WO2023008218A1 - レスベラトロールグルクロニドの新たな用途 - Google Patents

レスベラトロールグルクロニドの新たな用途 Download PDF

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WO2023008218A1
WO2023008218A1 PCT/JP2022/027758 JP2022027758W WO2023008218A1 WO 2023008218 A1 WO2023008218 A1 WO 2023008218A1 JP 2022027758 W JP2022027758 W JP 2022027758W WO 2023008218 A1 WO2023008218 A1 WO 2023008218A1
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resveratrol
glucuronide
active ingredient
effective amount
subject
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English (en)
French (fr)
Japanese (ja)
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昂洸 藤井
尚 井上
高史 宅見
俊雄 荒木
通済 本田
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池田食研株式会社
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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
    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • 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
    • A61K8/60—Sugars; Derivatives thereof
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q1/00—Make-up preparations; Body powders; Preparations for removing make-up
    • 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
    • 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
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
    • C12P7/22—Preparation of oxygen-containing organic compounds containing a hydroxy group aromatic

Definitions

  • the present invention relates to new uses of resveratrol glucuronide.
  • Resveratrol and resveratrol 3-O- ⁇ -D-glucoside have been reported to have anti-aging ability, antioxidant ability, ability to remove active oxygen, beautiful skin, and whitening effects (Patent Documents 1 and 2. ) and is widely used as a cosmetic material.
  • resveratrol has a very low solubility in water of about 0.03 mg/mL (Patent Document 1).
  • piceide is improved as compared with resveratrol, its solubility in water is about 0.4 mg/mL, and it is difficult to say that it has sufficient solubility (Patent Document 1).
  • conventional resveratrol and piceide have excellent functionality as cosmetic ingredients, their low water solubility is a problem.
  • Patent Document 2 a technique for improving water solubility by further adding a plurality of sugar residues to resveratrol glycosides such as piceid has been proposed.
  • Patent Document 2 a technique for improving water solubility by further adding a plurality of sugar residues to resveratrol glycosides such as piceid.
  • Non-Patent Document 1 resveratrol nonionic surfactant, and a method of solubilizing in water with a liquid polyhydric alcohol (Patent Document 3), a method of coexistence with vinylpyrrolidone copolymer (Patent Document 4), coexistence with catechin compounds (Patent Document 5), and a method of improving the solubility in water by adding cyclodextrin (Non-Patent Document 1) have already been reported, but both of these require expensive reagents. issues remain.
  • Non-Patent Document 2 it is widely known that water solubility is improved by adding glucuronic acid to a compound, and glucuronidation in drug metabolism and the like is well known (Non-Patent Document 2).
  • Non-Patent Document 3 glycosidation by adding glucose or the like to a compound is already known to have the effect of improving the water solubility of the compound (Non-Patent Document 3). It is not known about the effect on water solubility at the time.
  • quercetin glucoside which is a kind of polyphenol glycoside, has a LogP value of 0.0, which is one of the indicators of hydrophilicity (or hydrophobicity) (a positive value indicates high hydrophobicity, and a negative value indicates high hydrophilicity).
  • Non-Patent Document 4 whereas quercetin glucuronide has a LogP of 0.256 (Non-Patent Document 5), indicating that the conversion of the glucose residue to glucuronic acid deteriorates the water solubility.
  • Non-Patent Document 5 the expected LogP described in PubChem (calculated with XLogP 3.0) is 1.6 (Non-Patent Document 6).
  • 1.7 the expected LogP of piceid calculated by the same method
  • resveratrol has excellent functionality, but due to its low water solubility, organic solvents such as ethanol and surfactants are required when blending it into water-based formulations such as lotions. , it was impossible to dissolve at a high concentration without coexisting with additives such as cyclodextrin. In recent years, there has been a tendency to prefer additive-free products (organic solvent-free, etc.) in cosmetics, etc., so there is a demand for technology that dissolves cosmetic ingredients in water under conditions of high concentration and without the use of additives. .
  • the present invention relates to providing materials that have excellent functionality and are highly water-soluble and that can be used for cosmetics, pharmaceuticals, food and drink, and the like.
  • flavin-binding glucose dehydrogenase flavin-binding GDH, EC 1.1.5.9
  • flavin-binding GDH EC 1.1.5.9
  • the glucose -It was found that when an enzyme having 6-dehydrogenase activity acts on a glucose derivative such as glucoside, the hydroxymethyl group at the 6-position of the glucose skeleton is oxidized to specifically generate a glucuronic acid derivative, and resveratrol glucuronide is conveniently produced.
