WO2024128298A1 - Agent pour améliorer l'endurance et/ou réduire la fatigue physique - Google Patents

Agent pour améliorer l'endurance et/ou réduire la fatigue physique Download PDF

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WO2024128298A1
WO2024128298A1 PCT/JP2023/044944 JP2023044944W WO2024128298A1 WO 2024128298 A1 WO2024128298 A1 WO 2024128298A1 JP 2023044944 W JP2023044944 W JP 2023044944W WO 2024128298 A1 WO2024128298 A1 WO 2024128298A1
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improving
sialyllactose
salt
endurance
agent
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Japanese (ja)
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幸宏 菱田
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協和発酵バイオ株式会社
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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
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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 an agent for at least one of improving endurance and reducing physical fatigue, use of sialyllactose or a salt thereof for producing the agent, sialyllactose or a salt thereof for use as the agent, a method for at least one of a method for improving endurance and a method for reducing physical fatigue, an adenosine monophosphate protein kinase activator, a composition for preventing sarcopenia, improving lipid metabolism, improving insulin resistance, and improving glucose metabolism, a glycogen synthase activator, and a composition for improving endurance.
  • Endurance is the ability to maintain a certain level of physical activity. Endurance is not limited to competitive sports such as marathons, but is essential for sustaining all physical activity, including work, housework, walking, and other daily activities. A decrease in activity capacity caused by overload of physical activity is called physical fatigue. By improving endurance, you can create a body that does not tire easily and can maintain a healthy daily life, which can be expected to speed up recovery from physical fatigue.
  • Sialyllactose (hereinafter also referred to as "SL") is a sialic acid compound in which lactose and N-acetylneuraminic acid are bonded, and is a type of oligosaccharide found in breast milk, cow's milk, and dairy products.
  • the SLs found in human breast milk are known to be 3'-sialyllactose (hereinafter also referred to as "3'-SL”), in which N-acetylneuraminic acid is bonded to the galactose residue of lactose via an ⁇ 2-3 bond, and 6'-sialyllactose (hereinafter also referred to as "6'-SL”), in which N-acetylneuraminic acid is bonded via an ⁇ 2-6 bond.
  • 3'-SL 3'-sialyllactose
  • 6'-SL 6'-sialyllactose
  • Non-Patent Document 1 discloses that SL acts as a prebiotic and contributes to the formation and development of the intestinal flora of infants and young children, and also exhibits a preventive effect against pathogenic bacteria infection, including pathogenic Escherichia coli, in the maturation of intestinal tissue and in the intestine.
  • pathogenic bacteria infection including pathogenic Escherichia coli
  • immunostimulatory and anti-inflammatory actions specifically effects against irritable colitis and necrotizing enteritis, are also disclosed.
  • Patent Literature 1 discloses that SL acts on the central nervous system, including improving memory function, by regulating gangliosides in the brain, while Patent Literature 2 reports that the action of SL on the central nervous system improves fatigue.
  • the present invention therefore aims to provide an agent for improving endurance and/or reducing physical fatigue, which contains sialyllactose or a salt thereof as an active ingredient.
  • an agent containing sialyllactose or a salt thereof as an active ingredient exhibits endurance-improving effects and physical fatigue-reducing effects, and further discovered that these effects are due to the adenosine monophosphate protein kinase activating effect or glycogen synthase activating effect of sialyllactose or a salt thereof, thus completing the present invention.
  • the present invention relates to the following.
  • An agent for improving endurance and/or reducing physical fatigue comprising sialyllactose or a salt thereof as an active ingredient.
  • Sialyllactose or a salt thereof for use as an agent for improving endurance and/or reducing physical fatigue.
  • a glycogen synthase activator comprising sialyllactose or a salt thereof as an active ingredient.
  • a composition for improving endurance comprising the activator according to [8] as an active ingredient.
  • the present invention also relates to the following: Use of sialyllactose or a salt thereof for producing an adenosine monophosphate protein kinase activator. Sialyllactose or a salt thereof for use as an adenosine monophosphate protein kinase activator. A method for activating adenosine monophosphate protein kinase, comprising administering sialyllactose or a salt thereof.
