WO2013129334A1 - AGONISTE QUI IMITE L'EFFET CINÉTIQUE, ET CO-ACTIVATEUR POUR AMPK ET PPARδ - Google Patents

AGONISTE QUI IMITE L'EFFET CINÉTIQUE, ET CO-ACTIVATEUR POUR AMPK ET PPARδ Download PDF

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Publication number
WO2013129334A1
WO2013129334A1 PCT/JP2013/054806 JP2013054806W WO2013129334A1 WO 2013129334 A1 WO2013129334 A1 WO 2013129334A1 JP 2013054806 W JP2013054806 W JP 2013054806W WO 2013129334 A1 WO2013129334 A1 WO 2013129334A1
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mangosteen
extract
mangostin
pparδ
agent
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PCT/JP2013/054806
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English (en)
Japanese (ja)
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雅裕 勝川
太郎 堀場
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キッコーマン株式会社
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/38—Clusiaceae, Hypericaceae or Guttiferae (Hypericum or Mangosteen family), e.g. common St. Johnswort
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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

Definitions

  • the present invention relates to a motor effect mimicking agent and a AMPK and PPAR ⁇ coactivator containing a mangosteen extract and / or a specific compound derived from mangosteen.
  • AMPK AMP-activated protein kinase
  • GW501516 is known as a compound that activates PPAR ⁇ , and is used in the field of basic experiments as a synthetic agonist.
  • certain pyrrole derivatives have PPAR ⁇ agonist activity (see, for example, Patent Document 4).
  • Mangosteen (scientific name: Garcinia mangostana L.) is a hypericaceae plant native to Southeast Asia. Mangosteen fruit or pericarp has traditionally been used as a therapeutic agent for dysentery and infectious diarrhea, antibacterial and parasite control, malaria, urinary tract infection, syphilis, mania, etc. 3). Also known are 5 ⁇ -reductase inhibitors (see, for example, Patent Document 5), whitening / anti-inflammatory effects (see, for example, Patent Document 6), and I ⁇ B kinase inhibitors (for example, see, Patent Document 7).
  • a safer agent that can be obtained with less exercise is, for example, prevention of bedridden patients due to muscle weakness of elderly people who cannot exercise, prevention of muscle weakness of hospitalized patients such as fractures
  • prevention of muscle weakness in space (low-gravity) space suppression of muscle weakness due to genetic disease (eg muscular dystrophy), diet by improving basal metabolism more efficiently with less exercise there is a possibility.
  • an object of the present invention is to provide a highly safe coactivator capable of activating both AMPK and PPAR ⁇ .
  • the present invention also provides a safe and effective exercise effect mimicking agent capable of obtaining a favorable biological response recognized when exercise is performed without performing exercise or with less exercise.
  • Another object of the present invention is to provide the above agent at a low cost and in a form suitable for continuous intake.
  • the present inventor has conducted extensive research and found that an extract derived from mangosteen and a specific compound contained in the extract have an action of activating both AMPK and PPAR ⁇ . It was. It has also been found that when a mangosteen-derived extract is administered to a rat, a favorable biological response that is inherently observed when exercising can be obtained without exercising. Furthermore, it has also been found that a mangosteen extract having the above-mentioned action can be easily obtained from mangosteen peel and the like, and that a food and drink containing the mangosteen extract is a food and drink having a taste suitable for continuous intake, The present invention has been completed.
  • the present invention based on the above findings by the present inventors is as follows.
  • Mangosteen extract has the following formula (I) (Where R 1 and R 4 are independently of each other C 1 -C 5 -alkyl or alkenyl; R 2 and R 3 independently of one another are hydroxy or C 1 -C 6 -alkoxy; Here, R 1 and R 2 may be bonded to each other to form a 5- to 8-membered ring containing an oxygen atom in addition to a carbon atom as a ring atom.
  • a food or drink containing the agent according to [5] Contains 0.001 to 50% by weight of ⁇ -mangostin; and 0.0001 to 50% by weight of ⁇ -mangostin; Food and drink.
  • Exercise including mangosteen extract, comprising extracting one or more raw materials selected from the group consisting of mangosteen fruit, fruit juice, concentrated fruit juice, squeezed residue, pericarp and these dried products using an ethanol solvent A method for producing an effect mimicking agent or an AMPK and PPAR ⁇ coactivator.
  • a method of exerting an effect of mimicking exercise effect comprising a step of administering an effective amount of a mangosteen extract to a subject.
  • a method for activating AMPK and PPAR ⁇ comprising a step of administering an effective amount of a mangosteen extract to a subject.
  • the method according to [18], wherein the exercise effect mimicking action is fat accumulation suppression, heat production promotion, muscle differentiation promotion, exercise endurance improvement or muscle atrophy suppression.
  • a method of exerting an effect of mimicking a movement effect comprising a step of administering an effective amount of ⁇ -mangostin to a subject.
  • a method for exerting a mimicking effect on a motor effect comprising a step of administering an effective amount of ⁇ -mangostin and ⁇ -mangostin to a subject.
  • a method for activating AMPK and PPAR ⁇ comprising a step of administering an effective amount of ⁇ -mangostin to a subject.
  • a method for activating AMPK and PPAR ⁇ comprising a step of administering an effective amount of ⁇ -mangostin to a subject.
  • a method for activating AMPK and PPAR ⁇ comprising a step of administering an effective amount of ⁇ -mangostin to a subject.
  • 3- A method for activating PPAR ⁇ comprising administering an effective amount of isomangosteen to a subject.
  • both AMPK and PPAR ⁇ can be activated, and a highly safe coactivator can be provided.
  • a safe and highly effective mimicking effect mimicking agent capable of obtaining a favorable biological response that is originally recognized when exercising, without exercising or with less exercising.
  • the active ingredient of the agent of the present invention is an ingredient that can be obtained from mangosteen and can be safely ingested.
  • said agent can also be provided as taste food-drinks suitable for continuous ingestion.
  • the above-mentioned highly effective agent can be obtained easily and efficiently from mangosteen peel and the like, so that the waste can be effectively used.
