、医薬品又は医薬部外品として使用してもよい。
中でも、本発明の活性酸素産生抑制用組成物は、経口用組成物であることが好ましく、例えば、飲食品、医薬品(経口用医薬品)又は医薬部外品(経口用医薬部外品)とすることがより好ましい。
飲食品の例としては、特定保健用食品、機能性表示食品、栄養機能食品、栄養補助食品、健康食品、機能性食品、乳幼児用食品、老人用食品等が挙げられる。
機能性表示食品とは、食品表示基準第二条第一項第十号に基づき、事業者の責任において、科学的根拠に基づいた機能性を表示した食品をいう。販売前に安全性及び機能性の根拠に関する情報などが消費者庁長官に届け出られたものをいう。
栄養機能食品とは、一日に必要な栄養成分が不足しがちな場合、その補給・補完のために利用できる食品をいう。
皮膚外用組成物として使用する場合、本発明の活性酸素産生抑制用組成物は、テープ剤、軟膏剤、洗顔料(洗顔用化粧料)、化粧水、パック、マッサージクリーム、ミルキーローション、乳液、クリーム、エッセンス(美容液)等のスキンケア化粧料、石鹸、液体洗浄料、入浴剤、日焼け止めクリーム、サンオイル、デオドラントスプレー、ボディローション、ボディクリーム、ハンドクリーム等のボディケア化粧料として調製することができる。
また、化粧料は、さらに化粧料に使用可能な担体や賦形剤を含んでいてもよい。
非経口投与の例としては経皮、局所、経鼻、舌下、経肺、経腸、経粘膜、注射等による投与が挙げられる。
経口投与のための製剤の剤型としては、液剤、錠剤、散剤、丸剤、細粒剤、顆粒剤、糖衣錠、カプセル剤、懸濁液、乳剤、シロップ剤、エキス剤、エマルジョン、マイクロカプセル剤、トローチ剤、飴剤、バッカル剤、チュアブル剤等が挙げられる。
非経口投与のための製剤の剤型としては、エアロゾール剤、注射剤、点滴、吸入剤、輸液剤、坐薬、経皮吸収剤、点鼻剤、点眼剤、パップ剤、湿布、クリーム、ゲル、ローション等が挙げられる。
さらに、本発明の活性酸素産生抑制用組成物を医薬品又は医薬部外品として使用する場合、当該医薬品又は医薬部外品は、医薬的に許容可能な担体、賦形剤、緩衝剤、結合剤、崩壊剤、滑沢剤、抗酸化剤、着色剤から成る群より選択されるいずれか一つ以上の添加剤を含んでいてもよい。
上記含有量は、アセチル基を有するトリテルペン酸及び/又はその塩が2種以上含まれる場合には、それらの合計である。
上記摂取量に関して、アセチル基を有するトリテルペン酸及び/又はその塩を2種以上摂取する場合には、それらの合計である。
上記使用量に関して、アセチル基を有するトリテルペン酸及び/又はその塩を2種以上使用する場合には、それらの合計である。
また、本発明の活性酸素産生抑制用組成物を摂取又は投与させる対象として、活性酸素の抑制を希望する又は必要とする対象が挙げられる。
一態様として、上述した酸化ストレスに起因する状態又は疾患の予防、改善又は治療を希望する又は必要とする対象が挙げられる。
すなわち、アセチル基を有するトリテルペン酸及び/又はその塩をを対象に投与する活性酸素産生抑制方法も本発明の1つである。
また、活性酸素の産生を抑制するためのアセチル基を有するトリテルペン酸及び/又はその塩の使用も本発明の一つである。
すなわち、アセチル基を有するトリテルペン酸及び/又はその塩を有効成分として含む脳機能低下の抑制又は改善用組成物も本発明の1つである。
本発明の脳機能低下の抑制又は改善用組成物が、上記飲食品、外用剤、医薬品又は、医薬部外品として使用される場合その製造方法は特に限定されず、活性酸素抑制用組成物と同様とすることができる。
また、本発明の脳機能低下の抑制又は改善用組成物が原料組成物である場合、本発明の活性酸素産生抑制用組成物における原料組成物と同様の配合量にてアセチル基を有するトリテルペン酸及び/又はその塩を含有させることができる。
また、脳機能低下を抑制又は改善するためのアセチル基を有するトリテルペン酸及び/又はその塩の使用も本発明の1つである。この場合、脳機能低下は加齢による脳機能低下であってよい。