  • resveratrol glucuronide was found to have excellent hyaluronidase inhibitory activity, collagenase inhibitory activity, antioxidant activity and tyrosinase inhibitory activity, leading to the completion of the present invention.
  • the present invention relates to the following [1] to [10].
  • a tyrosinase inhibitor containing resveratrol glucuronide as an active ingredient [7] A tyrosinase inhibitor containing resveratrol glucuronide as an active ingredient. [8] A melanogenesis inhibitor containing resveratrol glucuronide as an active ingredient. [9] A whitening agent containing resveratrol glucuronide as an active ingredient. [10] A skin external preparation containing resveratrol glucuronide.
  • the present invention also relates to the following [11] to [38].
  • [11] Use of resveratrol glucuronide for producing a hyaluronidase inhibitor.
  • [12] Use of resveratrol glucuronide for producing an anti-inflammatory agent.
  • [13] Use of resveratrol glucuronide for producing an antiallergic agent.
  • [14] Use of resveratrol glucuronide for producing a collagenase inhibitor.
  • [16] Use of resveratrol glucuronide for producing an anti-aging agent.
  • resveratrol glucuronide for use in hyaluronidase inhibition; [22] resveratrol glucuronide for anti-inflammatory use; [23] resveratrol glucuronide for antiallergic use; [24] resveratrol glucuronide for use in collagenase inhibition; [25] resveratrol glucuronide for use as an antioxidant; [26] A resveratrol glucuronide for use in anti-aging.
  • resveratrol glucuronide for use in tyrosinase inhibition
  • resveratrol glucuronide for use in suppressing melanogenesis
  • resveratrol glucuronide for use in skin lightening.
  • a method of inhibiting hyaluronidase comprising administering or using an effective amount of resveratrol glucuronide to a subject in need thereof.
  • An anti-inflammatory method comprising administering or using an effective amount of resveratrol glucuronide to a subject in need thereof.
  • An antiallergic method comprising administering or using an effective amount of resveratrol glucuronide to a subject in need thereof.
  • a method of inhibiting collagenase comprising administering or using an effective amount of resveratrol glucuronide to a subject in need thereof.
  • An antioxidant method comprising administering or using an effective amount of resveratrol glucuronide to a subject in need thereof.
  • An anti-aging method comprising administering or using an effective amount of resveratrol glucuronide to a subject in need thereof.
  • a method of inhibiting tyrosinase comprising administering or using an effective amount of resveratrol glucuronide to a subject in need thereof.
  • a method for inhibiting melanogenesis comprising administering or using an effective amount of resveratrol glucuronide to a subject in need thereof.
  • a whitening method comprising administering or using an effective amount of resveratrol glucuronide to a subject in need thereof.
  • Resveratrol glucuronide has hyaluronidase inhibitory activity, collagenase inhibitory activity, antioxidant activity, and tyrosinase inhibitory activity, and is extremely water-soluble, so it is useful as a cosmetic material, pharmaceutical material, food material, etc. Therefore, according to the present invention, resveratrol glucuronide can be blended at a high concentration regardless of the form of the formulation, and excellent effects such as anti-aging, skin beautification, and whitening of the skin are expected.
  • FIG. 1 shows the results of 1 H-NMR analysis and 13 C-NMR analysis of resveratrol glucuronide. Hyaluronidase inhibition rate of resveratrol glucuronide and piceide is shown.
  • Figure 2 shows the collagenase inhibition rate of resveratrol glucuronide.
  • Figure 2 shows the tyrosinase inhibition rate of resveratrol glucuronide.
  • Resveratrol glucuronide used in the present invention is a compound obtained by converting the glucose residue of resveratrol glucoside (molecular formula: C 20 H 22 O 8 ) into glucuronic acid.
  • Resveratrol glucuronide exists in stereoisomers, and pure stereoisomers or mixtures thereof can be used in the present invention.
  • Resveratrol glucuronide is preferably trans-resveratrol-3-O- ⁇ -D-glucuronide represented by the following formula (1).