  • an adenosine monophosphate protein kinase activator containing sialyllactose or a salt thereof as an active ingredient to manufacture a composition for one or more of the following: prevention of sarcopenia, improvement of lipid metabolism, improvement of insulin resistance, and improvement of glucose metabolism.
  • One or more methods for preventing sarcopenia, improving lipid metabolism, improving insulin resistance, and improving glucose metabolism comprising administering an adenosine monophosphate protein kinase activator containing sialyllactose or a salt thereof as an active ingredient.
  • sialyllactose or a salt thereof for producing a glycogen synthase activator.
  • a method for activating glycogen synthase comprising administering sialyllactose or a salt thereof.
  • glycogen synthase activator containing sialyllactose or a salt thereof as an active ingredient for producing a composition for improving endurance A glycogen synthase activator containing sialyllactose or a salt thereof as an active ingredient for use as a composition for improving endurance.
  • a method for improving endurance comprising administering a glycogen synthase activator containing sialyllactose or a salt thereof as an active ingredient.
  • the agent of the present invention contains sialyllactose or a salt thereof as an active ingredient, which can improve endurance and/or reduce physical fatigue.
  • the agent of the present invention contains sialyllactose or a salt thereof as an active ingredient, which can activate adenosine monophosphate protein kinase and/or glycogen synthase.
  • FIG. 1 is a graph showing the distance traveled immediately after swimming exercise of nematodes reared in the presence of 3'-SL, 6'-SL, sialic acid, or lactose.
  • FIG. 2 shows a heat map and a dendrogram of metabolites in nematodes after they were reared in the presence of 3'-SL or 6'-SL and subjected to swimming exercise.
  • FIG. 3 is a graph showing the oxygen consumption rate in mitochondria of nematodes reared in the presence of 3'-SL or 6'-SL.
  • FIG. 4 is a graph showing the distance traveled by nematodes lacking a specific gene that were reared in the presence of 3'-SL or 6'-SL and subjected to swimming exercise.
  • FIG. 5 is a graph showing the distance traveled by nematodes lacking a specific gene that were reared in the presence of 3'-SL or 6'-SL and subjected to swimming exercise.
  • the present invention will be described in detail below, but these are merely examples of preferred embodiments and the present invention is not limited to these contents.
  • the numerical range “to” includes the numerical values before and after it. For example, "0% by mass to 100% by mass” means a range from 0% by mass or more to 100% by mass or less.
  • the agent for improving endurance and/or reducing physical fatigue contains sialyllactose or a salt thereof as an active ingredient.
  • the agent for improving endurance and/or reducing physical fatigue contains SL or a salt thereof as an active ingredient, and can contribute to improving endurance or reducing physical fatigue. Furthermore, the endurance-improving effect and physical fatigue-reducing effect of SL are due to the activation of adenosine monophosphate protein kinase (hereinafter also referred to as "AMPK") and the activation of glycogen synthesis.
  • AMPK adenosine monophosphate protein kinase
  • AMPK is encoded by, for example, the aak-1 gene of humans or nematodes, and is an important regulatory protein involved in maintaining intracellular energy homeostasis. AMPK promotes energy metabolism by sensing the intracellular energy state and regulating lipid metabolism and glucose metabolism. AMPK is distributed in many organs and tissues, such as the liver and heart, and is a master regulator that mediates beneficial cellular adaptations in many important tissues and organs. Such adaptations are also beneficial in exercise and various physical activities. It is known that AMPK is also activated by exercise (Annu Rev Physiol, 2022 Feb 10, 84, 209-227.), and that exercise-induced activation of AMPK improves endurance (Cell, 2008 Aug 8, 134(3), 405-415.).
  • AMPK is known to be activated by exercise, fat cell-derived hormones such as leptin (Nature, 2002, volume 415, pages 339-343.) and adiponectin (Cell Metab, 2007 Jul, 6(1), 55-68.), and some diabetes treatment drugs such as metformin (J Clin Invest, 2001 Oct 15, 108(8), 1167-1174.).