上記方法及び使用におけるアセチル基を有するトリテルペン酸及び/又はその塩について、その摂取量(投与量)、投与対象及びこれらの好ましい態様は、上記活性酸素産生抑制用組成物の場合と同じである。上記方法及び使用は、治療的な方法及び使用であってもよく、非治療的な方法及び使用であってもよい。「非治療的」とは、医療行為、すなわち手術、治療又は診断を含まない概念である。
以下、実施例を示し、本発明の活性酸素産生抑制用組成物をより具体的に説明するが、本発明の範囲は、これらの実施例によって限定されるものではない。
(1)分化させたHL-60細胞の調製
ヒト骨髄性白血病細胞HL-60細胞は未分化状態で増殖を繰り返すが、DMSO(dimethyl sulfoxide)やレチノイン酸などを添加することにより成熟顆粒球に分化し、増殖能を失うとともに、分化の指標ともなっているNOXが細胞内に発現することが知られている。このNOXは、NOX阻害活性を評価するための指標として利用することができる。
まず、10%FBS含有RPMI1640培地で培養した未分化HL-60細胞を、1%DMSOを含有する10%FBS含有RPMI1640培地に5×105cells/mLとなるように懸濁した。その後、当該懸濁液を内径10cmのシャーレに15mLずつ分注してCO2インキュベータ(37℃)において3日間培養させた。
その後、10mLの1%DMSOを含有する10%FBS含有RPMI1640培地を各シャーレに追加して、さらに3日間培養した。
以上の工程を経て、HL-60細胞を、NOXを発現する顆粒球へと分化させた。
この分化したHL-60細胞を後述するNOX阻害活性の測定に用いた。
3-アセチルウルソル酸、3-アセチルオレアノール酸、ウルソル酸、オレアノール酸は市販の標品を用いた。
(2-1)3-アセチルウルソル酸の被験サンプル溶液群の調製
3-アセチルウルソル酸の濃度が2.5mg/mLとなるように、3-アセチルウルソル酸をDMSOに溶解させ、ここからDMSOを用いて2倍希釈系列の溶液を調製し、さらに各溶液をD-MEM培地で希釈し、終濃度が25、12.5、6.3、3.1、1.6μMの3-アセチルウルソル酸の被験サンプル溶液群を調製した。
3-アセチルオレアノール酸の濃度が2.5mg/mLとなるように、3-アセチルオレアノール酸をDMSOに溶解させ、ここからDMSOを用いて2倍希釈系列の溶液を調製し、さらに各溶液をD-MEM培地で希釈し、終濃度が25、12.5、6.3、3.1、1.6μMの3-アセチルオレアノール酸の被験サンプル溶液群を作製した。
ウルソル酸の濃度が5mg/mLとなるように、ウルソル酸をDMSOに溶解させ、ここからDMSOを用いて2倍希釈系列の溶液を調製し、さらに各溶液をD-MEM培地で希釈し、終濃度が50、25、12.5、6.3、3.1、1.6μMのウルソル酸の被験サンプル溶液群を調製した。
オレアノール酸の濃度が5mg/mLとなるように、オレアノール酸をDMSOに溶解させ、ここからDMSOを用いて2倍希釈系列の溶液を調製し、さらに各溶液をD-MEM培地に加え、終濃度が50、25、12.5、6.3、3.1、1.6μMのオレアノール酸の被験サンプル溶液群を調製した。
0.8mg/mLとなるように、WST-1(2-(4-Iodophenyl)-3-(4-nitrophenly)-5-(2,4-disulfophenyl)-2H-tetrazolium,monosodium salt)を、D-MEM培地に溶解し、WST-1溶液を調製した。
WST-1はスーパーオキシドと反応し、黄色フォルマザンを生成することになる。黄色フォルマザンは波長450nmの光を吸収するので、波長450nmの吸光度を測定することにより、黄色フォルマザンの生成量を測定することができる。また、黄色フォルマザンの生成量と、反応時のスーパーオキシドの量とは比例するので、黄色フォルマザンの生成量を測定することにより、スーパーオキシドの量を測定することができる。
