WO2023140406A1 - COMPOSITION PHARMACEUTIQUE COMPRENANT DU β-SITOSTÉROL POUR PRÉVENIR OU TRAITER LA SARCOPÉNIE - Google Patents

COMPOSITION PHARMACEUTIQUE COMPRENANT DU β-SITOSTÉROL POUR PRÉVENIR OU TRAITER LA SARCOPÉNIE Download PDF

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WO2023140406A1
WO2023140406A1 PCT/KR2022/001159 KR2022001159W WO2023140406A1 WO 2023140406 A1 WO2023140406 A1 WO 2023140406A1 KR 2022001159 W KR2022001159 W KR 2022001159W WO 2023140406 A1 WO2023140406 A1 WO 2023140406A1
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Prior art keywords
muscle
sitosterol
sarcopenia
preventing
pharmaceutical composition
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PCT/KR2022/001159
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English (en)
Korean (ko)
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유준일
하영술
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경상국립대학교병원
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Priority to PCT/KR2022/001159 priority Critical patent/WO2023140406A1/fr
Publication of WO2023140406A1 publication Critical patent/WO2023140406A1/fr

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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
    • 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
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating sarcopenia.
  • Sarcopenia began in 1989 when Irwin Rosenberg introduced the term 'sarcopenia', and it is a compound word of "sarco" meaning muscle in Greek and "penia” meaning reduction.
  • Sarcopenia refers to a disease in which muscle strength decreases due to a decrease in muscle mass due to various reasons such as aging.
  • the main causes of sarcopenia include nerve damage, skeletal muscle damage, reduced activity due to knee joint damage, use of glucocorticoids, cancer, and aging.
  • a decrease in muscle mass due to sarcopenia can affect overall physical health by causing a decrease in metabolism, adult diseases caused by an increase in body fat, and bone diseases.
  • An object of the present invention is to provide a pharmaceutical composition for preventing or treating sarcopenia.
  • An object of the present invention is to provide a food composition for preventing or improving sarcopenia.
  • An object of the present invention is to provide a method for preventing or treating sarcopenia.
  • a pharmaceutical composition for preventing or treating sarcopenia comprising beta-sitosterol or a pharmaceutically acceptable salt thereof.
  • composition inhibits the transcriptional activity of FoxO1 (Forkhead box O1) to reduce the expression of at least one selected from the group consisting of MuRF1 (Muscle ring finger 1) or MAFbx (muscle atrophy F-box).
  • FoxO1 Formhead box O1
  • MuRF1 Muscle ring finger 1
  • MAFbx muscle atrophy F-box
  • a food composition for preventing or improving sarcopenia comprising beta-sitosterol or a food-acceptable salt thereof.
  • the pharmaceutical composition and food composition of the present invention can increase muscular strength, muscular endurance, and muscle fiber thickness, and ultimately exhibit preventive and/or therapeutic effects on sarcopenia.
  • the pharmaceutical composition and food composition of the present invention can reduce the expression of proteins related to muscular atrophy by inhibiting the transcription factor FoxO1 through inhibition of AMPK activity.
  • Figure 1 shows the results of confirming the effect of ⁇ - sitosterol on the expression of muscle loss-related biomarkers in the muscle loss cell model treated with dexamethasone.
  • Figure 6 shows the results of confirming the effect of ⁇ - sitosterol on the expression of muscle atrophy-related proteins in the gastrocnemius of the dexamethasone-induced muscular atrophy mouse model.
  • Figure 10 shows the results of confirming the effect of ⁇ - sitosterol on the expression of muscular atrophy-related proteins in the tibialis anterior muscle of the dexamethasone-induced muscular atrophy mouse model.
  • 11 to 13 show the results of confirming the effect of ⁇ -sitosterol on the expression of proteins related to muscular atrophy in the tibialis anterior muscle of the dexamethasone-induced muscular atrophy mouse model.
  • Figure 14 shows the results confirming the effect of ⁇ - sitosterol on body weight, endurance, and grip strength in the dexamethasone-induced muscular atrophy mouse model.
  • Figure 15 shows the results of confirming the effect of ⁇ -sitosterol on body weight, muscle mass and long extensor weight in the dexamethasone-induced muscular atrophy mouse model.