  • Example 2 shows enhancement of phosphorylated AMPK (p-AMPK, activated form) in C2C12 cells by ⁇ -mangostin, ⁇ -mangosteen or mangosteen extract.
  • Example 5 which shows the raise of the gene expression in connection with the heat production in a gastrocnemius by a mangosteen extract.
  • Example 5 which shows the raise of the gene expression in connection with muscle differentiation in a gastrocnemius by a mangosteen extract.
  • Example 6) which shows the raise of the gene expression in connection with muscle differentiation in C2C12 cell by (alpha) -mangostin.
  • Example 8 The measurement result of the exercise endurance in the mouse
  • Example 11 which shows suppression of the gene (Atrogin-1) related to disuse muscle atrophy by the mangosteen extract.
  • Example 11 which shows suppression of gene (MuRF-1) expression related to disuse muscle atrophy by mangosteen extract.
  • the present invention relates to an exercise effect mimicking agent; AMPK and PPAR ⁇ coactivator; fat accumulation inhibitor; heat production promoter; muscle differentiation promoter; exercise endurance improver; muscle atrophy inhibitor; AMPK activator; Activators; PPAR ⁇ activators; and PPAR ⁇ and PPAR ⁇ coactivators.
  • AMPK activator Activators
  • PPAR ⁇ activators PPAR ⁇ and PPAR ⁇ coactivators
  • the agent of the present invention contains a mangosteen extract as an active ingredient.
  • the above mangosteen extract is one or more raw materials selected from mangosteen fruit, fruit juice, concentrated fruit juice, juice residue, pericarp and / or dried products thereof (hereinafter simply referred to as “mangosteen raw material”).
  • mangosteen raw material Is a processed product extracted with a polar solvent (hereinafter, a processed product obtained by extraction using a polar solvent may be simply abbreviated as “mangosteen extract”).
  • Mangosteen is known to contain about 40 types of polyphenols collectively called xanthones, and the above mangosteen extract is considered to contain these xanthones at a high concentration.
  • the mangosteen raw material is not particularly limited, and may contain solids such as mangosteen fruit and skin, or may be a solution obtained by removing solids such as mangosteen fruit and skin by filtration.
  • Mangosteen juice used in mangosteen juice, etc. is obtained by washing mangosteen fruit, removing the peel and crushing it, and then squeezing it. In the process of squeezing, squeezed residue and fruit skin are generated.
  • the juice residue and pericarp (especially pericarp) are rich in xanthones.
  • the squeezed residue and peel are generally discarded or used as livestock feed, but if this squeezed residue and peel are used, the waste raw material can be used effectively, and a composition containing a high concentration of xanthones is used. Since it can be obtained easily and efficiently, it is preferable from the viewpoint of effective utilization of waste raw materials.
  • the mangosteen extract in the agent of the present invention is preferably a mangosteen peel extract.
  • the extraction temperature of the mangosteen raw material using a polar solvent is from 0 ° C. to the boiling point of the polar solvent, and is usually performed at room temperature.
  • ethanol used as the polar solvent
  • it is preferably 0 ° C. or higher and lower than 55 ° C., more preferably 5 ° C. or higher and 40 ° C. or lower from the viewpoint of extraction efficiency.
  • it is particularly preferable to perform extraction at around 25 ° C., which is about room temperature.
  • water is used as the polar solvent, it is preferably 0 ° C. or higher and 100 ° C. or lower, more preferably 25 ° C. or higher and 100 ° C. or lower, from the viewpoint of extraction efficiency.
  • Extraction time is preferably 1 minute to 24 hours, but extraction may be performed for a longer time. Extraction may be performed by either standing or stirring.
  • a mangosteen extract can be obtained by adding 1 to 50 times, preferably 2 to 20 times the amount of polar solvent to the mangosteen raw material (in terms of dry product) and extracting.
  • the mangosteen raw material may be a dried product.
  • the polar solvent is not particularly limited as long as it is a polar solvent that can be an extraction solvent for food additives.
  • a polar solvent that can be an extraction solvent for food additives.
  • One or more organic solvents can be used.
  • ethanol (10 to 100 volume%), methanol (10 to 99.5 volume%), 1-butanol (30 to 99.5 volume%), hexane ( 5% by volume and less than 70% by volume) and an organic solvent selected from water can be used, more preferably ethanol or water can be used, and most preferably ethanol can be used.
  • an ethanol solvent of 10% by volume to 100% by volume can be used, preferably an ethanol solvent of 50% by volume to 100% by volume can be used, and more preferably about 70% by volume.
  • An ethanol solvent can be used.
  • the 70% by volume ethanol solvent refers to a mixture of water and ethanol in a volume ratio of 3: 7.
  • the mangosteen extract contained in the agent of the present invention is preferably an organic solvent extract of mangosteen, more preferably an alcoholic extract of mangosteen, and an ethanol extract of mangosteen. It is particularly preferred.
  • the mangosteen extract in the present invention may be in the form of a solution or puree, and can also be made into a concentrated liquid composition by concentration under reduced pressure or membrane concentration to an appropriate concentration. It may be a solid obtained by drying the mangosteen extract.
  • the dried product can be obtained by drying the solution-like extract using a known method such as drum drying, spray drying, or freeze drying. A dried mangosteen extract having excellent storage stability is obtained.
  • mangosteen extract varies slightly depending on the degree of purification, but since it has a small specific taste and odor, it can be added to the agent of the present invention in a relatively wide range of concentrations.
  • the mangosteen extract in the present invention contains 0.01% by weight or more of xanthones (preferably xanthones selected from the group consisting of ⁇ -mangosteen, ⁇ -mangosteen and 3-isomangosteen) in terms of dry weight.
  • xanthones preferably xanthones selected from the group consisting of ⁇ -mangosteen, ⁇ -mangosteen and 3-isomangosteen
  • the content is preferably 0.1% by weight or more, more preferably 0.5% by weight or more, and still more preferably 1% by weight or more.