  • resveratrol glucuronide is not particularly limited, and commercially available reagents can be used. Moreover, it can be manufactured by the method shown in the examples. That is, resveratrol glucoside, in the presence of a mediator, in the presence of a mediator, flavin-binding glucose dehydrogenase having glucose-6-dehydrogenase activity, including the step of producing resveratrol glucuronide, production of resveratrol glucuronide It can be manufactured by a method.
  • a flavin-binding glucose dehydrogenase having glucose-6-dehydrogenase activity refers to a hydroxy at the 6-position of glucose with flavin as a coenzyme.
  • Flavin-binding GDH of the present invention acts selectively on the 6-position of glucose and specifically oxidizes the hydroxymethyl group at the 6-position of glucose to the carboxy group, so that the enzyme acts on a glucose derivative such as glucoside.
  • Glucose-6-dehydrogenase activity is measured by allowing glucose-6-dehydrogenase to act on glucose, analyzing the reaction product by thin layer chromatography or HPLC, and obtaining a glucuronic acid standard in which the 6-position of glucose is oxidized. This can be confirmed by comparing with The flavin-binding GDH of the present invention has substantially no glucose-1-dehydrogenase activity and substantially does not produce gluconic acid from the substrate glucose.
  • substantially means that the production of gluconic acid cannot be confirmed as a result of thin-layer chromatography or HPLC analysis of the reaction product.
  • Flavin-binding GDH of the present invention is not particularly limited as long as it is an enzyme having glucose-6-dehydrogenase activity, but is preferably any of the following proteins (i) to (iii).
  • 1- to Protein iii) SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16 having an amino acid sequence in which several amino acid residues are deleted, substituted or inserted and having glucose-6-dehydrogenase activity , 18, 20, 22, 24, 26, 28, 30, 32, 34, 36 or 38, and has an amino acid sequence having a sequence identity of 80% or more, and has glucose-6-dehydrogenase activity protein with
  • amino acid sequences represented by The number of amino acid residue deletions, substitutions, or insertions in the amino acid sequences in which amino acid residues have been deleted, substituted, or inserted is SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36 or 38, as long as it exhibits an enzymatic activity equivalent to that of a protein having an amino acid sequence represented by 20, 22, 24, 26, 32, 34, 36 or 38, but preferably 1 to 20 -10 is more preferred, and 1-8 is more preferred.
  • an amino acid sequence represented by SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36 or 38 has a sequence identity of 80% or more, preferably 85% or more, more preferably 90% or more, even more preferably 95% or more, even more preferably 99% or more.
  • sequence identity percentages can be calculated using published or commercially available software whose algorithms compare a reference sequence as a query sequence. For example, BLAST, FASTA, GENETYX (Genetics), or the like can be used.
  • the amino acid sequences represented by SEQ ID NOs: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34 are, respectively, in order Colletotrichum plurivorum)MAFF305790 ⁇ F5126(Fungus_F5126) ⁇ .
  • Colletotrichum_sp. ⁇ (Colletotrichum gloeosporioides) ⁇ (Colletotrichum orbiculare) ⁇ (Colletotrichum tofieldiae) ⁇ (Colletotrichum godetiae)
  • SEQ ID NOs: 36 and 38 are sequences obtained by replacing the presumed secretory signal sequences of SEQ ID NOs: 32 and 34 with the Aspergillus oryzae-derived GDH signal sequence.
  • the amino acid sequence shown by SEQ ID NO: 4 or 6 is the same as the known amino acid sequence SEQ ID NO: 2 described in Patent No. 6455714 and SEQ ID NO: 1 described in Patent No. 5435180, SEQ ID NOS: 8, 10, 12, 18, 20 , 22, 24, 26, 28, 30, 32, and 34 are amino acid sequences registered in known databases, and proteins having the amino acid sequences have glucose-6-dehydrogenase activity. There are no reports of this.
  • Flavin-binding GDH of the present invention preferably has the following properties (1) to (8).
  • Flavins include flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), preferably FAD.
  • FAD flavin adenine dinucleotide
  • FMN flavin mononucleotide
  • Solubility water solubility
  • pH stability at least pH 5.5 ⁇ Stable Between 8.6
  • the enzyme has a residual enzymatic activity of 80% or more after treatment at 30° C. for 1 hour, at least between pH 5.5 and 8.6.