  • 16 to 17 show the results of confirming the effect of ⁇ -sitosterol on changes in muscle fiber thickness in the dexamethasone-induced muscular atrophy mouse model.
  • the present invention provides a pharmaceutical composition for preventing or treating sarcopenia comprising beta-sitosterol or a pharmaceutically acceptable salt thereof.
  • Beta-sitosterol is a compound represented by Formula 1 (C 29 H 50 O), and is known to have anti-ulcer, antibacterial, anti-inflammatory, and antioxidant effects, and recently its safety and efficacy have been recognized in the United States and Europe.
  • the compound of Formula 1 may be a material isolated from nature or chemically synthesized.
  • composition of the present invention includes beta-sitosterol or a pharmaceutically acceptable salt thereof, thereby reducing the expression of at least one selected from the group consisting of MuRF1 (Muscle ring finger 1) or MAFbx (muscle atrophy F-box).
  • MuRF1 Muscle ring finger 1
  • MAFbx muscle atrophy F-box
  • MuRF1 and MAFbx are downstream proteins of AMPK.
  • AMPK is known to be involved in the induction of muscle atrophy by directly involved in muscle protein degradation through the activation of the ubiquitin-proteasome pathway.
  • MAFbx is an F-box type E3 ligase
  • MuRF1 is a Ring Finger type E3 ligase.
  • Beta-sitosterol can also affect the expression of FoxOs, an AMPK downstream transcription factor.
  • beta-sitosterol can inhibit the transcriptional activity of FoxO1 (Forkhead box O1).
  • beta-sitosterol may not affect the expression of FoxO3.
  • beta-sitosterol inhibits the transcriptional activity of FoxO1 (Forkhead box O1) to reduce the expression of MuRF1 (Muscle ring finger 1) and MAFbx (muscle atrophy F-box), and can prevent, treat, or improve sarcopenia.
  • FoxO1 Formhead box O1
  • MuRF1 Muscle ring finger 1
  • MAFbx muscle atrophy F-box
  • pharmaceutically acceptable means that a compound or composition exhibits properties that do not cause serious irritation to an object, cell, tissue, etc. to which it is administered and do not impair the biological activity and physical properties of the compound.
  • pharmaceutically acceptable salt refers to a salt prepared using a specific compound according to the present invention with a relatively non-toxic acid or base.
  • a pharmaceutically acceptable salt may be, for example, an acid addition salt or a metal salt.
  • Acid addition salts can be formed from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid
  • non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • Such pharmaceutically non-toxic salts are sulfate, pyrosulfate, bisulphate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptane Noate, propylate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate , ethenesulfonate, chloro
  • the metal salt may be a sodium, potassium or calcium salt.
  • Metal salts can be prepared using bases, for example, alkali metal or alkaline earth metal salts can be obtained by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and/or drying the filtrate.
  • Sarcopenia refers to a condition in which muscles in the body are abnormally reduced or weakened due to various reasons such as aging, so that physical activity is not smooth. Sarcopenia was assigned a unique number of M62.84 in the 2016 International Classification of Disease, Tenth Revision, Clinical Modification (ICD-10-CM) Code, and was classified as a disease.
  • Sarcopenia may be caused by at least one cause selected from the group consisting of nerve damage, skeletal muscle damage, reduced activity due to knee joint damage, use of glucocorticoids, cancer, and aging.
  • prevention refers to overall prevention as well as preventive measures that result in any degree of reduction in the likelihood of developing a condition to be prevented or of a reoccurring or recurring condition, including slight, substantial or major reduction in the likelihood of developing or recurring of the condition, wherein the degree of reduction in likelihood is at least a minor reduction.
  • treatment refers to treatment that results in a beneficial effect on a subject or patient suffering from the condition being treated, including not only cure but also relief of any degree, including minor, substantial, major, and the degree of relief being at least minor.
  • the pharmaceutical composition of the present invention may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods, but is not limited thereto.
  • Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, dextrin, maltodextrin, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, but are not limited thereto. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants, but is not limited thereto.
  • Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, etc., such solid preparations are prepared by mixing the compound with at least one or more excipients, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like.
  • excipients for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like.
  • lubricants such as magnesium stearate and talc may also be used.