  • More than 40 types of xanthones are known. Among them, the total amount of ⁇ -mangostin, ⁇ -mangosteen, ⁇ -mangostin, gartanine, 8-deoxygartanine and 3-isomangostin, which is high in the content, Can be prescribed.
  • xanthones are considered to have antioxidant power.
  • the xanthones in the mangosteen extract can be analyzed using a technique known to those skilled in the art, and for example, can be analyzed using a high-performance liquid chromatograph with reference to the technique described in Example 1 described later. .
  • the mangosteen extract contains a compound represented by the following formula (I). It can be an active ingredient of the agent of the present invention.
  • the compound represented by the formula (I) can be an active ingredient of a PPAR ⁇ activator.
  • R 1 and R 4 are independently of each other C 1 -C 6 -alkyl or alkenyl, preferably C 1 -C 5 -alkyl or alkenyl, more preferably C 1 -C 5 -alkenyl.
  • R 1 and R 2 may be bonded to each other to form a 5- to 8-membered ring (preferably a 5- or 6-membered ring) containing not only a carbon atom but also an oxygen atom as a ring atom,
  • the 5- to 8-membered ring may have a substituent, and may preferably form a 6-membered ring containing an oxygen atom.
  • the compound represented by the above formula (I) is a compound represented by the following formula (II), and in the formula (II), R 3 and R 4 are defined for the above formula (I). It is as follows.
  • ⁇ -mangosteen has the formula (I) in which R 1 and R 4 are —CH 2 —CH ⁇ C (CH 3 ) 2 and R 2 is OH.
  • R 3 is a compound represented by —O—CH 3 .
  • ⁇ -Mangosteen is a compound in which R 1 and R 4 are —CH 2 —CH ⁇ C (CH 3 ) 2 and R 2 and R 3 are represented by OH in the above formula (I).
  • 3-Isomangosteen is a compound represented by the formula (II) wherein R 3 is —O—CH 3 and R 4 is represented by —CH 2 —CH ⁇ C (CH 3 ) 2 .
  • the compound represented by the above formula (I) is an active ingredient of the agent of the present invention.
  • ⁇ -mangosteen and ⁇ -mangosteen are Have also been found to be active ingredients of the agents of the present invention (particularly AMPK and PPAR ⁇ co-activators), and ⁇ -mangostin, ⁇ -mangostin and 3-isomangosteen are each independently It has been found that it becomes an active ingredient (particularly a PPAR ⁇ activator), and in particular, ⁇ -mangostin has been found to have a very high PPAR ⁇ activation action.
  • the agent of the present invention or the mangosteen extract contained in the agent of the present invention contains the compound represented by the above formula (I).
  • it contains one or more compounds selected from the group consisting of ⁇ -mangostin, ⁇ -mangostin and 3-isomangosteen, and more preferably a group consisting of ⁇ -mangostin, ⁇ -mangostin and 3-isomangostin.
  • the agent of the present invention or the mangosteen extract contained in the agent of the present invention exhibits a desired effect: ⁇ -mangostin, preferably 0.001 wt% or more and 100 wt% or less, more Preferably 0.01 wt% or more and 100 wt% or less; ⁇ -mangostin, preferably 0.0001 wt% or more and 100 wt% or less, more preferably 0.01 wt% or more and 100 wt% or less; Isomangostin is preferably contained in an amount of 0.001 to 100% by weight, more preferably 0.01 to 100% by weight.
  • the agent of the present invention when added to food and drink, it is 0.0001% by weight or more for ⁇ -mangostin, 0.00001% by weight or more for ⁇ -mangostin, and 0.001 for 3-isomangostin. It is desirable that the food or drink contains 0001% by weight or more. For example, the food or drink contains 0.001 to 50% by weight of ⁇ -mangostin; and 0.0001 to 50% by weight of ⁇ -mangostin. be able to. When ingested for the purpose of maintaining health over a long period, the amount may be smaller than the above range.
  • the mangosteen extract contained in the agent of the present invention preferably contains ⁇ -mangosteen and ⁇ -mangostin in a ratio of 1: 0.01 to 1: 100, and 1: 0.1 to 1: More preferably, it is included in a ratio of 10 and more preferably in a ratio of 1: 0.1 to 1: 1 (for example, about 1: 0.2).
  • the mangosteen extract contained in the agent of the present invention contains one or more compounds selected from the group consisting of ⁇ -mangostin, ⁇ -mangosteen and 3-isomangostin, and further includes ⁇ -mangostin, gartanine and One or more compounds selected from the group consisting of 8-deoxygartanine.
  • the present invention provides an exercise effect mimicking agent.
  • the “exercise effect mimicking agent” is a preferable biological response that is recognized when exercise is performed, such as fat accumulation suppression, heat production promotion, muscle differentiation promotion, skeletal muscle weight increase, exercise endurance Provide increased skeletal muscle fiber composition, increased energy metabolism, increased basal metabolism, improved musculoskeletal function, reduced muscle atrophy, etc. without exercise or more exercise with less exercise It refers to an agent that provides as much as obtained by exercise.
  • the action as a motor effect mimicking agent can be confirmed by examining whether or not one or more of the above biological responses can be obtained in vivo, as described in Examples 4, 8 and 10 below, for example. . Further, for example, as described in Examples 5, 6 and 11 described later, it can also be confirmed by examining whether the expression level of the gene involved in the biological response is changed in vivo or in vitro.
  • the action effect mimicking agent of the present invention is a fat accumulation inhibitor, a heat production promoter, a muscle differentiation promoter, a skeletal muscle weight increase agent, an exercise endurance improver, a skeletal muscle fiber composition change agent, an energy metabolism. It may be an enhancer, a basal metabolic rate increasing agent, a musculoskeletal function improving agent, or a muscle atrophy inhibitor.
  • the exercise effect mimicking agent of the present invention can be a heat production promoter, a muscle differentiation promoter, an exercise endurance improver, or a muscle atrophy inhibitor.
