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WO2025051119A1 - Approche visant à réduire ou inhiber les produits de glycation avancée - Google Patents

Approche visant à réduire ou inhiber les produits de glycation avancée Download PDF

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Publication number
WO2025051119A1
WO2025051119A1 PCT/CN2024/116602 CN2024116602W WO2025051119A1 WO 2025051119 A1 WO2025051119 A1 WO 2025051119A1 CN 2024116602 W CN2024116602 W CN 2024116602W WO 2025051119 A1 WO2025051119 A1 WO 2025051119A1
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Prior art keywords
acid
composition
analog
derivative
ester
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Ronghua YI
Jiasen YANG
Kylin LIAO
Shawn Wells
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Nanjing Nutrabuilding Bio Tech Co Ltd
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Nanjing Nutrabuilding Bio Tech Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/347—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A61K8/66—Enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/52—Stabilizers
    • A61K2800/522—Antioxidants; Radical scavengers

Definitions

  • the present invention relates to approach to reduce or inhibit advanced glycation end-product.
  • the invention relates to compositions and methods for reducing or inhibiting advanced glycation end products (AGEs) , especially for anti-glycation, or mitigating or preventing aging in a subject.
  • the composition may comprise an effective amount of ergothioneine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof; and an effective amount of another component.
  • AGEs Advanced glycation end-products
  • AGEs are modifications of proteins or lipids that become nonenzymatically glycated and oxidized after contact with aldose sugars.
  • Early glycation and oxidation processes result in the formation of Schiff bases and Amadori products.
  • Further glycation of proteins and lipids causes molecular rearrangements that lead to the generation of AGEs.
  • AGEs may fluoresce, produce reactive oxygen species (ROS) , bind to specific cell surface receptors, and form cross-links. Alternatively, they can undergo further oxidation, dehydration, polymerization and oxidative breakdown reactions to give rise to numerous other AGEs. Oxygen, reactive oxygen species (ROS) and redox active transition metals accelerate AGE formation. When an oxidative step is involved, the products are called AGEs. The gradual accumulation of AGEs in vivo in hyperglycemic environments and during aging will cause many bad effects, like aging.
  • ROS
  • UV irradiation is one of most crucial exogenous reasons, which could induce oxidative stress and lipid peroxidase-like malondialdehyde (MDA) and the activation of matrix metalloproteinase (MMP) .
  • MDA lipid peroxidase-like malondialdehyde
  • MMP matrix metalloproteinase
  • UV irradiation may precipitate the formation of AGEs in vivo.
  • Another one is a higher dietary intake of carbohydrates, inducing high glucose levels
  • the known mechanisms by which carbohydrates result in oxidative stress are the activation of mitochondrial oxidative metabolism of glucose, which leads to the generation of ROS.
  • the primary cause is the accumulation of oxidative damage caused by ROS.
  • EGT ergothioneine
  • OS oxidative stress
  • EGT is concentrated in cells and tissues wherein exposed to OS frequently, such as ocular tissues, liver, bone marrow and seminal fluid, etc. Hence, EGT could scavenge chronic ROS, to prevent the process of AGEs.
  • EGT or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof and especially the combination with one or more of: berberine, resveratrol, lipoic acid, ⁇ -hydroxybutyric acid, rhodiola rosea, ascorbic acid, dehydroascorbic acid, taurine, acetyltaurine, ⁇ -aminoisobutyric acid, nicotinamide nononucleotide, nicotinic acid, 1-NMN, dehydrozingerone, fisetin, chlorogenic acid, paraxanthine, dileucine, glutathione, quercetin, arachidonylethanolamide, methoxatin (PQQ) , CoQ10, spermidine, apigenin, astaxanthin, carotene, retinol, tocopherol, grain of paradise, or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof could be considered as
  • the present invention provides a method for reducing or inhibiting advanced glycation end products (AGEs) in a subject, comprising administrating to the subject a composition comprising: an effective amount of ergothioneine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof; and an effective amount of another component selected from: berberine, resveratrol, lipoic acid, ⁇ -hydroxybutyric acid, rhodiola rosea, ascorbic acid, dehydroascorbic acid, taurine, acetyltaurine, ⁇ -aminoisobutyric acid, nicotinamide nononucleotide, nicotinic acid, 1-NMN, dehydrozingerone, fisetin, chlorogenic acid, paraxanthine, dileucine, glutathione, quercetin, arachidonylethanolamide, methoxatin (PQQ) , CoQ10, spermidine, api
  • AGEs
  • the method is used for anti-glycation.