4μMとなるようにPMA(Phorbol 12-Myristate 13-acetate)をD-MEM培地に溶解し、PMA溶液を調製した。
PMAは、NOXを活性化し、スーパーオキシドを生じさせる機能を有することが知られている。
上記の分化させたHL-60細胞を遠心処理により集め、FBS及びフェノールレッドを含まないD-MEM培地に5×106cells/mLとなるように懸濁した。
次に、96wellのマイクロプレートに1wellあたり25μLの上記細胞懸濁液を注いだ。
次に、前述のように調製したWST-1溶液25μLをwellに添加した。
さらに、調製した3-アセチルウルソル酸の被験サンプル溶液群の各溶液、3-アセチルオレアノール酸の被験サンプル溶液群の各溶液、ウルソル酸の被験サンプル溶液群の各溶液、オレアノール酸の被験サンプル溶液群の各溶液、又は、DMEM培地25μLをwellに添加した。
各溶液を添加後、細胞懸濁液を撹拌した。
その後、調製したPMA溶液を25μL添加(培地中のPMA終濃度1μM)して、NOXを活性化し、37℃、60分間の反応を行った。
そして、波長450nmの吸光度を測定することにより、黄色フォルマザンの生成量を測定し、NOXにより生じたスーパーオキシドの生成量を測定した。
なお、この反応系において、培地にPMAを添加しない限りNOXが活性化しない。さらにNOX阻害剤として知られているVAS2870をポジティブコントロールとして評価したところ、IC50は8μMであった。これらのことから、この評価系はNOX阻害活性を評価することに適していることが確認された。
阻害活性比=(アセチル基を有するトリテルペン酸のIC50)/(アセチル基のないトリテルペン酸のIC50)・・・(i)
結果を表1に示す。
(1)アロニア抽出物の調製
バラ科アロニア・メラノカルパの搾汁粕を凍結乾燥したのち粉砕した。破砕物を含水エタノールで抽出したのち濾過し、減圧濃縮しエキス末を得た。
このエキス末を水で溶解し、酢酸エチル抽出を5回行った。酢酸エチル移行部をDiaion HP-20に供し、濃度の異なる含水エタノールで溶出させた。エタノール溶出部をSilica gel 60Nに供し、濃度の異なるヘキサン/酢酸エチル混合液で溶出させた。溶出液を逐次、薄層クロマトグラフィーにて確認し、スポットパターンが同一である溶出液をまとめ、一つの画分とした。これにより複数の画分を得た。
3-アセチルウルソル酸、3-アセチルオレアノール酸、ウルソル酸及びオレアノール酸の標品を準備した。その後、特許文献(特許第5466842号公報)に記載の方法に沿って、各標品及び上記各画分を、以下の条件で分析した。
各標品及び上記各分画を、以下の条件に従って高速液体クロマトグラフィー分析に供した。
使用カラム:野村化学社製Develosil C-30-UG5 (φ4.5μmx250mm)
移動相溶媒:90%アセトニトリル、0.05%トリフルオロ酢酸
流速:0.5mL/min
検出:UV (210nm)、ELSD
画分1及び画分2に関して、上記分析により得られたELSDクロマトグラムに基づき、下記の計算式(ii)及び(iii)により、アセチル基を有するトリテルペン酸及びアセチル基のないトリテルペン酸の含有量を算出した。結果を表2に示す。
画分1:アセチル基のないトリテルペン酸含有量(%)=[(オレアノール酸のピーク面積+ウルソル酸のピーク面積)/ピーク面積の合計]×100・・・(ii)
画分2:アセチル基を有するトリテルペン酸含有量(%)=[(3-アセチルオレアノール酸のピーク面積+3-アセチルウルソル酸のピーク面積)/ピーク面積の合計]×100・・・(iii)
(3-1)画分1の被験サンプル群の調製
濃度が10mg/mLとなるように画分1をDMSOに溶解し、ここからDMSOを用いて2倍希釈系列の溶液を調製し、さらに各溶液をD-MEM培地で希釈し、アセチル基のないトリテルペン酸の終濃度が76、38、19、9.5μg/mLの画分1の被験サンプル溶液群を調製した。