  • the action of these agents can be confirmed by examining whether a biological response corresponding to each agent can be obtained in vivo, or involved in a biological response corresponding to each agent in vivo or in vitro. It can also be confirmed by examining whether the expression level of the gene is changed.
  • the action as a “thermoproduction promoter” can be confirmed by examining whether the expression levels of UCP2 and UCP3, which are genes involved in heat production, increase as described in Example 5 described later. it can.
  • the action as a “muscle differentiation promoting agent” is to determine whether the expression level of MyoD, Myf5, Myogenin, MRF4, and the like, which are genes involved in muscle differentiation, increases.
  • the action as a “muscle atrophy inhibitor” is to examine whether the expression levels of Atrogin-1 and MuRF-1, which are genes involved in muscle atrophy, are reduced, as described in Example 11 described later, for example. Can be confirmed.
  • the “fat accumulation inhibitor” refers not only to an agent that suppresses the accumulation of new fat, but also to an agent that reduces the existing fat.
  • “Exercise endurance improver” refers to an agent that can improve exercise performance, such as enabling extension of travelable time.
  • “Muscle atrophy inhibitor” refers to an agent that delays or prevents the loss of muscle mass.
  • the present invention provides an AMPK activator and a PPAR ⁇ coactivator, an AMPK activator, a PPAR ⁇ activator, a PPAR ⁇ activator, and a PPAR ⁇ and PPAR ⁇ coactivator.
  • AMPK plays an extremely important role in the regulation of energy metabolism, and is activated by phosphorylation under conditions where the intracellular AMP / ATP ratio is increased, such as skeletal muscle movement. It is known to promote metabolism. In addition, in cells having PPAR ⁇ , it has been reported that exercise endurance is improved by AMPK activation (Non-patent Document 1, etc.). Therefore, the AMPK activator can be used as an agent that exhibits the above effects.
  • the action as an AMPK activator can be confirmed with reference to, for example, Example 2 described later.
  • PPAR- ⁇ leads to a decrease in blood triglyceride concentration through peroxisome growth.
  • lipid metabolism-related genes are the main target genes, they are targets for the development of drugs for improving hyperlipidemia. Therefore, the PPAR ⁇ activator can be used as an agent that exhibits the above effects.
  • the inventors of the present invention have the mangosteen extract (including ⁇ -mangostin and ⁇ -mangostin) obtained in Example 1 described below to act as a PPAR ⁇ activator and as a PPAR ⁇ and PPAR ⁇ coactivator. I have confirmed that.
  • PPAR ⁇ is expressed in many organs and plays a role in the transcriptional regulation of skeletal muscle metabolism. Further, it has been reported that endurance is improved by combining PPAR ⁇ activation and exercise (Non-patent Document 1, etc.). Therefore, the PPAR ⁇ activator can be used as an agent that exhibits the above effects.
  • the present inventors have confirmed that the mangosteen extract, ⁇ -mangosteen, ⁇ -mangosteen and 3-isomangosteen obtained in Example 1 described later act as a PPAR ⁇ activator.
  • the action as a PPAR ⁇ activator and a PPAR ⁇ activator can be confirmed with reference to, for example, Example 3 described later.
  • Non-patent Document 1 It has been reported that combining the activation of AMPK with the activation of PPAR ⁇ results in favorable biological responses observed during exercise, such as improvement in exercise endurance (Non-patent Document 1).
  • the AMPK and PPAR ⁇ coactivator to be used can also be used as an agent exhibiting the above-described effects.
  • the present inventors have confirmed that the mangosteen extract, ⁇ -mangostin and ⁇ -mangostin obtained in Example 1 described later act as an AMPK and PPAR ⁇ coactivator.
  • “AMPK and PPAR ⁇ co-activator” refers to an agent having both an AMPK activating action and a PPAR ⁇ activating action.
  • the “PPAR ⁇ and PPAR ⁇ co-activator” refers to an agent having both a PPAR ⁇ activation action and a PPAR ⁇ activation action.
  • the “AMPK activator” means an agent for AMPK activation. The same applies to other activators.
  • the agent of the present invention can be administered as it is to animals including humans, and can also be used as a reagent. Moreover, it can mix
  • the above-mentioned food / beverage products are preferably food for specified health use, nutritional functional food, health food, functional food, health supplement and the like.
  • the agent of the present invention further includes food additives such as sweeteners, coloring agents, preservatives, thickening stabilizers, antioxidants, bittering agents, sour agents, emulsifiers, strengthening agents, manufacturing agents, and flavors. It can also be used by blending with beverages such as soft drinks and other foods.
  • the above foods and drinks are exercise effect mimicking action, fat accumulation inhibiting action, heat production promoting action, muscle differentiation promoting action, skeletal muscle weight increasing action, exercise endurance improving action, skeletal muscle fiber composition changing action, energy metabolism enhancing action, Since it can have actions such as an action to increase basal metabolic rate, an action to improve function of the musculoskeletal action, an action to suppress muscle atrophy, etc., it can also be a food or drink with a display indicating that it has these actions.
  • Preferred forms of food and drink include foods and beverages such as rice cake, jelly, tablet confectionery, beverages, soup, noodles, rice crackers, Japanese confectionery, frozen confectionery, baked confectionery, etc., preferably fruit juice beverage, vegetable juice, fruit vegetable juice , Bottled beverages such as tea beverages, coffee beverages and sports drinks.
  • the agent of the present invention contains any one or more of mangosteen extract, ⁇ -mangosteen, ⁇ -mangosteen and 3-isomangosteen as an active ingredient, these all have less specific taste and odor, Even when the agent of the present invention is blended with food and drink such as fruit juice, vegetable juice, tomato processed beverage, mixed juice and soy milk, the original flavor of each food and drink is not impaired, and will be described later. As described in Example 13, the flavor and palatability of these foods and drinks (especially beverages having a blue odor) are improved. In recent years, these foods and drinks that have been drunk for the purpose of eliminating vegetable shortages, nutritional supplementation, health maintenance, beauty, etc.