  • AMPK is thought to contribute to the prevention or improvement of lifestyle-related diseases such as obesity and diabetes through the improvement of lipid metabolism, glucose metabolism, and insulin resistance (J Clin Invest, 2013 Jul, 123(7), 2764-2772.).
  • the SL or a salt thereof of the present invention can be used as an AMPK activator, and further can be used as a composition containing this AMPK activator as an active ingredient for one or more of the following purposes: preventing sarcopenia, improving lipid metabolism, improving insulin resistance, and improving glucose metabolism.
  • Glycogen is mainly synthesized in the liver and skeletal muscles, and glycogen in skeletal muscles is used as an energy source for muscle contraction. It has been disclosed that mice lacking glycogen synthase specifically in muscle have reduced endurance (Molecular metabolism, 2016, Volume 5, Issue 3, 221-232.), and glycogen is known to affect endurance. Glycogen synthase is encoded by the gsy-1 gene of humans or nematodes, for example. Therefore, the SL or a salt thereof of the present invention can be used as a glycogen synthase activator containing them as an active ingredient, and further can be used as a composition for improving endurance containing this glycogen synthase activator as an active ingredient.
  • the SL used in the present invention may be 3'-SL or 6'-SL.
  • the SL used in the present invention may be obtained by any production method, such as fermentation, enzymatic methods, extraction from natural products, or chemical synthesis.
  • salts of SL include acid addition salts, metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts.
  • acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, and phosphate, and organic acid salts such as acetate, maleate, fumarate, citrate, malate, lactate, ⁇ -ketoglutarate, gluconate, and caprylate.
  • metal salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, zinc salts, etc.
  • ammonium salts include salts of ammonium and tetramethylammonium, etc.
  • organic amine addition salts include salts of morpholine and piperidine, etc.
  • amino acid addition salts include salts of glycine, phenylalanine, lysine, aspartic acid, and glutamic acid.
  • SL salts sodium salts are preferably used, but other salts or a suitable combination of two or more salts may also be used.
  • an adenosine monophosphate protein kinase activator or a glycogen synthase activator according to an embodiment of the present invention, SL or a salt thereof can be administered as is, but it is usually preferable to provide it as a preparation of various kinds.
  • the agent for improving endurance and/or reducing physical fatigue, adenosine monophosphate protein kinase activator or glycogen synthase activator according to the embodiment of the present invention can be a formulation in any form.
  • the formulation can be prepared by mixing the active ingredient with one or more pharmacologically acceptable carriers and by any method well known in the technical field of pharmaceuticals.
  • the formulation may further contain any other active ingredient for treatment.
  • additives such as excipients, binders, disintegrants, lubricants, dispersants, suspending agents, emulsifiers, diluents, buffers, antioxidants, and bacteria inhibitors can be used.
  • Dosage forms may include oral preparations such as tablets, powders, granules, pills, suspensions, emulsions, infusions/decoctions, capsules, syrups, liquids, elixirs, extracts, tinctures, and liquid extracts, as well as parenteral preparations such as injections, drips, creams, and suppositories, with oral preparations being preferred.
  • oral preparations such as tablets, powders, granules, pills, suspensions, emulsions, infusions/decoctions, capsules, syrups, liquids, elixirs, extracts, tinctures, and liquid extracts, as well as parenteral preparations such as injections, drips, creams, and suppositories, with oral preparations being preferred.
  • the formulation can be prepared by adding sugars such as lactose, glucose, sucrose, mannitol, and sorbitol; starches from potato, wheat, corn, and the like; inorganic substances such as calcium carbonate, calcium sulfate, sodium bicarbonate, and sodium chloride; excipients such as crystalline cellulose, plant powders such as licorice powder and gentian powder; disintegrants such as starch, agar, gelatin powder, crystalline cellulose, carmellose sodium, carmellose calcium, calcium carbonate, sodium bicarbonate, and sodium alginate; lubricants such as magnesium stearate, talc, hydrogenated vegetable oil, macrogol, and silicone oil; binders such as polyvinyl alcohol, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, carmellose, gelatin, and starch paste; surfactants such as fatty acid esters; and
  • the dosage form suitable for oral administration is a liquid preparation such as a syrup
  • it can be formulated by adding water, sugars such as sucrose, sorbitol, and fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil, and soybean oil, preservatives such as p-hydroxybenzoic acid esters, parahydroxybenzoic acid derivatives such as methyl parahydroxybenzoate, preservatives such as sodium benzoate, and flavors such as strawberry flavor and peppermint.