  • Liquid preparations for oral administration include suspensions, solutions for oral use, emulsions, syrups, etc., and various excipients such as wetting agents, sweeteners, aromatics, preservatives, etc. may be included in addition to water and liquid paraffin, which are commonly used simple diluents.
  • Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories.
  • Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
  • As a base for the suppository witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogeratin and the like may be used.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level may be determined according to the type of patient's disease, severity, drug activity, drug sensitivity, administration time, administration route and discharge rate, treatment period, factors including concurrently used drugs, and other factors well known in the medical field.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, which can be easily determined by a person skilled in the art.
  • the effective amount may vary depending on the patient's age, sex, and body weight, and is generally 1 to 6000 mg per kg of body weight, preferably 60 to 600 mg, which may be administered once or divided into three doses. However, since it may increase or decrease according to the route of administration, severity of disease, sex, weight, age, etc., the dosage is not limited to the scope of the present invention in any way.
  • the pharmaceutical composition of the present invention may be provided by mixing with conventionally known substances for preventing or treating sarcopenia.
  • the pharmaceutical composition of the present invention may be administered in combination with a known compound exhibiting a preventive or therapeutic effect on sarcopenia.
  • the present invention provides a food composition for preventing or improving sarcopenia comprising beta-sitosterol or a food-acceptable salt thereof.
  • Beta-sitosterol and sarcopenia have been described above, so a detailed description thereof will be omitted.
  • accepted food means that the compound or composition does not cause serious irritation to the organism, cells, tissues, etc. to which it is administered, and exhibits characteristics that do not impair the biological activity and physical properties of the compound.
  • acceptable food salt refers to a salt prepared using a specific compound according to the present invention and a relatively non-toxic acid or base, and the acceptable salt may be, for example, an acid addition salt or a metal salt.
  • the acid addition salt and the metal salt may be within the above range, but are not limited thereto.
  • the food composition may be prepared and processed in the form of tablets, capsules, powders, granules, liquids, pills and the like.
  • a food composition may contain conventional food additives, and its suitability as a food additive is determined by the standards and standards for the item in accordance with the General Rules of the Food Additive Code and General Test Methods approved by the Food and Drug Administration, unless otherwise specified.
  • Items listed in the Food Additives Codex include, for example, chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, kaoliang pigment, and guar gum; It includes, but is not limited to, mixed preparations such as sodium L-glutamate preparations, alkali additives for noodles, preservative preparations, and tar color preparations.
  • chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid
  • natural additives such as persimmon pigment, licorice extract, crystalline cellulose, kaoliang pigment, and guar gum
  • a food composition in the form of a tablet may be granulated by a conventional method of mixing the composition with an excipient, a binder, a disintegrant, and other additives, and then compression molded by adding a lubricant or the like, or directly compressed.
  • the food composition in the form of a tablet may contain a flavoring agent and the like, if necessary.
  • hard capsules may be prepared by filling a mixture obtained by mixing the composition with additives such as excipients in a conventional hard capsule
  • soft capsules may be prepared by filling a mixture obtained by mixing the composition with additives such as excipients into a capsule base such as gelatin.
  • the soft capsule may contain a plasticizer such as glycerin or sorbitol, a coloring agent, a preservative, and the like, if necessary.
  • the food composition in the form of a ring may be prepared by molding a mixture of the composition, excipients, binders, disintegrants, etc. in a conventionally known method, and, if necessary, may be coated with sucrose or other coating agents, or starch, The surface may be coated with a material such as talc.
  • a food composition in the form of a granule may be prepared by a conventionally known method of a mixture of the composition and an excipient, a binder, a disintegrant, etc., and may contain a flavoring agent, a flavoring agent, and the like, if necessary.
  • Food compositions include beverages, meat, chocolate, foods, and confectionery. It may be pizza, ramen, other noodles, chewing gum, candy, ice cream, alcoholic beverages, vitamin complexes, and health supplements.
  • the food composition may be applied orally for use as a nutrient, and the application form is not particularly limited.
  • the daily intake is preferably 5000 mg or less, more preferably 2000 mg or less, and most preferably 500 to 1500 mg or 650 mg daily.
  • one tablet can be administered with water once a day.