濃度が10mg/mLとなるように画分2をDMSOに溶解し、ここからDMSOを用いて2倍希釈系列の溶液を調製し、さらに各溶液をD-MEM培地で希釈し、アセチル基を有するトリテルペン酸の終濃度が96、48、24、12、6、3、1.5、0.75μg/mLの画分2の被験サンプル溶液群を調製した。
実施例1と同じ方法で、コントロール溶液、WST-1溶液及びPMA溶液を調製した。
各標品の被験サンプル溶液群に代えて、画分1の被験サンプル群及び画分2の被験サンプル群を用いた以外は、実施例1と同じ方法で、画分1及び画分2のNOX阻害活性を測定した。
得られた測定結果に基づき、画分1及び画分2のIC50(μg/mL)を求めた。
さらに、(i)の式を用いて画分1中のアセチル基のないトリテルペン酸に対する画分2中のアセチル基を有するトリテルペン酸の阻害活性比を算出した。
結果を表2に示す。
アロニア抽出物の脳機能低下抑制効果は、実施例2で得られたエキス末を用いて評価した。老化促進モデルのひとつであるSenescent Accelerated Model Prone 10(SAMP10)マウスは、加齢に伴う脳機能障害を早期に示すことが知られており、加齢に伴う脳機能低下に対する影響を評価することができる。そこで、この動物を用いて、アロニア抽出物の脳機能改善効果を検討した。なお、一連の動物実験は、動物愛護管理法他関連法令を遵守し、社内動物実験委員会の審査を経て機関の長が承認した計画に基づき実施した。
脳機能は受動回避試験(ステップスルーテスト)を用いて評価した。受動回避反応とは不快な刺激から逃れる学習行動であり、受動回避試験は記憶機能等の脳機能を評価できる系として知られている。
(1-1):獲得試行
マウスをステップスルー型受動的回避反応装置(室町機械(株)製)の明室(幅9cm、奥行き11.5cm、高さ15cm)に入れてから、30秒後に暗室(幅14cm、奥行き17.5cm、高さ15cm)の扉を開きマウスが暗室に進入するまでの時間(明室潜時)を測定した。測定後、暗室中のマウスに0.20mAの微弱電流を1秒流してから元のケージに収容した。
(1-2):再生試行
獲得試行実施の翌日に再生試行試験を実施した。マウスに獲得試行同様の操作を行い、明室潜時を測定した。ただし暗室に進入したマウスに電流刺激は与えなかった。潜時は最大で300秒まで計測し、再生試行における明室潜時が長いほど記憶機能が高いとして評価した。
若齢対照群、老齢対照群及び老齢アロニア摂取群において、体重および摂餌量に群間差はなかった。獲得試行および再生試行における明室潜時の評価結果を図1に示した。獲得試行における明室潜時は、いずれの群においても差はなかった。再生試行において、若齢対照群に比べて老齢対照群では有意な明室潜時の低下が観察された。これは本試験において加齢に伴う脳機能の低下を評価できていることを示す。再生試行において老齢対照群に比べ、老齢アロニア抽出物摂取群では有意な明室潜時の回復が観察された。この結果より、アロニア抽出物が加齢に伴う脳機能低下を抑制することが判明した。
アロニアに含まれるウルソル酸とアセチルウルソル酸の脳機能改善作用を明室潜時の回復によって比較した。SAMP10マウスは14週齢にて購入し、8ヵ月齢まで馴化した後、ランダムに2群に分け、0.006%ウルソル酸を含むAIN-93M飼料又は0.002%アセチルウルソル酸を含むAIN-93M飼料を12週間摂取させ、11ヵ月齢時点で参考例1の方法に従い、脳機能を評価した(0.006%ウルソル酸摂取群(N=8)、0.002%アセチルウルソル酸摂取群(N=10))。
ウルソル酸は市販の試薬を購入して使用した(純度95%以上)。3-アセチルウルソル酸は、ウルソル酸にアセチル基を付加する反応により合成し、Silica Gelで精製した。得られた白色粉末を上述の(2-1)トリテルペン類の分析条件に記載の方法で分析したところ、3-アセチルウルソル酸標品と同じ保持時間にピークが確認され、他の主要なピークは検出されなかった。このようにして得られた3-アセチルウルソル酸を評価サンプルとして使用した。