  • the method is used for mitigating or preventing aging.
  • the aging is characterized by fine wrinkles, loss of elasticity, orange-peel or dull appearance of skin, reduced epidermal and dermal thickness, epidermal atrophy, decreased mitotic rate of basal keratinocytes, decreased proliferative capacity, cellular senescence, atrophy of dermal extracellular matrix, change of physiological properties of connective tissues.
  • the reducing or inhibiting advanced glycation end products is achieved by controlling blood glucose, scavenging chronic ROS, reducing H 2 O 2 and MDA productions and/or expression of MMP-1.
  • the scavenging chronic ROS includes improving activities of anti-oxidative enzymes, such as SOD, CAT, GSH, and GSH-Px.
  • anti-oxidative enzymes such as SOD, CAT, GSH, and GSH-Px.
  • another component or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof is administrated at a daily dose of 0.1-2000 mg
  • the ergothioneine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof is administrated at a daily dose of 1-1500 mg.
  • another component or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof may be administrated at a daily dose of 100-2000 mg, 300-1800 mg, 500-1500 mg, 800-1200 mg, 0.2-1800 mg, 0.3-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 50-500 mg, 60-500 mg, 80-400 mg, 100-400 mg, 0.1-100 mg, 1-90 mg, 5-80 mg, 10-70 mg, 20-60 mg, 0.1-50 mg, 0.2-30 mg, 0.3-20 mg, 0.3-15 mg, 0.5-10 mg, 1-8 mg, the ergothioneine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof may be administrated at a daily dose of 2-1000 mg, 2-500 mg, 3-100 mg, 3-50 mg, or 5-50 mg.
  • the daily dose is administered in divided doses or a single dose.
  • the administration is at least once a day or more times a day.
  • the administration is
  • the ratio of another component or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof and the ergothioneine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof ranges from 1: 300 to 1500: 1. In some embodiments, the ratio of another component or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof and the ergothioneine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof may also be 1: 200 to 1200: 1, 1: 150 to 1000: 1, 1: 120 to 800: 1, 1: 100 to 400: 1, 1: 80 to 200: 1, 1: 50 to 150: 1, 1: 25 to 100: 1, 1: 10 to 80: 1, 1: 5 to 60: 1, 1: 3 to 40: 1, 1: 2 to 20:1, 1: 1 to 10: 1, or 1: 1.
  • the subject is human or cattle or pet. In some embodiments, the subject is human.
  • the composition is prepared as a food, a drink, a supplement, a cosmetic product, or a pharmaceutical formulation.
  • the administration is through various routes selected from oral administration, intravenous injection, intramuscular injection, intraperitoneal injection, topical application, or sublingual application.
  • the composition is formulated in solutions, liquid suspensions, parenteral solutions, injections, tablets, pills, granules, powders, films, suppositories, (micro) capsules, aerosols, tonics, syrups, beverages, nourishments, snacks, bars, gums, sugars, a facial mask composition, a functionalized cream composition, a functionalized essence, a skin care composition, a make-up composition or a functionalized food composition.
  • the present invention provides a composition
  • a composition comprising ergothioneine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof; and another component selected from: berberine, resveratrol, lipoic acid, ⁇ -hydroxybutyric acid, rhodiola rosea, ascorbic acid, dehydroascorbic acid, taurine, acetyltaurine, ⁇ -aminoisobutyric acid, nicotinamide nononucleotide, nicotinic acid, 1-NMN, dehydrozingerone, fisetin, chlorogenic acid, paraxanthine, dileucine, glutathione, quercetin, arachidonylethanolamide, methoxatin (PQQ) , CoQ10, spermidine, apigenin, astaxanthin, carotene, retinol, tocopherol, grain of paradise, or a pharmaceutically acceptable salt, acid, ester, analog
  • the composition is used for anti-glycation.