  • the present invention provides a composition for inhibiting at least one expression selected from the group consisting of FoxO1 (Forkhead box O1), MuRF1 (Muscle ring finger 1) and MAFbx (muscle atrophy F-box) containing beta-sitosterol or a salt thereof.
  • FoxO1 Formhead box O1
  • MuRF1 Muscle ring finger 1
  • MAFbx muscle atrophy F-box
  • composition for inhibiting expression can inhibit the expression of FoxO1 (Forkhead box O1), MuRF1 (Muscle ring finger 1) and MAFbx (muscle atrophy F-box) in vitro .
  • FoxO1 Formhead box O1
  • MuRF1 Muscle ring finger 1
  • MAFbx muscle atrophy F-box
  • the present invention provides a method for preventing or treating sarcopenia comprising administering beta-sitosterol or a pharmaceutically acceptable salt thereof to a subject.
  • Beta-sitosterol and sarcopenia have been described above, so a detailed description thereof will be omitted.
  • the subject may be a subject diagnosed with sarcopenia or a subject prior to onset of sarcopenia.
  • the subject may be an animal including a mammal.
  • the administration method may be oral administration or parenteral administration, and the specific method is not limited.
  • dexamethasone treatment group control group, Control
  • dexamethasone + sitosterol treatment group experimental group, DS
  • 20 mg/kg of dexamethasone was intraperitoneally administered between 10 and 11 am for 14 days to the control group and the DS group to create a muscular atrophy model.
  • no drug including vehicle was administered to the control group.
  • the DS treatment group was orally administered with sitosterol once daily at a dose of 200 mg/kg from 1 week before dexamethasone administration until the end of the experiment. Body weight was measured every 3 days before and after administration of dexamethasone.
  • Each control group and experimental group were euthanized on the day the experiment ended, and the left tibialis anterior muscle and gastrocnemius muscle were rapidly frozen in liquid nitrogen and stored at -80 ° C for use in identifying target proteins through Western blot.
  • Forelimb grip strength was measured in grams using a grip strength device (Bioseb, Chaville, France). The gauge was attached to a stainless steel T-bar. To test the grip strength, the mouse was held by its tail, placed with its front paws on the T-bar, and the tail was gently pulled back at a constant rate of about 2 cm/sec until the grip was released. The average of 5 measurements in each animal was calculated and evaluated.
  • Myoblasts were seeded at 3 ⁇ 10 5 /well in a 6-well culture plate containing 90% DMEM, 10% FBS, 100 units/ml of penicillin and streptomycin (PS)-added growth medium, and cultured in a 37°C CO 2 incubator.
  • a differentiation medium containing 2% horse serum (HS) and 100 unit/ml PS was used and cultured for 7 days while exchanging the differentiation medium once every 2 days.
  • HS horse serum
  • muscle atrophy was induced by treatment with dexamethasone (1 ⁇ M) or TNF- ⁇ (20 ng/ml) for 48 hours.
  • ⁇ -sitosterol SIGMA
  • ⁇ -sitosterol a useful component of field crops
  • Cells were washed twice with cold PBS and total RNA was isolated using Trizol solution.
  • the extracted 2 ⁇ g RNA was synthesized into cDNA using the iScript TM cDNA Synthesis Kit (Bio-Rad) according to the manual, and mRNA expression was performed on the ViiA TM 7 Real-Time PCR System (Applied Biosystems) using TaqMan analysis.
  • MuRF1 (Mm01185221_m1), MAFbx (Mm00499523_m1), MyoD (Mm00440387_m1), MyoG (Mm00446194_m1) and Myostatin (Mm01254559_m1) were used. After denaturation at 95°C for 10 minutes, the amplification was repeated 40 times at intervals of 15 seconds at 95°C and 60 seconds at 60°C, and the data obtained were analyzed.
  • mice muscle tissue was obtained, washed twice with cold PBS, dissolved in RIPA buffer, and total protein was extracted.
  • the extracted protein was separated using a 7.5% or 10% acrylamide gel and then transferred to a nitrocellulose membrane.
  • the membrane was blocked in a blocking buffer (0.1% Tween 20, 5% skim milk) and then incubated overnight at 4°C with a primary antibody.
  • the cells were washed with TBST 3 times, reacted with a peroxidase-conjugated secondary antibody for 1 hour, and then washed 3 times with TBST again. Protein bands were identified using the ECL detection system.