  • sugars such as sucrose, sorbitol, and fructose
  • glycols such as polyethylene glycol and propylene glycol
  • oils such as sesame oil, olive oil, and soybean oil
  • preservatives such as p-hydroxybenzoic acid esters, parahydroxybenzoic acid derivatives such as methyl parahydroxybenzoate, preservatives such as sodium benzoate, and flavors such as strawberry flavor and peppermint.
  • the dosage form suitable for parenteral administration is an injection
  • it is preferably composed of a sterile aqueous agent containing SL or a salt thereof that is isotonic with the blood of the recipient.
  • a solution for injection can be prepared using a carrier consisting of a salt solution, a glucose solution, or a mixture of a salt solution and a glucose solution.
  • additives generally used in food and beverages may be added to a preparation suitable for oral administration.
  • additives include sweeteners, colorants, preservatives, thickening stabilizers, antioxidants, colorants, bleaching agents, fungicides, gum bases, bittering agents, enzymes, glazing agents, acidulants, seasonings, emulsifiers, strengthening agents, manufacturing agents, fragrances, and spice extracts.
  • the dosage form of the preparation is preferably the most effective one for improving endurance and/or reducing physical fatigue, and may be oral or parenteral, such as intravenous, intraperitoneal or subcutaneous, with oral administration being preferred.
  • the concentration of SL or a salt thereof in the agent for improving endurance and/or reducing physical fatigue is appropriately selected depending on the type of preparation and the effect expected from administration of the preparation, etc., but for example, in the case of an oral preparation, the concentration of SL or a salt thereof is preferably 0.1 to 100% by mass, more preferably 0.2 to 100% by mass, even more preferably 1 to 100% by mass, particularly preferably 50 to 100% by mass, and most preferably 80 to 100% by mass.
  • the agent for improving endurance and/or reducing physical fatigue may further contain a component having an endurance exercise effect, so long as the effect of the present invention is not impaired.
  • a component having an endurance exercise effect include B vitamins, caffeine, green tea extract such as catechin, L-carnitine, capsaicin, taurine, branched amino acids (valine, leucine, isoleucine), citrulline, arginine, ⁇ -alanine, astaxanthin, carnosine, carnitine, ⁇ -lipoic acid, coenzyme Q10, etc.
  • the agent for improving endurance and/or reducing physical fatigue may be taken together with a protein or a supplement having a fat burning effect.
  • the protein may be a commercially available product obtained by extracting and purifying protein contained in animals or plants.
  • Target subjects for administration in the present invention include, but are not limited to, humans or animals in need of reducing fatigue caused by physical activity in daily life, improving endurance and reducing fatigue in work involving muscular exertion, improving endurance during exercise in the narrow sense, and promoting recovery from fatigue during or after exercise in the narrow sense.
  • the agent for improving endurance and/or reducing physical fatigue can be used in a form suitable for human or animal food, medicine, or quasi-drug.
  • an adenosine monophosphate protein kinase activator or a glycogen synthase activator can be used in foods, functional foods, foods for the sick, and foods for specified health uses that are labeled as improving endurance and/or reducing physical fatigue.
  • General foods and beverages include, for example, various beverages, various foods, processed foods, liquid foods (such as soups), seasonings, nutritional drinks, and confectioneries.
  • processed foods refers to natural ingredients (such as animals and plants) that have been processed and/or cooked.
  • processed foods include processed meat products, processed vegetable products, processed fruit products, frozen foods, retort foods, canned foods, bottled foods, and instant foods.