  • the composition is used for mitigating or preventing aging.
  • the aging is characterized by fine wrinkles, loss of elasticity, orange-peel or dull appearance of skin, reduced epidermal and dermal thickness, epidermal atrophy, decreased mitotic rate of basal keratinocytes, decreased proliferative capacity, cellular senescence, atrophy of dermal extracellular matrix, change of physiological properties of connective tissues.
  • the reducing or inhibiting advanced glycation end products is achieved by controlling blood glucose, scavenging chronic ROS, reducing H 2 O 2 and MDA productions and/or expression of MMP-1.
  • the scavenging chronic ROS includes improving activities of anti-oxidative enzymes, such as SOD, CAT, GSH, and GSH-Px.
  • anti-oxidative enzymes such as SOD, CAT, GSH, and GSH-Px.
  • another component or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof is administrated at a daily dose of 0.1-2000 mg
  • the ergothioneine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof is administrated at a daily dose of 1-1500 mg.
  • another component or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof may be administrated at a daily dose of 100-2000 mg, 300-1800 mg, 500-1500 mg, 800-1200 mg, 0.2-1800 mg, 0.3-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 50-500 mg, 60-500 mg, 80-400 mg, 100-400 mg, 0.1-100 mg, 1-90 mg, 5-80 mg, 10-70 mg, 20-60 mg, 0.1-50 mg, 0.2-30 mg, 0.3-20 mg, 0.3-15 mg, 0.5-10 mg, 1-8 mg, the ergothioneine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof may be administrated at a daily dose of 2-1000 mg, 2-500 mg, 3-100 mg, 3-50 mg, or 5-50 mg.
  • the daily dose is administered in divided doses or a single dose.
  • the administration is at least once a day or more times a day.
  • the administration is
  • the ratio of another component or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof and the ergothioneine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof ranges from 1: 300 to 1500: 1. In some embodiments, the ratio of another component or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof and the ergothioneine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof may also be 1: 200 to 1200: 1, 1: 150 to 1000: 1, 1: 120 to 800: 1, 1: 100 to 400: 1, 1: 80 to 200: 1, 1: 50 to 150: 1, 1: 25 to 100: 1, 1: 10 to 80: 1, 1: 5 to 60: 1, 1: 3 to 40: 1, 1: 2 to 20:1, 1: 1 to 10: 1, or 1: 1.
  • the subject is human or cattle or pet. In some embodiments, the subject is human.
  • the composition is prepared as a food, a drink, a supplement, a cosmetic product, or a pharmaceutical formulation.
  • the composition is formulated in solutions, liquid suspensions, parenteral solutions, injections, tablets, pills, granules, powders, films, suppositories, (micro) capsules, aerosols, tonics, syrups, beverages, nourishments, snacks, bars, gums, sugars, a facial mask composition, a functionalized cream composition, a functionalized essence, a skin care composition, a make-up composition or a functionalized food composition.
  • the present invention provides use of a composition for preparing food, drink, supplement, cosmetic product, or pharmaceutical formulation for reducing or inhibiting advanced glycation end products (AGEs) in a subject, wherein the composition comprises ergothioneine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof; and another component selected from: berberine, resveratrol, lipoic acid, ⁇ -hydroxybutyric acid, rhodiola rosea, ascorbic acid, dehydroascorbic acid, taurine, acetyltaurine, ⁇ -aminoisobutyric acid, nicotinamide nononucleotide, nicotinic acid, 1-NMN, dehydrozingerone, fisetin, chlorogenic acid, paraxanthine, dileucine, glutathione, quercetin, arachidonylethanolamide, methoxatin (PQQ) , CoQ10, spermidine,
  • AGEs advanced
  • the composition is used for anti-glycation.
  • the composition is used for mitigating or preventing aging.