  • May-Grunwald and Giemsa staining which clearly shows the cell nucleus and root canal structure, was performed using cells treated with ⁇ -sitosterol, a useful component of field crops, and inducing muscle atrophy.
  • the differentiated myotube cells were washed with PBS, fixed with 100% methanol, and stained with May-Grunwald staining solution diluted in a 1:3 ratio in sodium phosphate buffer (1 mM NaH 2 PO 4 H 2 O, 1 mM Na 2 HPO 4 , pH 6.0) for 5 minutes.
  • the stained cells were washed with distilled water and stained for 10 minutes by adding Giemsa staining solution diluted in distilled water at a ratio of 1:10. Randomly divided into 4 compartments, stained cells were photographed under a microscope at 100 magnification, and cells were randomly selected in each compartment and the diameter of myotubes was measured using the ImageJ program.
  • the right tibialis anterior and gastrocne-mius muscles were removed, embedded in OCT compound (Lab-Tek: Miles Laboratories, Inc., Naperville, IL, USA), an embedding agent for frozen sections, and immediately frozen. Frozen section slides were prepared using a cryosection machine (Leica CM 1950; Heidelberg, Germany) to a thickness of 5 ⁇ m, and blocked with 10% goat serum at room temperature for 1 hour.
  • MAFbx an enzyme related to muscle building protein catabolism
  • mRNA expression of MAFbx and MuRF decreased in the group treated with 2uM of ⁇ -sitosterol (see FIGS. 1 and 2 to 5).
  • AMPK is known to be involved in the induction of muscle atrophy by directly involved in muscle protein degradation through the activation of the ubiquitin-proteasome pathway.
  • AMPK When AMPK is activated, it activates the ubiquitin-proteasome pathway through the increase of MAFbx/atrogin-1, an F-box type E3 ligase, and MuRF1, a Ring Finger type E3 ligase, which are muscle-specific ubiquitin ligases specifically expressed in skeletal muscle via FoxO3a, resulting in muscle atrophy. Therefore, changes in the expression of AMPK and muscle atrophy-related proteins according to the treatment of beta-sitosterol, a useful component of field crops, were confirmed.
  • the expression level of FoxOs an AMPK downstream transcription factor
  • the expression of FoxO1 increased in the tibialis anterior muscle and gastrocnemius muscle of the dexamethasone-induced muscular atrophy mouse model, and the expression level decreased when ⁇ -sitosterol was administered.
  • the expression level of FoxO3 protein did not increase in the dexamethasone-treated group, but increased in the ⁇ -sitosterol-treated group, suggesting that the signaling pathway related to the muscular atrophy of FoxO3 is not a regulatory mechanism of the protective effect of ⁇ -sitosterol on muscular atrophy.
  • ⁇ -sitosterol inhibits muscular atrophy induced by dexamethasone treatment, and this phenomenon is thought to be due to blocking of the ubiquitin-proceasome pathway by inhibiting FoxO1, a transcription factor through inhibition of AMPK activity.
  • a mouse model of dexamethasone-induced muscular atrophy was created and the efficacy of inhibiting muscular atrophy induced by ⁇ -sitosterol, a useful component of field crops, was analyzed.
  • the weight change there was no significant difference in body weight between the four groups during the adaptation period of the experimental animals (see FIG. 14 above).
  • the Dexa group showed a significant difference in body weight compared to the control group.
  • the DS group also had a significant difference in body weight compared to the control group.
  • no significant difference was observed between the DS group and the Dexa group.
  • the DS group showed a significant difference from the Dexa group (refer to the middle of FIG. 14).
  • the grip strength of the Dexa group decreased compared to the control group.
  • the grip strength of the DS group was 100.26 g, showing a significant difference compared to the Dexa group (see FIG. 14 below).
  • the tibialis anterior muscle and the gastrocnemius muscle which are muscles of the hind leg, were cut out from the same mouse model and weighed. The weight of these muscles decreased in the Dexa group. In the case of the tibialis anterior muscle, there was no significant weight difference in the DS administration group, and in the case of the gastrocnemius muscle, there was no significant weight difference in the DS administration group (see FIG. 15).