  • the foods of the present invention may also be provided in a form sealed in a bag or container.
  • the bags and containers used in the present invention may be any bags and containers normally used for foods.
  • the shape of the food can be in any food shape that is normally distributed, such as a solid (e.g., powder or granules), liquid, liquid food, jelly, tablet, granule, capsule, paste, or suspension.
  • Food can be produced by a method commonly used by those skilled in the art, and carbohydrates, proteins, lipids, dietary fiber, vitamins, biologically essential trace metals (e.g., manganese sulfate, zinc sulfate, magnesium chloride, potassium carbonate, etc.), flavorings, and other ingredients may be added, so long as they do not interfere with at least one of the effects of SL or its salts of improving endurance and reducing physical fatigue.
  • the amount of SL or a salt thereof in the above-mentioned composition varies depending on the form of use, but in the form of food, it is preferably 5 to 70% by mass, more preferably 10 to 60% by mass, and even more preferably 20 to 60% by mass. In the case of beverages, it is preferably 0.05 to 10% by mass, more preferably 0.1 to 5% by mass, and even more preferably 0.5 to 3% by mass. In the case of food tablets such as tablets and/or capsules, it is preferably 10 to 95% by mass, more preferably 20 to 90% by mass, and even more preferably 50 to 85% by mass.
  • the amount of SL or a salt thereof is preferably 0.01 to 100% by mass, more preferably 0.5 to 80% by mass, and even more preferably 1 to 70% by mass.
  • the present invention also encompasses the following: - Use of sialyllactose or a salt thereof for producing an agent for improving endurance and/or reducing physical fatigue. - Sialyllactose or a salt thereof for use as an agent for improving endurance and/or reducing physical fatigue. - A method which is at least one of a method for improving endurance and a method for reducing physical fatigue, comprising administering sialyllactose or a salt thereof. Use of sialyllactose or a salt thereof for producing an adenosine monophosphate protein kinase activator. Sialyllactose or a salt thereof for use as an adenosine monophosphate protein kinase activator.
  • a method for activating adenosine monophosphate protein kinase comprising administering sialyllactose or a salt thereof.
  • sialyllactose or a salt thereof as an active ingredient to manufacture a composition for one or more of the following: prevention of sarcopenia, improvement of lipid metabolism, improvement of insulin resistance, and improvement of glucose metabolism.
  • An adenosine monophosphate protein kinase activator containing sialyllactose or a salt thereof as an active ingredient for use as a composition for one or more of preventing sarcopenia, improving lipid metabolism, improving insulin resistance, and improving glucose metabolism.
  • One or more methods for preventing sarcopenia, improving lipid metabolism, improving insulin resistance, and improving glucose metabolism which comprise administering an adenosine monophosphate protein kinase activator containing sialyllactose or a salt thereof as an active ingredient.
  • sialyllactose or a salt thereof for producing a glycogen synthase activator.
  • a method for activating glycogen synthase comprising administering sialyllactose or a salt thereof.
  • a glycogen synthase activator containing sialyllactose or a salt thereof as an active ingredient for producing a composition for improving endurance A glycogen synthase activator containing sialyllactose or a salt thereof as an active ingredient for use as a composition for improving endurance.
  • a method for improving endurance comprising administering a glycogen synthase activator containing sialyllactose or a salt thereof as an active ingredient.
  • the dosage and frequency of administration of the agent for improving endurance and/or reducing physical fatigue, adenosine monophosphate protein kinase activator, glycogen synthase activator, etc. will vary depending on the administration form, the age and weight of the recipient, and the nature or severity of the symptoms to be improved, but will generally be administered once or several times a day so that the daily dose of SL or a salt thereof for an adult is preferably 50 mg to 30 g, more preferably 100 mg to 10 g, and particularly preferably 200 mg to 3 g.
  • the dosage and frequency of administration of the agent for improving endurance and/or reducing physical fatigue is not particularly limited, and may be administered, for example, before or after physical activity in daily life, work involving muscular exertion, or exercise in the narrow sense that may cause fatigue, but it is preferable to administer it before physical activity in daily life, work involving muscular exertion, or exercise in the narrow sense.