  • the agent of the present invention can be blended in a beverage having a blue odor, preferably blended in fruit juice, vegetable juice, tomato processed beverage, mixed juice or soy milk, more preferably, It can be blended in vegetable juice, tomato processed beverage or soy milk.
  • amino acid-containing beverages that have been released many times in recent years have been drunk for the purpose of maintaining health such as reducing muscle fatigue, maintaining stamina, and increasing metabolism.
  • L-type amino acids such as isoleucine, leucine, valine, serine, asparagine, glutamine, arginine, lysine, cysteine, methionine, phenylalanine, tryptophan, histidine, and proline have a bitter taste depending on the concentration.
  • the mangosteen extract is equivalent to or more than BCAA (combination of branched chain amino acids leucine, isoleucine and valine) and has an effect of improving exercise endurance and suppressing fat accumulation.
  • BCAA combination of branched chain amino acids leucine, isoleucine and valine
  • the agent of the present invention containing a mangosteen extract can be taken as an alternative to a beverage containing amino acids.
  • the agent of the present invention containing a mangosteen extract can be added to a beverage containing amino acids in the hope of an additive / synergistic effect with amino acids.
  • the mangosteen extract when a mangosteen extract is added to a beverage to make a food or drink containing the agent of the present invention, the mangosteen extract is somewhat different depending on the degree of purification, but because there is little peculiar taste to taste and smell, comparison For example, it can be added in an amount of 10 mg to 25,000 mg, more preferably 100 mg to 10,000 mg in terms of dry matter per 1,000 mL of beverage.
  • the agent of the present invention contains a mangosteen extract and the agent of the present invention is blended in a food or drink
  • its intake can be adjusted as appropriate according to the use, but preferably in terms of dry matter of the mangosteen extract Can be 10 mg to 25,000 mg at a time, more preferably 100 mg to 10,000 mg at a time, and even more preferably 100 mg to 1,000 mg at a time.
  • the number of intakes is not particularly limited, but is preferably 1 to 3 times a day, and the number of intakes may be increased or decreased as necessary.
  • the agent of the present invention When the agent of the present invention is blended into a pharmaceutical composition, it can be formulated by a known technique together with pharmaceutically acceptable excipients and the like.
  • a pharmaceutical composition include those in known dosage forms such as powders, granules, solids such as tablets, and liquids such as liquids and pastes.
  • the pharmaceutical composition includes tablets, capsules, granules, fine granules, powders, solutions, syrups, oral preparations such as chewable and troches, liquids, ointments and other coatings, poultices, patches, injections, tongues It can be used as dosage forms such as laxatives, inhalants, eye drops and suppositories. From the viewpoint that the flavor is not impaired even if the agent of the present invention is blended, the pharmaceutical composition is preferably an oral agent.
  • the dosage is appropriately adjusted according to various conditions such as the activity of individual drugs, patient symptoms, age, weight, etc. For example, it is preferably 10 mg to 25,000 mg at a time, more preferably 100 mg to 10,000 mg at a time, and more preferably 100 mg to 1,000 mg at a time in terms of dried mangosteen extract.
  • the agent of the present invention is a pharmaceutical composition containing ⁇ -mangosteen
  • the dose is, for example, 0.1 mg to 25 mg at a time, preferably 1 mg to 10 mg at a time in terms of ⁇ -mangostin.
  • the number of administrations is not particularly limited, but is preferably 1 to 3 times a day, and the number of administrations may be increased or decreased as necessary.
  • a pharmaceutical composition containing the same can be used for the treatment or prevention of diseases in which the action of the above-mentioned agent of the present invention can be related to treatment or prevention.
  • diseases include, for example, muscular dystrophy, low back pain, amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (muscle dystrophy, skeletal muscle weight increasing action, etc., which can be related to treatment or prevention. SMA) and the like. Therefore, the present invention can also provide a method for treating or preventing these diseases.
  • the agent of the present invention is an exercise effect mimicking action, fat accumulation inhibiting action, heat production promoting action, muscle differentiation promoting action, skeletal muscle weight increasing action, exercise endurance improving action, skeletal muscle fiber composition changing action, energy metabolism enhancing action, Since it can have effects such as basal metabolic rate increasing action, musculoskeletal function improving action, muscle atrophy suppressing action, etc., animals, especially mammals (dogs, cats, cows, horses, etc.) can be mentioned with the expectation of the above actions. ).
  • the agent of the present invention having the above-mentioned action is, for example, prevention of bedridden patients due to muscle weakness of elderly people who cannot exercise, prevention of muscle weakness of hospitalized patients such as fractures, prevention of muscle weakness in space (low gravity) space, There is a possibility that it can be used in various fields such as suppression of muscle weakness (for example, muscular dystrophy) due to a genetic disease, diet by improving basal metabolism more efficiently with less exercise.
  • the present invention also includes: a method of exerting a mimicking effect on a motor effect comprising the step of administering to a subject an effective amount of a mangosteen extract; a co-activity of AMPK and PPAR ⁇ comprising the step of administering an effective amount of a mangosteen extract to a subject
  • a method of exerting a mimicking effect on a motor effect comprising a step of administering an effective amount of ⁇ -mangostin to a subject; a mimicking effect of a motor effect comprising a step of administering an effective amount of ⁇ -mangostin and ⁇ -mangostin to a subject
  • AMPK and PPAR ⁇ co-activation method comprising the step of administering an effective amount of ⁇ -mangostin to the subject;
  • AMPK and PPAR ⁇ co-activation method comprising the step of administering an effective amount of ⁇ -mangostin to the subject
  • a method of activating PPAR ⁇ comprising administering to the subject an
  • the cells were collected, and a sample for Western blotting was prepared by the following procedure.
  • the cells were washed with ice-cooled PBS, 700 ⁇ L / well of PBS was added, and the cells were collected in a 1.5 mL tube using a cell scraper on ice. Centrifugation was performed at 5,000 rpm and 4 ° C. for 5 minutes, and the supernatant was aspirated.