ウルソル酸摂取群及びアセチルウルソル酸摂取群において、体重および摂餌量に群間差はなかった。獲得試行および再生試行における明室潜時の評価結果を図2に示した。獲得試行における明室潜時はいずれの群においても差はなかった。再生試行において脳機能改善作用が知られているウルソル酸に比べ、アセチルウルソル酸はより低用量でウルソル酸より強い脳機能改善作用が見られた。この結果より、ウルソル酸とアセチルウルソル酸が加齢に伴う脳機能低下抑制作用をもつこと、アセチル基を有するトリテルペン酸はアセチル基のないトリテルペン酸と比較して加齢の伴う脳機能低下抑制作用が強いことが判明した。
Claims (21)
- アセチル基を有するトリテルペン酸及び/又はその塩を有効成分として含む活性酸素産生抑制用組成物。
- NADPHオキシダーゼ(NOX)を阻害することにより活性酸素の産生を抑制する請求項1に記載の活性酸素産生抑制用組成物。
- 前記アセチル基を有するトリテルペン酸及び/又はその塩が、3-アセチルウルソル酸、3-アセチルオレアノール酸及びこれらの塩からなる群から選択される少なくとも1種である請求項1又は2に記載の活性酸素産生抑制用組成物。
- 酸化ストレスに起因する状態又は疾患の予防、改善、若しくは、治療のために使用される請求項1~3のいずれか一項に記載の活性酸素産生抑制用組成物。
- 脳機能低下の抑制又は改善のために使用される請求項1~4のいずれか一項に記載の活性酸素産生抑制用組成物。
- 前記脳機能低下が、加齢による脳機能低下である請求項5に記載の活性酸素産生抑制用組成物。
- 前記酸化ストレス若しくは前記脳機能低下に起因する状態又は疾患が、もの忘れ、認知機能低下、記憶力低下、判断力低下、認知症、及び、アルツハイマー病からなる群から選択される少なくとも1つの状態又は疾患である請求項4又は5に記載の活性酸素産生抑制用組成物。
- 酸化ストレス若しくは脳機能低下に起因する状態又は疾患の予防、改善、若しくは、治療用である旨の表示を付した、請求項1~7のいずれか一項に記載の活性酸素産生抑制用組成物。
- 経口用組成物である請求項1~8のいずれか一項に記載の活性酸素産生抑制用組成物。
- 前記経口用組成物が、飲食品、医薬品又は医薬部外品である請求項9に記載の活性酸素産生抑制用組成物。
- アセチル基を有するトリテルペン酸及び/又はその塩を対象に投与する、活性酸素産生抑制方法。
- 活性酸素の産生を抑制するための、アセチル基を有するトリテルペン酸及び/又はその塩の使用。
- アセチル基を有するトリテルペン酸及び/又はその塩を有効成分として含む脳機能低下の抑制又は改善用組成物。
- 加齢による脳機能低下の抑制又は改善のために使用される請求項13に記載の脳機能低下の抑制又は改善用組成物。
- 前記アセチル基を有するトリテルペン酸及び/又はその塩が、3-アセチルウルソル酸、3-アセチルオレアノール酸及びこれらの塩からなる群から選択される少なくとも1種である請求項13又は14に記載の脳機能低下の抑制又は改善用組成物。
- 脳機能低下に起因する疾患又は状態が、もの忘れ、認知機能低下、記憶力低下、判断力低下、認知症、及び、アルツハイマー病からなる群から選択される少なくとも1つの状態又は疾患である請求項13~15のいずれか一項に記載の脳機能低下の抑制又は改善用組成物。
- 脳機能低下に起因する状態又は疾患の予防、改善、若しくは、治療用である旨の表示を付した、請求項13~16のいずれか一項に記載の脳機能低下の抑制又は改善用組成物。
- 経口用組成物である請求項13~17のいずれか一項に記載の脳機能低下の抑制又は改善用組成物。
- 前記経口用組成物が、飲食品、医薬品又は医薬部外品である請求項18に記載の脳機能低下の抑制又は改善用組成物。
- アセチル基を有するトリテルペン酸及び/又はその塩を対象に投与する、脳機能低下の抑制又は改善方法。