  • pH stability is preferably pH 4.3-9.3, pH 5.5-8.7, pH 3.2-9.3, pH 5.5-9.3, pH 4.4-9.3, pH 4.0 ⁇ 9.6, pH4.4-9.3, pH5.0-9.3, pH3.3-9.6, pH5.5-8.6, pH4.3-9.6, pH5.0-9 .6, pH 4.0-8.6, pH 4.9-8.7, pH 3.3-9.9, pH 4.4-9.8, pH 4.0-8.8, pH 4.4-9.8 , pH 4.0-9.6. Even if the pH is the same, the residual activity may differ depending on the type of buffer solution.
  • Thermostability Stable at at least 35°C, the enzyme is stable at least at 35°C in 100 mM potassium phosphate buffer (pH 6.0, 7.0 or 8.0), 100 mM Tris-HCl buffer ( After 60 minutes of treatment in pH 8.0), it has a residual enzyme activity of 80% or more. Preferably it is stable up to 40°C, up to 45°C or up to 50°C.
  • Substrate specificity The activity on maltose, xylose and galactose is 2.0% or less when the activity on glucose is 100%. High substrate specificity.
  • the activity on 50 mM D-glucose is 100%, the activity on 50 mM maltose, D-xylose, and D-galactose is 2.0% or less, preferably 0.3% or less, 0 .9% or less or 0.2% or less.
  • Km value (against glucose) 30 mM or more The Km value for D-glucose is preferably 150-300 mM, 50-120 mM, or 30-80 mM.
  • the flavin-binding GDH of the present invention has low activity on xylose because it specifically acts on the 6-position of glucose.
  • Diaporte e.g., Diaporthe helianthi
  • Cuschia e.g., Khuskia oryzae
  • Acremonium strictum e.g., Lasiosphaeris hirsute
  • Fusarium e.g, Fusarium langsetiae
  • microorganisms belonging to the genus Phialemoniosis eg, Phialemoniopsis curvata
  • the flavin-binding GDH of the present invention is an enzyme derived from the microorganism (wild strain or mutant strain), a recombinant enzyme obtained by genetic engineering using the gene encoding the flavin-binding GDH of the present invention, chemical synthesis Any synthetic enzyme obtained by Recombinant enzymes are preferred.
  • the gene encoding the flavin-binding GDH of the present invention is preferably a gene consisting of any one of the following (a) ⁇ (e) DNA.
  • a DNA encoding a protein having a base sequence in which several bases are deleted, substituted or added and having glucose-6-dehydrogenase activity (c) against the nucleotide sequence represented by SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35 or 37
  • 1 to several in the nucleotide sequence represented by SEQ ID NO: 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35 or 37 1 to several bases in a base sequence having deleted, substituted or added bases is preferably 1 to 10, more preferably 1 to 5, more preferably 1 to 3, 1 or 2 is more preferred.
  • base deletion means the absence or disappearance of a base
  • base substitution means that a base is replaced with another base
  • base addition means that a base is added.
  • An “addition” includes the addition of bases to one or both ends of a sequence, and the insertion of another base between bases in a sequence.
  • sequence identity of the base sequences is preferably 85% or higher, more preferably 90% or higher, even more preferably 95% or higher, and even more preferably 99% or higher.
  • Sequence identity of nucleotide sequences can be determined using the algorithm BLAST (Pro. Natl. Acad. Sci. USA, 1993, 90:5873-5877) by Karlin and Altschul. Based on this algorithm BLAST, programs called BLASTN and BLASTX have been developed (J.Mol.Biol., 1990, 215, p.403-410). Also, a homology analysis (Search homology) program of genetic information processing software Genetyx may be used. Specific techniques for these analysis methods are publicly known (see https://www.ncbi.nlm.nih.gov).
  • stringent conditions refer to conditions under which nucleotide sequences with high identity hybridize with each other and nucleotide sequences with lower identity do not hybridize with each other. "Stringent conditions" can be changed as appropriate depending on the degree of identity desired. The more stringent the conditions, the more identical sequences will hybridize. For example, stringent conditions include conditions described in Molecular Cloning: A Laboratory Manual (Second Edition, J. Sambrook et. al, 1989).
  • composition of 1 x SSC 0.15 M sodium chloride, 0.015 M sodium citrate, pH 7.0
  • 0.5% SDS 0.5% SDS
  • 5 x Denhardt 100 mg/mL herring sperm DNA
  • examples include conditions such as incubating with the probe at a constant temperature of 65° C. for 8 to 16 hours for hybridization.