  • Example 1 Based on the literature (Laranjeiro, Ricardo, Girish Harinath, Daniel Burke, Bart P. Braeckman, and Monica Driscoll. 2017. “Single Swim Sessions in C. Elegans Induce Key Features of Mammalian Exercise.” BMC Biology15 (1).), the effect of administering SL on endurance was evaluated using the nematode Caenorhabditis elegans N2 strain (obtained from the Caenorhabditis Genetics Center).
  • nematode eggs were synchronized by stirring for 45 to 60 seconds using a 2% hypochlorous acid solution, and then cultured overnight in M9 buffer (3 g/L KH2PO4 , 6 g/L Na2HPO4 , 5 g/L NaCl, 1 mM MgSO4 ) to obtain larvae immediately after hatching (hereinafter referred to as L1 larvae).
  • M9 buffer 3 g/L KH2PO4 , 6 g/L Na2HPO4 , 5 g/L NaCl, 1 mM MgSO4
  • the obtained L1 larvae were synchronized, and then about 200 L1 larvae per plate were reared in an incubator at 20°C for 11 days on NGM agar plates (3 g/L NaCl, 17 g/L agar, 2.5 g/L peptone, 1 mM CaCl2 , 5 mg/L cholesterol (dissolved in ethanol), 1 mM MgSO4 , 25 mM KPO4 buffer (pH 6)) coated with the following evaluation samples and E. coli OP strain (obtained from Caenorhabditis Genetics Center).
  • the reared nematodes (hereinafter referred to as "aged animals") were subjected to a swimming exercise stress test described below.
  • SIA sialic acid
  • LAC lactose
  • the aged animals were suspended in M9-Tween buffer (3 g/L KH 2 PO 4 , 6 g/L Na 2 HPO 4 , 5 g/L NaCl, 1 mM MgSO 4 ) for each plate, collected in a 15 mL tube, centrifuged (2,500 rpm, 1 minute), and the supernatant was removed to collect the nematodes.
  • 2 ml of M9-Tween buffer was added to the collected nematodes, and they were subjected to swimming exercise in the buffer for 120 minutes.
  • the nematodes reared on the control plate were divided into a group subjected to swimming exercise (control group) and a control group not subjected to swimming exercise.
  • the control group not subjected to swimming exercise was reared for another 120 minutes on an NGM agar plate coated with E. coli OP50 strain, instead of being suspended in M9-Tween buffer and subjected to swimming exercise.
  • Example 2 In order to analyze the mechanism of the endurance-improving effect of 3'-SL or 6'-SL found in Example 1, metabolite profiles were analyzed when 3'-SL or 6'-SL was administered to nematodes and they were subjected to an exercise load.
  • Example 2 L1 larvae obtained in the same manner as in Example 1 were synchronized and then reared on NGM agar plates coated with E. coli OP strain in an incubator at 16° C. for 96 hours.
  • the NGM agar plates were the same as in Example 1.
  • the number of L1 larvae reared was about 200/plate, and the amount of E. coli OP50 strain applied was about 10 cfu/plate.
  • the nematodes thus reared were collected and further reared on NGM agar plates supplemented with 3'-SL or 6'-SL and E. coli OP strain in the same manner as in Example 1.
  • the concentration of 3'-SL or 6'-SL added was 2 mg/ml. Purified water was used as a control.
  • the amount of E. coli OP50 strain applied was approximately 10 7 cfu/plate.
  • Example 2 the nematodes were suspended in M9-Tween buffer, collected, and subjected to swimming exercise.
  • a control group (Control group) was set up in which the nematodes were raised on NGM agar plates coated with E. coli OP strain, and a group (Crawling group) was set up in which the nematodes were allowed to move freely on NGM agar plates not coated with E. coli OP strain.
  • the collected supernatant was dried using a centrifugal concentrator and then dissolved in 100 ⁇ l of pyridine anhydrous 99.8% (Sigma-Aldrich) containing 0.2 mg/ml methyl palmitate.