- 脳機能低下の抑制又は改善のための、アセチル基を有するトリテルペン酸及び/又はその塩の使用。
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US16/957,490 US20210015830A1 (en) | 2017-12-28 | 2018-12-26 | Composition for inhibiting reactive oxygen species production |
JP2019562114A JP7240331B2 (ja) | 2017-12-28 | 2018-12-26 | 活性酸素産生抑制用組成物 |
SG11202005482SA SG11202005482SA (en) | 2017-12-28 | 2018-12-26 | Composition for inhibiting reactive oxygen species production |
CN201880084285.8A CN111565580A (zh) | 2017-12-28 | 2018-12-26 | 用于抑制活性氧产生的组合物 |
CA3086834A CA3086834A1 (en) | 2017-12-28 | 2018-12-26 | Composition for inhibiting reactive oxygen species production |
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JP (1) | JP7240331B2 (ja) |
CN (1) | CN111565580A (ja) |
CA (1) | CA3086834A1 (ja) |
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KR20210083828A (ko) * | 2019-12-27 | 2021-07-07 | 전북대학교산학협력단 | 반추동물의 반추위 내 내생독소 억제용 조성물 |
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- 2018-12-26 CA CA3086834A patent/CA3086834A1/en active Pending
- 2018-12-26 US US16/957,490 patent/US20210015830A1/en not_active Abandoned
- 2018-12-26 JP JP2019562114A patent/JP7240331B2/ja active Active
- 2018-12-26 CN CN201880084285.8A patent/CN111565580A/zh active Pending
- 2018-12-26 WO PCT/JP2018/047880 patent/WO2019131774A1/ja active Application Filing
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TW201934531A (zh) | 2019-09-01 |
CA3086834A1 (en) | 2019-07-04 |
TWI803554B (zh) | 2023-06-01 |
US20210015830A1 (en) | 2021-01-21 |
JP7240331B2 (ja) | 2023-03-15 |
SG11202005482SA (en) | 2020-07-29 |
JPWO2019131774A1 (ja) | 2020-12-24 |
CN111565580A (zh) | 2020-08-21 |
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