  • the aging is characterized by fine wrinkles, loss of elasticity, orange-peel or dull appearance of skin, reduced epidermal and dermal thickness, epidermal atrophy, decreased mitotic rate of basal keratinocytes, decreased proliferative capacity, cellular senescence, atrophy of dermal extracellular matrix, change of physiological properties of connective tissues.
  • the reducing or inhibiting advanced glycation end products is achieved by controlling blood glucose, scavenging chronic ROS, reducing H 2 O 2 and MDA productions and/or expression of MMP-1.
  • the scavenging chronic ROS includes improving activities of anti-oxidative enzymes, such as SOD, CAT, GSH, and GSH-Px.
  • anti-oxidative enzymes such as SOD, CAT, GSH, and GSH-Px.
  • another component or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof is administrated at a daily dose of 0.1-2000 mg
  • the ergothioneine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof is administrated at a daily dose of 1-1500 mg.
  • another component or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof may be administrated at a daily dose of 100-2000 mg, 300-1800 mg, 500-1500 mg, 800-1200 mg, 0.2-1800 mg, 0.3-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 50-500 mg, 60-500 mg, 80-400 mg, 100-400 mg, 0.1-100 mg, 1-90 mg, 5-80 mg, 10-70 mg, 20-60 mg, 0.1-50 mg, 0.2-30 mg, 0.3-20 mg, 0.3-15 mg, 0.5-10 mg, 1-8 mg, the ergothioneine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof may be administrated at a daily dose of 2-1000 mg, 2-500 mg, 3-100 mg, 3-50 mg, or 5-50 mg.
  • the daily dose is administered in divided doses or a single dose.
  • the administration is at least once a day or more times a day.
  • the administration is
  • the ratio of another component or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof and the ergothioneine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof ranges from 1: 300 to 1500: 1. In some embodiments, the ratio of another component or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof and the ergothioneine or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof may also be 1: 200 to 1200: 1, 1: 150 to 1000: 1, 1: 120 to 800: 1, 1: 100 to 400: 1, 1: 80 to 200: 1, 1: 50 to 150: 1, 1: 25 to 100: 1, 1: 10 to 80: 1, 1: 5 to 60: 1, 1: 3 to 40: 1, 1: 2 to 20:1, 1: 1 to 10: 1, or 1: 1.
  • the composition is formulated in solutions, liquid suspensions, parenteral solutions, injections, tablets, pills, granules, powders, films, suppositories, (micro) capsules, aerosols, tonics, syrups, beverages, nourishments, snacks, bars, gums, sugars, a facial mask composition, a functionalized cream composition, a functionalized essence, a skin care composition, a make-up composition or a functionalized food composition.
  • the term “or” is meant to include both “and” and “or. ” In other words, the term “or” may also be replaced with “and/or. ”
  • the term “comprise” or “include” and their conjugations refer to a situation wherein said terms are used in their non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. It also encompasses the more limiting verb ‘to consist essentially of’a nd ‘to consist of’ .
  • the term "effective amount” refers to the amount required to achieve the effect as taught herein.
  • the specific effective dose level for any particular subject will depend upon a variety of factors including the conditions being treated and the severity of the conditions; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of another component and/or ergothioneine or its analog or its derivatives employed; the duration of the treatment; and like factors well known in the medical arts. For example, it is well known within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired effect and to gradually increase the dosage until the desired effect is achieved.
  • an amount may be considered “effective” even if the condition is not totally eradicated or prevented, but it or its symptoms and/or effects are improved or alleviated partially in the subject.
  • the term “pharmaceutically acceptable” means pharmaceutically, physiologically, alimentarily, and/or nutritionally acceptable, and refers to those compositions or combinations of agents, materials, or compositions, and/or their dosage forms, which are within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the term “mammal” or “subject” may be used interchangeably to refer to any animal to which the presently disclosed methods and compositions may be applied or administered.
  • the animal may have an illness or other disease, but the animal does not need to be sick to benefit from the presently disclosed methods and compositions.
  • any animal may apply the disclosed combinations, compositions or kits, or be a recipient of the disclosed methods.
  • “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
  • the animal subject is preferably a human, the methods and compositions of the invention have application in veterinary medicine.