  • GC-MS gas chromatography-mass
  • the area under the curve (AUC) of the peaks identified using MZMine was calculated, and a total of 106 types of metabolite profiles were obtained. These metabolite profiles were subjected to principal component analysis, and a heat map was created for the top 50% of metabolites that showed the greatest contribution to the second principal component. Furthermore, the similarity of the profiles of each metabolite in each experimental group was summarized in a dendrogram. The heat map and dendrogram are shown in Figure 2.
  • the heatmap revealed that there were multiple metabolites in each group that showed similar metabolite level patterns. Based on the patterns of these metabolite levels, among the metabolites generally known to be associated with exercise, the metabolites that increased in the exercise load control group (swimming group) were classified as "activity", and the metabolites that decreased were classified as "rest”. In addition, among the metabolites generally known to be associated with nutritional status, the metabolites that increased in the exercise load control group (control group) were classified as "energy abundance”, and the metabolites that decreased were classified as "energy depletion”.
  • metabolites classified as "energy abundance” or “energy depletion” related to nutritional state which increased in the no-exercise control group (Control group), decreased in the SL-administered groups (Swimming + 3'-SL group and swimming + 6'-SL group), and metabolites which decreased in the no-exercise control group (Control group) increased in the SL-administered groups.
  • metabolites classified as "energy abundance” such as ascorbic acid, kynurenine, phenylalanine, and tyrosine, are known to affect exercise performance (Martin KS, Azzolini M, Ruas JL.
  • the kynurenine connection how exercise shifts muscle tryptophan metabolism and affects energy homeostasis,the immune system, and the brain.
  • the effects of phenylalanine on exercise-induced fat oxidation Apreliminary, double-blind, placebo-controlled, crossover trial.
  • Example 3 The effect of administration of SL on the oxygen consumption rate (OCR) in mitochondria of C. elegans was evaluated.
  • the L1 larvae were raised on NGM agar plates containing a solution of 3'-SL or 6'-SL dissolved in purified water at a concentration of 2 mg/ml and E. coli OP strain at 16°C for 72 hours until the L4 stage, and L4 larvae were obtained.
  • the NGM agar plates were the same as in Example 1. 100 ⁇ L/plate of the solution containing 3'-SL or 6'-SL was used. Approximately 200 L1 larvae were raised/plate, and the amount of E. coli OP50 strain applied was approximately 10 7 cfu/plate.
  • the control group was raised on an agar plate applied with purified water.
  • the L4 larvae were suspended in M9-Tween buffer and collected. 30 ⁇ l of the suspension containing 80 L4 larvae was cultured in a sealed Polymethylmethacrylate (PMMA) 48-well plate (Merrem) at 22°C, and the OCR was measured after 1 hour.
  • PMMA 48-well plate has two 20 mm thick plates, an upper plate and a lower plate.
  • the upper plate is a 48-well plate filled with fluorinated silicone polymer as an oxygen-sensitive coating.
  • the lower plate has 48 wells for culturing nematodes in M9 buffer, and the bottom of each well is coated with fluorinated silicone polymer.
  • the OCR was measured using a Q2 Respiration Analyzer (Fytagoras B.V.).
  • This Q2 Respiration Analyzer automatically tracks the oxygen concentration over a fixed period of time.
  • a large number of capsuled samples can be placed inside the analyzer, and the oxygen concentration inside the capsule is automatically measured at fixed intervals and the data is output.
  • the results of the oxygen consumption rate calculated from the oxygen concentration are shown in Figure 3. *** means p ⁇ 0.001.