  • Preparation of flavin-binding GDH using a gene encoding flavin-binding GDH of the present invention for example, by introducing an expression vector containing a gene encoding flavin-binding GDH of the present invention into host cells such as microorganisms, obtained It is possible to produce the flavin-binding GDH of the present invention by culturing the resulting transformant.
  • the transformant may retain the gene encoding the flavin-binding GDH of the present invention in the form of a vector, or may retain the gene in the genome.
  • Genes encoding flavin-binding GDH of the present invention, with reference to the gene sequence information disclosed herein, prepared in a state isolated using any method used in the art such as PCR method can be done.
  • the type of vector is not particularly limited, and includes vectors commonly used for protein production, such as plasmids, cosmids, phages, viruses, YACs, and BACs. Among them, plasmid vectors are preferred, and commercially available protein expression plasmid vectors such as pET and pBIC can be preferably used. Procedures for introducing genes into plasmid vectors are well known in the art.
  • Host microorganisms to be transformed to express the flavin-binding GDH of the present invention include, for example, Escherichia genus, Rhodococcus genus, Streptomyces genus, Bacillus genus , genus Brevibacillus, genus Staphylococcus, genus Enterococcus, genus Listeria, genus Saccharomyces, genus Pichia, genus Shizosaccharomyces, genus Kluyveromyces Kluyveromyces), Aspergillus, Penicillium, and Trichoderma bacteria, yeast, and filamentous fungi.
  • the medium and culture conditions used for culturing the transformant can be appropriately selected by those skilled in the art according to the type of transformant. For example, using a medium containing carbon sources, inorganic nitrogen sources, organic nitrogen sources, inorganic salts, and other necessary organic micronutrients that can be assimilated by microorganisms, under aerobic conditions such as aeration, stirring, and shaking. can be done.
  • the medium may be a synthetic medium, a natural medium, a semi-synthetic medium, or a commercially available medium.
  • the medium is preferably a liquid medium.
  • the pH of the medium is preferably in the range of, for example, pH 5 to pH 9, and the pH may be adjusted during culture in consideration of productivity.
  • the culture temperature is preferably 10° C. to 40° C.
  • the culture period is preferably 2 days to 14 days.
  • the culture After culturing, the culture can be used, but is preferably used after performing a separation operation such as centrifugation to obtain a culture supernatant. Alternatively, it is used after obtaining microbial cells, crushing the microbial cells by an arbitrary method, and obtaining a supernatant from the crushed liquid.
  • the culture may be a culture solution, microbial cells, or processed products thereof (freeze-dried cells, acetone-dried cells, etc.). Alternatively, it may be an immobilized enzyme or immobilized bacterial cells immobilized by any method.
  • Purification of the flavin-binding GDH of the present invention produced by the transformant can utilize a known purification method. For example, a purified enzyme can be obtained by combining purification procedures such as ultrafiltration, salting out, solvent precipitation, heat treatment, dialysis, ion exchange chromatography, hydrophobic chromatography, gel filtration, and affinity chromatography.
  • the form of flavin-binding GDH is not particularly limited, may be a culture supernatant, crude enzyme, purified enzyme, immobilized enzyme, even a microorganism containing flavin-binding GDH good.
  • Microorganisms containing flavin-binding GDH are preferably recombinant microorganisms introduced with a gene encoding flavin-binding GDH.
  • Microorganisms containing flavin-binding GDH, whether alive or dead also includes treated microbial cells as described above.
  • Production of resveratrol glucuronide is usually carried out in aqueous media such as water, buffers, monohydric alcohols, dihydric alcohols and the like.
  • various pH adjusters, surfactants, antifoaming agents, etc. may be added as necessary.
  • the substrate concentration is preferably about 10 mM to 1,000 mM.
  • Mediators are also called electron carriers, electron acceptors, redox mediators.
  • Mediators include osmium compounds (e.g., osmium (II)-2,2'-bipyridine complex), quinone compounds (e.g., benzoquinone, 1,4-naphthoquinone, vitamin K3 (menadione)), phenolic compounds (tert -butylhydroquinone, hydroquinone, 4-aminophenol, butylhydroxyanisole, eugenol, catechol, guaiacol, pyrogallol, vanillin, n-propyl gallate), phenazine compounds (e.g.