  • lysis buffer (1 ⁇ PBS, 1% NP-40, 0.25% sodium deoxycholate, 0.1% SDS, 1 mM PMSF, 1 ⁇ inhibitor cocktail: Sigma)
  • lysis buffer 1 ⁇ PBS, 1% NP-40, 0.25% sodium deoxycholate, 0.1% SDS, 1 mM PMSF, 1 ⁇ inhibitor cocktail: Sigma
  • SDS sample buffer final concentration 0.05M Tris-HCl, 1% SDS, 10% glycerol, 0.1% BPB, 0.1M DTT
  • the sample was subjected to blotting after electrophoresis on a 7.5% acrylamide gel, and blocked with a 5% BSA-PBST solution at room temperature for 60 minutes. Thereafter, the primary antibodies (anti-AMPK, anti-phospho AMPK (Thr172), anti-ACC and anti-phospho ACC; all manufactured by Cell signaling technology) were each diluted 1000 times, and the antibody reaction was overnight at 4 ° C. Went. After the primary antibody reaction, the membrane was washed three times with PBS-T, and the secondary antibody (anti-rabbit IgG HRP conjugate; manufactured by Sigma) was diluted 5,000 times and the antibody reaction was performed at room temperature for 1 hour. It was. After the secondary antibody reaction, the membrane was washed 3 times with PBS-T, reacted with an HRP luminescent substrate (Immobilon), and detected with Image Gauge (Fujifilm).
  • the primary antibodies anti-AMPK, anti-phospho AMPK (Thr172), anti-ACC and anti-phospho ACC; all manufactured by
  • FIG. 1 shows bands in which total AMPK (t-AMPK) and phosphorylated AMPK (p-AMPK) were detected.
  • t-AMPK total AMPK
  • p-AMPK phosphorylated AMPK
  • FIG. 1 reveals that mangosteen extract 1 obtained in Example 1 has AMPK activation ability.
  • ⁇ -mangosteen and ⁇ -mangostin contained in the mangosteen extract 1 each have AMPK activation ability alone. It should be noted that ⁇ -mangosteen and ⁇ -mangostin had the same ability to activate AMPK.
  • the mangosteen extract 1 containing both of these has higher AMPK activation ability than the ⁇ -mangostin or ⁇ -mangostin alone contained in the extract, and the additive effect of ⁇ -mangostin and ⁇ -mangostin is higher. It was considered to have AMPK activation ability.
  • a human fetal kidney cell line (HEK293, ATCC) was cultured at 37 ° C. in a 5% CO 2 incubator using DMEM supplemented with 10% FBS. Cells were seeded on a 24 well plate at 5 ⁇ 10 4 cells / well and cultured for 1 day.
  • a chimeric protein expression plasmid (pGal4DBD / PPAR LBD) of a DNA binding domain of Gal4 (Gal-4DBD) and a ligand binding domain of PPAR ⁇ (or ⁇ or ⁇ ) (PPAR-LBD), a plasmid containing a Gal4 response element and a firefly luciferase gene ( pG5-Luc), and a control plasmid (pRL-CMV) in which a CMV promoter was linked upstream of the Renilla luciferase gene (both plasmids from Promega) were simultaneously added at 0.05 ⁇ g, 0.075 ⁇ g, and 0.025 ⁇ g, respectively.
  • OPTI-MEM (G) supplemented with 0.75 ⁇ L / well of transfection reagent (Lipofectamine 2000 Reagent; manufactured by Invitrogen)
  • transfection reagent Lipofectamine 2000 Reagent; manufactured by Invitrogen
  • the medium was changed and the plasmid was introduced.
  • 250 ⁇ L / well of DMEM supplemented with 10% FBS was added to each well.
  • Table 2 shows the ability of mangosteen extract 1 to activate PPAR ⁇ (or ⁇ or ⁇ ).
  • the values in Table 2 are relative to PPAR ⁇ (or ⁇ or ⁇ ) -dependent transcription activity in the control (DMSO added instead of sample) as 100. ** indicates a significant difference of 1% risk rate by T test of each group relative to the control group. From Table 2, it was revealed that the mangosteen extract 1 obtained in Example 1 is effective for activating PPAR ⁇ or ⁇ . Mangosteen extract 1 obtained in Example 1 has PPAR ⁇ activation action and PPAR ⁇ activation action, but does not have PPAR ⁇ activation action, and it was revealed that the specificity to PPAR ⁇ and PPAR ⁇ is high. .
  • Table 3 shows the PPAR ⁇ activation ability of mangosteen extract 1, ⁇ -mangosteen, ⁇ -mangosteen and 3-isomangosteen at various concentrations. From Table 3, it was revealed that not only the mangosteen extract 1 obtained in Example 1, but also ⁇ -mangosteen, ⁇ -mangosteen and 3-isomangosteen all have PPAR ⁇ activation ability. In particular, it was revealed that ⁇ -mangostin exhibits PPAR ⁇ activation ability even at a low concentration and has high PPAR ⁇ activation ability. Regarding the PPAR ⁇ activation ability of mangosteen extract 1, it was considered that ⁇ -mangostin contributed more than ⁇ -mangostin present in the extract.
  • PPAR ⁇ activation action may be effective for activation of fatty acid metabolism, prevention / improvement of hypertriglyceridemia, prevention / improvement of hypercholesterolemia, prevention / improvement of fatty liver, It is considered that PPAR ⁇ activation may be effective for activation of fatty acid metabolism, promotion of burning of body fat, prevention / improvement of obesity, improvement of basal metabolism, along with prevention / improvement of insulin resistance and diabetes, It was thought that it may be effective for prevention and improvement of arteriosclerosis.
  • subcutaneous adipose tissue, epididymal adipose tissue, mesenteric adipose tissue, perirenal adipose tissue and gastrocnemius muscle were collected, and for each, after measuring the adipose tissue weight and muscle tissue weight, divided by the body weight of each individual, Each tissue amount was measured and compared in both groups. In addition, liver was also collected.
  • Table 4 shows the ratio of each tissue to the total weight, calculated by dividing the weight of each tissue by the body weight.