  • the dosage of another component and/or ergothioneine, or a pharmaceutically acceptable salt, acid, ester, polymer, analog or derivative thereof and/or composition comprising the same may range broadly, depending upon the desired effects and the indication.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.01 mg and 3000 mg of another component and/or ergothioneine or its analog or derivative, preferably between 0.1 mg and 2000 mg, e.g., 0.5 to 1000 mg, or between about 0.1 mg and about 1,000 mg of another component and/or ergothioneine or its analog or derivative per kg of body weight of the subject.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the subject.
  • the compounds are administered for a period of time, for example for a week or more, or for months or years.
  • compositions of the invention can be administered in a variety of ways, including orally, intragastrically, and parenterally (e.g., intravenous and intraarterial as well as other suitable parenteral routes) , and the like.
  • parenteral solution refers to a solution that can be administered elsewhere in the body than the mouth and alimentary canal. It is not delivered via the intestinal tract.
  • parenteral solution can be delivered intravenously.
  • a “tonic” refers to a medicinal substance taken to give a feeling of vigor or well-being.
  • a “syrup” refers to a thick sticky liquid derived from a sugar-rich plant, for example, sugar cane, corn, and maple.
  • compositions include, but not limited to, oral, rectal, topical, aerosol, injection and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.
  • “Intraperitoneal” as used here means within or administered through the peritoneum.
  • the peritoneum is a thin, transparent membrane that lines the walls of the abdominal (peritoneal) cavity and contains/encloses the abdominal organs such as the stomach and intestines.
  • sublingual refers to situated or applied under the tongue.
  • a “functionalized cream composition” includes a cream composition that has a potentially positive effect on health beyond basic nutrition.
  • An “essence” includes an extract or concentrate obtained from a particular plant or other matter and used for flavoring or scent.
  • a “functionalized essence” includes an essence that has a potentially positive effect on health beyond basic nutrition.
  • a “functionalized food composition” includes a food composition that has a potentially positive effect on health beyond basic nutrition.
  • Figure 1 is a graph of a percentage inhibition of fluorescence of the AGEs relative to the control.
  • Figure 2 is a graph of blood glucose levels of six groups of mice at the beginning of the trial (0 week) , after the D-galactose injection (8th week) , and at the end of the trial (14th week) .
  • Figure 3 is a graph of MDA content of six groups of mice at the end of the trial (14th week) .
  • Figure 4 is a graph of H2O2 content of six groups of mice at the end of the trial (14th week) .
  • Figure 5 is a graph of SOD activity of six groups of mice at the end of the trial (14th week) .
  • Figure 6 is a graph of CAT activity of six groups of mice at the end of the trial (14th week) .
  • Figure 7 is a graph of GSH activity of six groups of mice at the end of the trial (14th week) .
  • Figure 8 is a graph of GSH-Px activity of six groups of mice at the end of the trial (14th week) .
  • Figure 9 is a graph of MMP-1 content of six groups of mice at the end of the trial (14th week) .
  • Figure 10 is a graph of autophagy activity in keratinocytes relative to the control.
  • Figure 11 is a graph of carboxymethyl lysine (CML) mole fraction in human keratinocytes.
  • another component may be one or more of: berberine, resveratrol, lipoic acid, ⁇ -hydroxybutyric acid, rhodiola rosea, ascorbic acid, dehydroascorbic acid, taurine, acetyltaurine, ⁇ -aminoisobutyric acid, nicotinamide nononucleotide, nicotinic acid, 1-NMN, dehydrozingerone, fisetin, chlorogenic acid, paraxanthine, dileucine, glutathione, quercetin, arachidonylethanolamide, methoxatin (PQQ) , CoQ10, spermidine, apigenin, astaxanthin, carotene, retinol, tocopherol, grain of paradise, or a pharmaceutically acceptable salt, acid, ester, analog or derivative thereof.
  • the following examples were performed to some of the above “another component” and/or EGT.
  • mice When all mice were on fasting, approximately 10 ⁇ L of blood was collected by tail nick for 3 times, respectively at the beginning of the trial (0 week) , after the D-galactose injection (8th week) , and at the end of the trial (14th week) .