  • phenazine methosulfate 1-methoxy-5-methylphena) sodium methyl sulfate, methylene blue
  • ferricyanides eg, potassium ferricyanide
  • flavonoids quercetin dihydrate, hesperidin
  • the amount of mediator to be used can be appropriately set depending on the type thereof, but is usually preferably about 0.5 mM to 50 mM.
  • Conditions for acting flavin-binding GDH of the present invention to resveratrol glucoside are not particularly limited as long as flavin-binding GDH is not deactivated.
  • the reaction proceeds under normal temperature and pressure, and under neutral to alkaline conditions.
  • the reaction temperature is generally 10° C. to 60° C., preferably 20° C. to 40° C.
  • the reaction time is generally 30 minutes to 72 hours, preferably 1 hour to 48 hours, more preferably 3 hours to 24 hours. be.
  • the reaction pH is preferably pH 5.0 to pH 9.0.
  • the amount of flavin-binding GDH of the present invention used is preferably 1 U/mL to 50 U/mL as a final concentration.
  • the oxidase includes phenol oxidase such as laccase (EC 1.10.3.2) and peroxidase (EC 1.11.1.7).
  • phenol oxidase such as laccase (EC 1.10.3.2)
  • peroxidase EC 1.11.1.7
  • catalase EC 1.11.1.6
  • the amount of these enzymes used is preferably about 0.25 U/mL to 500 U/mL as a final concentration.
  • the 6-hydroxymethyl group of the glucose skeleton of the substrate resveratrol glucoside is oxidized to a carboxyl group, and resveratrol glucuronide is specifically produced.
  • the production rate of resveratrol glucuronide is almost 100% according to the analysis result of thin layer chromatography.
  • resveratrol glucuronide has a LogP value of -2.15, which is an indicator of the hydrophilicity (or hydrophobicity) of an organic compound, compared to piceido (LogP value 1.01). It is highly hydrophilic and has excellent solubility in water.
  • resveratrol glucuronide has hyaluronidase inhibitory activity, collagenase inhibitory activity, antioxidant activity (diphenylpicrylhydrazyl (DPPH) radical scavenging activity) and tyrosinase inhibitory activity.
  • Hyaluronidase is an enzyme that breaks down hyaluronic acid. Hyaluronidase is activated during inflammation, destroys the connective tissue matrix, and mediates tissue infiltration of the inflammatory system, enhancement of vascular permeability, and release of histamine from mast cells in type I allergy. Therefore, anti-allergic and anti-inflammatory effects are expected by inhibiting the activity of hyaluronidase.
  • Type I allergies include hay fever, allergic rhinitis, bronchial asthma, atopic dermatitis, food allergy, anaphylactic shock, and the like.
  • hyaluronic acid is widely distributed in the skin, synovial fluid, vitreous body, and the like, and when hyaluronic acid decreases, the skin loses moisture and firmness, causing spots and sagging. Therefore, by inhibiting the activity of hyaluronidase, skin beautification and anti-aging effects are also expected.
  • Collagenase is an enzyme that breaks down collagen. Collagen is responsible for maintaining the firmness and elasticity of the skin. Collagen decreases with aging, and its degradation is accelerated by collagenase that is activated by UV stimulation. Therefore, by inhibiting the activity of collagenase, the firmness of the skin is maintained, and an anti-aging effect is expected.
  • Reactive oxygen species include superoxide, hydroxyl radicals, hydrogen peroxide, and singlet oxygen, and these reactive oxygen species are associated with various skin diseases such as inflammation, skin darkening, DNA damage, age spots, wrinkles, and the like. known to be closely involved in skin aging in humans. Therefore, it is expected to improve photoaging, pigmentation, age spots, and dullness of the skin associated with active oxygen due to its antioxidant ability.
  • Tyrosinase is an enzyme involved in melanin biosynthesis from tyrosine. In vivo, tyrosinase produces dopaquinone from tyrosine, and melanin is produced as the oxidation reaction progresses. Therefore, by inhibiting the activity of tyrosinase, the production of melanin can be suppressed and a whitening effect can be obtained.
  • resveratrol glucuronide based on its hyaluronidase inhibitory activity, collagenase inhibitory activity, antioxidant activity and tyrosinase inhibitory activity, can be applied to the skin to prevent skin aging (e.g., skin firmness, wrinkles and sagging).
  • skin aging e.g., skin firmness, wrinkles and sagging.