  • QQ255 strain (genotype: gsy-1 (gk397885) II., obtained from Caenorhabditis Genetics Center) (hereinafter also referred to as "QQ") in which the gsy-1 gene (NIH Gene ID: 174924) has been deleted
  • CB7468 strain (genotype: acs-22 (gk373989) X., obtained from Caenorhabditis Genetics Center) (hereinafter also referred to as "CB") in which the acs-22 gene (NIH Gene ID: 181138) has been deleted
  • CB CB7468 strain
  • VC225 strain (genotype: tps-1 (ok373) X., obtained from Caenorhabditis Genetics Center) (hereinafter also referred to as "VC")
  • WT wild-type Caenorhabditis elegans N2 strain
  • the NB245 strain (genotype: aak-1(tm1944) III; aak-2(gt33) X., obtained from the Caenorhabditis Genetics Center) (hereinafter also referred to as "NB"), in which the aak-1 gene (NIH Gene ID: 176230) and the aak-2 gene (NIH Gene ID: 181727) have been deleted, the MT15434 strain (genotype: tph-1(mg280) II., obtained from the Caenorhabditis Genetics Center) (hereinafter also referred to as "MT"), the skn-1 gene (NIH Gene ID: The GR2245 strain (genotype: skn-1 (mg570) IV., obtained from: Caenorhabditis Genetics Center) (hereinafter also referred to as "GR") lacking the ador-1 gene (NIH Gene ID: 177343), the EG6890 strain (genotype: ador-1 (ox48
  • Soares lab (hereinafter also referred to as "EG") lacking the ador-1 gene (NIH Gene ID: 174890), and the wild-type Caenorhabditis elegans N2 strain (hereinafter also referred to as "WT”) as a control were used, and the evaluation sample was applied to an NGM agar plate.
  • the effect of adding 3'-SL or 6'-SL on endurance was evaluated in the same manner as in Example 1.
  • the concentration of 3'-SL or 6'-SL in the evaluation samples was 2 mg/ml. Purified water was used as a control.
  • the results are shown in Figure 5.
  • (-) indicates no exercise load, and (+) indicates exercise load.
  • * indicates p ⁇ 0.05, ** indicates p ⁇ 0.01, and *** indicates p ⁇ 0.001.
  • the agent of the present invention contains sialyllactose or a salt thereof as an active ingredient, and thereby exerts at least one of the effects of improving endurance and reducing physical fatigue.

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Abstract

La présente invention concerne : un agent pour améliorer l'endurance et/ou réduire la fatigue physique qui contient du sialyllactose ou un sel de celui-ci en tant que principe actif ; l'utilisation de sialyllactose ou d'un sel de celui-ci pour produire l'agent ; le sialyllactose ou un sel de celui-ci à utiliser en tant qu'agent ; un procédé pour améliorer l'endurance et/ou réduire la fatigue physique ; une composition qui est au moins l'un parmi un activateur de protéine kinase de monophosphate d'adénosine et des compositions pour prévenir la sarcopénie, pour améliorer le métabolisme lipidique, pour améliorer la résistance à l'insuline, et pour améliorer le métabolisme du glucose ; un activateur de glycogène synthase ; et une composition pour améliorer l'endurance.
PCT/JP2023/044944 2022-12-14 2023-12-14 Agent pour améliorer l'endurance et/ou réduire la fatigue physique WO2024128298A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010131712A1 (fr) * 2009-05-15 2010-11-18 財団法人ヒューマンサイエンス振興財団 Agent pharmaceutique destine au traitement des maladies associees a une diminution de la fonction de la proteine gne, composition et additif alimentaires
WO2019087140A1 (fr) * 2017-11-02 2019-05-09 Glycom A/S Un ou plusieurs hmos pour réduire ou prévenir la fatigue et/ou améliorer la focalisation ou la concentration
JP2021127321A (ja) * 2020-02-14 2021-09-02 森永乳業株式会社 持久力向上用組成物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010131712A1 (fr) * 2009-05-15 2010-11-18 財団法人ヒューマンサイエンス振興財団 Agent pharmaceutique destine au traitement des maladies associees a une diminution de la fonction de la proteine gne, composition et additif alimentaires
WO2019087140A1 (fr) * 2017-11-02 2019-05-09 Glycom A/S Un ou plusieurs hmos pour réduire ou prévenir la fatigue et/ou améliorer la focalisation ou la concentration
JP2021127321A (ja) * 2020-02-14 2021-09-02 森永乳業株式会社 持久力向上用組成物

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