  • a glucometer was used to measure the glucose level.
  • Figure 2 is a graph of blood glucose levels of six groups of mice at the beginning of the trial (0 week) , after the D-galactose injection (8th week) , and at the end of the trial (14th week) .
  • AGEs were formed successfully by D-galactose.
  • blood glucose levels were decreased significantly except group 1.
  • groups 4 and 6 were nearly close to the normal level. Two combinations (groups 4 and 6) thus are very effective for blood glucose control.
  • Figure 3 is a graph of MDA content of six groups of mice at the end of the trial (14th week) . As shown in Figure 3, the content of MDA in groups 4 and 6 nearly decreased to be normal, and were even 80%and 70%lower than that in non-supplement group, respectively. So, these combinations could inhibit ROS-mediated lipid peroxidation significantly, such as reducing the MDA level.
  • Oxidative stress is increased during aging.
  • the changes of oxidoreductase activities should be paid high attention.
  • Skins were lysed into homogenate using normal saline or RIPA tissue cracking agent.
  • the levels of H 2 O 2 , SOD, CAT, GSH, and GSH-Px in the skin were detected with relative kits as reference.
  • Measurement of the activities of four typical anti-oxidative enzymes, such as SOD, CAT, GSH, and GSH-Px could indicate whether the supplementation has the ROS-cleaning ability.
  • SOD activity of six groups of mice at the end of the trial (14th week) was each measured.
  • CAT activity of six groups of mice at the end of the trial (14th week) was each measured.
  • GSH activity of six groups of mice at the end of the trial (14th week) was each measured.
  • GSH-Px activity of six groups of mice at the end of the trial (14th week) was each measured.
  • Figure 4 is a graph of H 2 O 2 content of six groups of mice at the end of the trial (14th week) . As shown in Figure 4, the H 2 O 2 content in group 4 and 6 was decreased about 4.5 and 3.5 times as compared to the non-supplement group.
  • the activities of four typical anti-oxidative enzymes were significantly improved after berberine or EGT or combination supplementation.
  • the SOD, CAT, GSH and GSH-Px activities in groups 4 and 6 all increased markedly, compared to non-supplementation group.
  • the supplementation can scavenge chronic ROS.
  • Quantitative polymerase chain reaction (QPCR) and western blot methods were used to measure the expression of MMP-1 in the skin. MMP-1 content of six groups of mice at the end of the trial (14th week) was each measured.
  • Figure 9 is a graph of MMP-1 content of six groups of mice at the end of the trial (14th week) . As shown in Figure 9, the MMP-1 expression decreased significantly in groups 4 and 6 (by about 2 and 1.9 times) , compared to group 1.
  • the supplementation, especially in group 4 not only could reduce H 2 O 2 production and MMP-1 expression during aging, but also exhibits superior anti-oxidation abilities and are effective at reducing oxidative stress in vivo.
  • LC-MS methods and keratinocyte cell culture were used to assess impact of autophagy modulators and skin care materials on carboxymethyl lysine (CML) amount, a representative AGE.
  • CML carboxymethyl lysine
  • Keratinocyte cell culture For autophagy and CML experiments, neonatal human epidermal keratinocytes were expanded in CO 2 , in a 37°C incubator using Epilife Media with human keratinocyte growth supplement and gentamicin/amphotericin B. Cells never exceeded 70%confluency nor passage 5.
  • CML assay keratinocytes were plated in 24 well plates at a density of 1,000 cells/well and incubated for 24 h. Glyceraldehyde (GLA) treatment (500 ⁇ M) in medium was used to induce glycation.
  • GLA Glyceraldehyde
  • the glycation medium was removed, the cells rinsed, and fresh medium containing treatments and/or controls was added and the plates further incubated for another 24 h.
  • the medium was removed, the cells rinsed, and the cells put in -80°C until analysis for lysine and CML.