  • Table 4 shows the sum of the epididymal adipose tissue, mesenteric adipose tissue and perirenal adipose tissue as the total abdominal fat weight and the addition of subcutaneous fat to the total adipose tissue weight.
  • * indicates a significant difference in the risk rate of 5% according to the T test of each group relative to the control group.
  • Table 4 shows the ratio of the gastrocnemius muscle to the total weight, calculated by dividing the gastrocnemius muscle weight by the body weight. From Table 4, when the mangosteen extract was administered, an increase in the ratio of the gastrocnemius muscle (skeletal muscle) weight to the total weight was observed in KKAy mice that are genetically obese. Mangosteen extract was considered to have an increasing effect on muscle mass without active exercise. When the mangosteen extract was administered, the adipose tissue weight decreased, while the muscle mass increased, suggesting that there was no difference in body weight from the control group.
  • RNA was RNA sequenced using PrimeScript RT reagent kit (manufactured by Takara) according to the protocol attached to the product to obtain cDNA.
  • PrimeScript RT reagent kit manufactured by Takara
  • real-time quantitative PCR was performed by SYBR Premix Ex Taq (manufactured by Takara) and MX3005P Real Time QPCR System (manufactured by Agilent Technology). The primer sequences used are as follows.
  • GAPDH forward 5′-TGACCATCAAGAAGGTGGTGA-3 ′ (SEQ ID NO: 1) GAPDH reverse: 5′-CCTGTTGCTGTAGCCGTATT-3 ′ (SEQ ID NO: 2)
  • UCP2 forward 5′-ACAGATGTGGTAAAGGTCCG-3 ′ (SEQ ID NO: 3)
  • UCP2 reverse 5′-CAGTTGACAATGGCATTACG-3 ′ (SEQ ID NO: 4)
  • UCP3 forward 5′-TTTGGAGCTGGCTTCTTGTG-3 ′ (SEQ ID NO: 5)
  • Myf5 forward 5′-AGGAAAAAGACCCTGA
  • FIG. 2 it was revealed that the gene expression of UCP2 and UCP3, which are genes involved in heat production, increased in the group administered with the mangosteen extract.
  • FIG. 3 revealed that in the group to which the mangosteen extract was administered, the gene expression of MyoD, which is a gene involved in muscle differentiation, showed an increasing tendency, and the gene expression of Myf5 was increased. From these results, it was suggested that ingestion of the mangosteen extract promotes muscle differentiation and increases heat production in the muscle without actively exercising.
  • ⁇ -Mangostin C2C12 cells (mouse-derived myoblasts similar to those used in Example 1) were seeded on a 6-well plate and added to 2 mL of DMEM supplemented with 10% FBS. And cultured until confluent. Thereafter, differentiation was induced in a differentiation induction medium of 2 mL of DMEM supplemented with 2% HS containing 10 ⁇ M ⁇ -mangostin. As a control, cells with DMSO added to the medium were cultured. Three days after differentiation induction, all of the medium was removed, and 1 mL of TRIZOL (manufactured by Invitrogen) was added to recover the cells.
  • TRIZOL manufactured by Invitrogen
  • RNA extraction, reverse transcription reaction, PCR and the like were performed using the same method as in Example 5, and the gene expression of MyoD, Myf5, Myogenin and MRF4, which are genes involved in muscle differentiation, was measured by real-time PCR.
  • the same primer as in Example 4 was used.
  • mangosteen extract 2 (mangosteen peel extract): 8,210 g of pericarp was collected from 11,824 g of Thai mangosteen fruit, freeze-dried and then pulverized to obtain 2,701 g of pericarp powder. 500 g of this skin powder was stirred and extracted for 2 hours at room temperature using 10 times the amount of 70% ethanol. The extract was concentrated and freeze-dried to obtain 224.96 g of mangosteen extract 2.
  • Table 5 shows the results of analyzing the contents of ⁇ -mangosteen and ⁇ -mangostin for the mangosteen extract 2 using the same method as in Example (1-2).
  • the mangosteen extract 2 derived from the fruit skin contained xanthones at a higher concentration than the mangosteen extract 1 derived from the flesh part.
  • a group containing 5% by weight of BCAA leucine: isoleucine: valine prepared at a ratio of 2: 1: 1) in a dry matter equivalent (positive control); and any of mangosteen extract and BCAA
  • the animals were divided into groups (controls) that received a control diet that did not contain any food, and were fed by free intake for 8 weeks. The animal's exercise endurance was measured once every two weeks. After the measurement, a recovery period of one week was provided, and the next measurement was performed. In addition, during the measurement (recovery period), the mice were allowed to run at 15 m / min for 30 minutes at a frequency of once every two days in order to maintain acclimatization of the treadmill of the mice.
  • Table 8 shows the ratio of each tissue per body weight, calculated by dividing the weight of each tissue by the body weight.
  • Table 8 shows the ratio of each muscle per body weight calculated by dividing the weight of each muscle by the body weight. From Table 8, when the mangosteen extract was administered, the increase in the ratio per body weight was observed in all of the gastrocnemius, soleus, thigh and tibialis. The effect was equivalent to or more than that of the BCAA group administered 10 times the amount of mangosteen extract. When moderate exercise was performed, the mangosteen extract was considered to have an increasing effect on muscle mass.
  • mangosteen extract 3 (mangosteen peel extract): The skin was collected from the freshly purchased Thai mangosteen fruit, freeze-dried, and pulverized to obtain a skin powder. 1,000 g of the skin part powder was extracted by stirring at room temperature for 2 hours with 10 times the amount of 70% ethanol. The extract was concentrated and freeze-dried to obtain 288.63 g of mangosteen extract 3 (mangosteen peel extract). Table 9 shows the results of analyzing the contents of ⁇ -mangosteen and ⁇ -mangostin for the mangosteen extract 3 using the same method as in Example (1-2). The mangosteen extract 3 derived from the fruit skin contained xanthones at a higher concentration than the mangosteen extract 1 derived from the flesh part.
  • FIG. 6 shows the result of calculating the ratio of muscle atrophy in each skeletal muscle by the muscle weight of the left limb with respect to the muscle weight of the right limb.