  • an important feature of skeletal muscle atrophy is a decrease in myofiber size and number. Therefore, immunofluorescence staining was performed on the tibialis anterior muscle and gastrocnemius muscle tissues of the muscle loss model mouse to compare histological characteristics of muscle fiber morphological changes. Specifically, mouse muscle tissue was fluorescently stained with wheat germ agglutinin, Alexa Fluor488 conjugate (W11261; invitrogen/Thermo Fisher Scientific, US) antibody and images were taken. As a result, compared to the control group, the muscle fiber atrophy was generally reduced in the Dexa group, and the thickness of the muscle fiber decreased. In contrast, an increase in muscle fiber thickness was observed in the gastrocnemius muscle of the DS-administered group (see FIGS. 16 to 17).

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Abstract

La présente invention concerne une composition pharmaceutique pour la prévention ou le traitement de la sarcopénie. Plus spécifiquement, du fait que la composition comprend du β-sitostérol ou un sel pharmaceutiquement acceptable de celui-ci, la force musculaire et l'endurance peuvent être augmentées et la fibre musculaire épaissie, et enfin la présente invention peut avoir pour effet de prévenir et/ou de traiter la sarcopénie.
PCT/KR2022/001159 2022-01-21 2022-01-21 COMPOSITION PHARMACEUTIQUE COMPRENANT DU β-SITOSTÉROL POUR PRÉVENIR OU TRAITER LA SARCOPÉNIE WO2023140406A1 (fr)

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JP2017193497A (ja) * 2016-04-19 2017-10-26 オリザ油化株式会社 筋肉増強剤

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JP2017193497A (ja) * 2016-04-19 2017-10-26 オリザ油化株式会社 筋肉増強剤

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HWANG, S.L. ; KIM, H.N. ; JUNG, H.H. ; KIM, J.E. ; CHOI, D.K. ; HUR, J.M. ; LEE, J.Y. ; SONG, H. ; SONG, K.S. ; HUH, T.L.: "Beneficial effects of beta-sitosterol on glucose and lipid metabolism in L6 myotube cells are mediated by AMP-activated protein kinase", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, ELSEVIER, AMSTERDAM NL, vol. 377, no. 4, 26 December 2008 (2008-12-26), Amsterdam NL , pages 1253 - 1258, XP025691156, ISSN: 0006-291X, DOI: 10.1016/j.bbrc.2008.10.136 *
NAJI TAA, AMADOU I, ZHAO R-Y, TANG X, SHI Y-H, LE G-W: "Effects of Phytosterol in Feed on Growth and Related Gene Expression in Muscles of Broiler Chickens", TROPICAL JOURNAL OF PHARMACEUTICAL RESEARCH, PHARMACOTHERAPY GROUP, NG, vol. 13, no. 1, NG , pages 9, XP093079801, ISSN: 1596-5996, DOI: 10.4314/tjpr.v13i1.2 *
WONG HOI SHAN, CHEN JIHANG, LEONG POU KUAN, LEUNG HOI YAN, CHAN WING MAN, KO KAM MING: "A Cistanches Herba Fraction/β-Sitosterol Causes a Redox-Sensitive Induction of Mitochondrial Uncoupling and Activation of Adenosine Monophosphate-Dependent Protein Kinase/Peroxisome Proliferator-Activated Receptor γ Coactivator-1 in C2C12 Myotubes: A Possible Mechanism Underlying the Weight Reductio", EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE, OXFORD UNIVERSITY PRESS, US, vol. 2015, no. thesis no. 142059, US , pages 1 - 12, XP093079810, ISSN: 1741-427X, DOI: 10.1155/2015/142059 *
WONG HOI SHAN, LEONG POU KUAN, CHEN JIHANG, LEUNG HOI YAN, CHAN WING MAN, KO KAM MING: "β-Sitosterol increases mitochondrial electron transport by fluidizing mitochondrial membranes and enhances mitochondrial responsiveness to increasing energy demand by the induction of uncoupling in C2C12 myotubes", JOURNAL OF FUNCTIONAL FOODS, ELSEVIER BV, NL, vol. 23, 1 May 2016 (2016-05-01), NL , pages 253 - 260, XP093079805, ISSN: 1756-4646, DOI: 10.1016/j.jff.2016.02.045 *

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