  • Keratinocytes were plated in 96-well plates with 10,000 cells/well. After 24 h, the keratinocytes were treated with materials (berberine, and/or resveratrol, and/or EGT) or controls and incubated for another 24 h. Rapamycin, a known autophagy activator, was added as a positive control. The cells were stained with DAPI and the reagent per manufacturer protocol, the fluorescence of the cells was read in a SpectraMax plate reader using the following excitation/emission channels: FITC 480 nm/530 nm and DAPI 340 nm/480 nm.
  • the ratio of FITC/DAPI channels was calculated and normalized to the average FITC/DAPI ratios from the controls to calculate fold autophagosome activation. fluorescence was quantitated by excitation/emission using a FITC channel and divided by DAPI channel to calculate ratio. Treatment ratios were then divided by control to calculate fold autophagosome induction.
  • Keratinocytes were plated in 8-well slide cassettes with 5,000 cells/well. Treatments and incubations were the same as above after which the keratinocytes were stained using the staining reagent and DAPI.
  • CML measurement A total of 1000 ⁇ L methanol was added into each well of keratinocytes on the 24-well plate. The cells were mechanically detached from the plate and transferred into a glass vial. Samples were completely dried down. A total of 1 mL of 6M HCl was added to each sample. Samples were incubated in a heating block for 16 h at 110°C, dried, then reconstituted with 500 ⁇ L of a dilution solution (0.1%formic acid in 50/50 ultra-pure water/acetonitrile) . The standards and the samples were subjected to analysis using hydrophilic interaction (HILIC) liquid chromatography with tandem mass spectrometry. CML can be baseline resolved from lysine by a HILIC column.
  • HILIC hydrophilic interaction
  • MRM Multiple Reaction Monitoring
  • Figure 10 is a graph of autophagy activity in keratinocytes relative to the control.
  • Figure 11 is a graph of CML mole fraction in human keratinocytes.
  • Berberine + EGT group and resveratrol + EGT group significantly increased in vitro autophagosome levels over control quantitatively (Fig. 10) , indicating these combinations induce autophagy in vitro.
  • control group BBR group (25 mg/day)
  • EGT group 25 mg/day
  • BBR+EGT group 25 + 25 mg/day
  • resveratrol group 25 mg/day
  • 30 min after meal respectively.
  • Resveratrol + EGT group 25 +25 mg/day capsules were taken once a day for 60 consecutive days.
  • Skin smoothness scores were performed on days 30 and 60 (5-point scale, 1 score was very not smooth, 3 score was average, 5 score was very smooth) .
  • the two combinations (BBR + EGT, Resveratrol + EGT) could effectively improve the smoothness of the skin, thus mitigating or preventing aging, such as preventing or reducing fine wrinkles, loss of elasticity, orange-peel, cellular senescence.

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Abstract

L'invention concerne de nouvelles méthodes visant à réduire ou inhiber les produits de glycation avancée (AGE) chez un sujet, lesdites méthodes consistant à administrer au sujet une composition contenant une quantité efficace d'ergothionéine ou d'un sel pharmaceutiquement acceptable, d'un acide, d'un ester, d'un analogue ou d'un dérivé de celle-ci ; et une quantité efficace d'un autre composant ou d'un sel pharmaceutiquement acceptable, d'un acide, d'un ester, d'un analogue ou d'un dérivé de celui-ci.L'invention concerne également une composition contenant de l'ergothionéine ou un sel pharmaceutiquement acceptable, un acide, un ester, un analogue ou un dérivé de celle-ci ; et un autre composant ou un sel pharmaceutiquement acceptable, un acide, un ester, un analogue ou un dérivé de celui-ci, destinée à réduire ou inhiber des produits de glycation avancée (AGE) chez un sujet.
PCT/CN2024/116602 2023-09-06 2024-09-03 Approche visant à réduire ou inhiber les produits de glycation avancée Pending WO2025051119A1 (fr)

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CN101766550A (zh) * 2008-12-30 2010-07-07 欧莱雅公司 单糖与抗坏血酸的组合及其美容学应用
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CN101766550A (zh) * 2008-12-30 2010-07-07 欧莱雅公司 单糖与抗坏血酸的组合及其美容学应用
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