  • the muscle weight of the left limb (nervectomy) relative to the right limb (sham surgery) is small, indicating that the induction of disuse muscle atrophy has occurred reliably.
  • the mangosteen extract was administered, the atrophy of the soleus and tibial muscles was reduced, and when BCAA (positive control) was administered, the atrophy of the soleus and tibial muscles was reduced.
  • the mangosteen extract was considered to have a disuse muscular atrophy inhibitory effect.
  • Atrogin-1 forward 5′-ACCTGCCCTTGTGCTTACAA-3 ′ (SEQ ID NO: 15)
  • FIG. 7 shows that the expression of Atrogin-1 in the right limb (sham surgery) of the mangosteen peel extract group is lower than that in the right limb (sham surgery) of the control group, and the same is true for the left limb (nervectomy).
  • FIG. 8 shows a similar tendency with MuRF-1, suggesting that the consumption of mangosteen extract suppresses disuse muscle atrophy.
  • Mangosteen extracts 4 and 5 Mangosteen juice extract
  • Mangosteen juice containing 100% pulp from Thailand hereinafter 100% mangosteen juice
  • 70% mangosteen juice containing 30% peel extract hereinafter "mangosteen juice" 70% pulpy mangosteen juice
  • the pericarp extract is a hot water extract of pericarp obtained by washing mangosteen fruit and extracting the pericarp generated in the process of obtaining mangosteen fruit juice with hot water, followed by filtration. Add 49.5 volumes of 99.5% ethanol to each 1L of juice, stir at room temperature for 2 hours, filter using filter paper, concentrate the liquid layer with an evaporator, and freeze-dry.
  • a method for producing season packed mangosteen juice includes mangosteen washing, sorting, crushing, heating, squeezing, blending, deaeration, sterilization, filling, cooling, and boxing.
  • the mangosteen extract is added to the squeezed mangosteen juice and prepared in the preparation step.
  • Salt is added only in the case of salt, nitrogen gas is mixed and degassed under reduced pressure, and the dissolved oxygen concentration is 3 ppm or less. Then, it is sterilized by heating at 121 ° C. for about 1 minute, cooled to 90 ° C., and filled into cans.
  • the manufacturing method of a concentrated reduction product opens a mangosteen concentrate in an opening process, and dilutes with water to a normal salt-free soluble solid content (4.5 or more). Thereafter, the mangosteen extract is added and prepared, and it is manufactured through deaeration, sterilization, filling, cooling, and boxing processes.
  • the mangosteen extract used as a raw material can be produced by referring to the method described in Example 1, 7, 9 or 12, for example.
  • Vegetable Mixed Juice Mangosteen juice obtained by diluting squeezed mangosteen juice or mangosteen concentrate to a specified salt-free soluble solid content (4.5 or more), various vegetable juices and xanthones It is prepared through degassing, sterilization, filling, cooling, and boxing processes.
  • xanthones used as raw materials include ⁇ -mangostin, ⁇ -mangostin, ⁇ -mangosteen, gartanine, isomangosteen, desoxygaltanine, caravaxanthone, hydroxy caravaxanthone, garcinone, mangostanol and the like.
  • both AMPK and PPAR ⁇ can be activated, and a highly safe coactivator can be provided.
  • a safe and highly effective exercise effect mimicking agent that can obtain a preferable biological response that is recognized when exercise is performed without performing exercise or with less exercise. You can also.
  • said agent can also be provided as taste food-drinks suitable for continuous ingestion.
  • the above-mentioned highly effective agent can be obtained easily and efficiently from mangosteen peel and the like, so that the waste can be effectively used.
  • the present invention has industrial applicability in the fields of foods and drinks, pharmaceuticals and reagents.

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Abstract

L'objectif de la présente invention est de fournir un agoniste qui imite l'effet cinétique et un co-activateur pour AMPK et PPARΔ. La présente invention concerne : un agoniste qui imite un effet cinétique, lequel comprend un extrait de mangoustan; et un co-activateur pour AMPK et PPARΔ, lequel comprend un extrait de mangoustan.
PCT/JP2013/054806 2012-02-28 2013-02-25 AGONISTE QUI IMITE L'EFFET CINÉTIQUE, ET CO-ACTIVATEUR POUR AMPK ET PPARδ WO2013129334A1 (fr)

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JP2018058792A (ja) * 2016-10-05 2018-04-12 サッポロホールディングス株式会社 Ｐｃｓｋ９阻害剤及びコレステロール代謝改善用食品組成物
JP2018523678A (ja) * 2015-09-21 2018-08-23 インダストリー−アカデミック コーオペレイション ファウンデーション キョンサン ナショナル ユニバーシティ β−マンゴスチンを有効成分として含有する肌美白用組成物
CN112438922B (zh) * 2019-08-27 2023-04-07 百岳特生物技术（上海）有限公司 山竹发酵液用于制备美肌及/或减脂组合物的用途

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Cited By (6)

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Publication number Priority date Publication date Assignee Title
JP2018523678A (ja) * 2015-09-21 2018-08-23 インダストリー−アカデミック コーオペレイション ファウンデーション キョンサン ナショナル ユニバーシティ β−マンゴスチンを有効成分として含有する肌美白用組成物
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WO2017086232A1 (fr) * 2015-11-17 2017-05-26 国立研究開発法人国立循環器病研究センター Agent prophylactique/thérapeutique
JP2018058792A (ja) * 2016-10-05 2018-04-12 サッポロホールディングス株式会社 Ｐｃｓｋ９阻害剤及びコレステロール代謝改善用食品組成物
JP7105536B2 (ja) 2016-10-05 2022-07-25 ポッカサッポロフード＆ビバレッジ株式会社 Ｐｃｓｋ９阻害剤及びコレステロール代謝改善用食品組成物
CN112438922B (zh) * 2019-08-27 2023-04-07 百岳特生物技术（上海）有限公司 山竹发酵液用于制备美肌及/或减脂组合物的用途

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