  • resveratrol glucuronide is a hyaluronidase inhibitor, anti-inflammatory agent, anti-allergic agent, collagenase inhibitor, antioxidant, anti-aging agent, tyrosinase inhibitor, melanogenesis inhibitor, whitening agent (hereinafter referred to as "hyaluronidase inhibitor etc.), for inhibiting hyaluronidase activity, for anti-inflammatory, for anti-allergy, for inhibiting collagenase activity, for antioxidant, for anti-aging, for inhibiting tyrosinase activity, Since it suppresses melanin production, it can be used for skin whitening, and can be used for producing hyaluronidase inhibitors and the like.
  • the form of application of the hyaluronidase inhibitor to humans or non-human animals is not particularly limited, and examples thereof include external skin application (transdermal), transmucosal, nasal, enteral, injection, suppository, inhalation, and the like. parenteral or oral.
  • External skin preparations may be in the form of pharmaceuticals, quasi-drugs, or cosmetics.
  • Cosmetics Specifically, ointments, creams, gels, patches, ticks, liniments, lotions, sprays, basic cosmetics (skin lotions, milky lotions, creams, serums, gels, packs, etc.), makeup Makeup cosmetics (foundation, lipstick, etc.), cleansers for face or body (shampoo, rinse, hair treatment, hair cream, etc.), bath agents, and the like.
  • preferred forms are basic cosmetics and make-up cosmetics, and more preferred forms are water-based products (such as lotions).
  • Foods and drinks include foods with health claims such as foods for specified health uses and foods with function claims.
  • oral solid preparations tablets (uncoated tablets, coated tablets, etc.), capsules, granules, powders, lozenges, etc.
  • oral liquid preparations liquids, syrups, drinks, etc.
  • various food compositions Breads, cakes, noodles, sweets, frozen foods, ice creams, candies, soups, dairy products, beverages, seasonings, nutritional supplements, etc.
  • preferred forms are water-based products (oral liquid preparations, beverages, etc.).
  • a pharmaceutically acceptable carrier or cosmetically acceptable carrier include various oils, surfactants, gelling agents, buffers, preservatives, antioxidants, solvents, dispersants, chelating agents, Thickeners, ultraviolet absorbers, emulsion stabilizers, pH adjusters, pigments, fragrances, and the like can be mentioned.
  • Additives acceptable for foods include, for example, solvents, softeners, oils, emulsifiers, preservatives, acidulants, sweeteners, bittering agents, pH adjusters, stabilizers, coloring agents, antioxidants, and thickeners. , pigments, fragrances, and the like.
  • Other active ingredients, medicinal ingredients, and cosmetic ingredients include, for example, plant extracts, bactericides, moisturizers, anti-inflammatory agents, antibacterial agents, keratolytic agents, cooling agents, antiseborrheic agents, cleansers, and makeup ingredients. etc.
  • the content of resveratrol glucuronide in the formulation of the present invention varies depending on the form of the formulation, so it cannot be said unconditionally, but due to the high functionality and water solubility of resveratrol glucuronide, for example, As a standard, it is preferably 0.0006% by mass or more, more preferably 0.002% by mass or more, still more preferably 0.01% by mass or more, and preferably 20% by mass or less, more preferably 5% by mass or less. is. No formulations containing such high concentrations of resveratrol glucuronide are heretofore known.
  • the content of the organic solvent is preferably 30% by mass or less, more preferably 0 to 5% by mass, still more preferably less than 1% by mass, and substantially 0% by mass, that is, the organic solvent More preferably not.
  • the content of the surfactant in the formulation of the present invention is preferably 25% by mass or less, more preferably 0 to 5% by mass, and substantially 0% by mass, that is, it does not contain a surfactant. More preferred.
  • the amount of resveratrol glucuronide administered or used may be an amount that can achieve the effects of the present invention.
  • the dose or amount used may vary according to the target species, body weight, sex, age, condition, or other factors. , for example, about 0.001 to 2 mg/cm 2 as resveratrol glucuronide.
  • oral administration for example, about 5 to 20 mg of resveratrol glucuronide per day per adult (60 kg).
  • such an amount is divided once to several times a day, and administered repeatedly and continuously for 1 day or more, preferably 7 days or more, more preferably 14 days or more, and even more preferably 42 days or more. or can be used.
  • Subjects to whom the formulation of the present invention is administered or used include, for example, humans desiring anti-aging, anti-allergic, anti-inflammatory, skin-beautifying, and whitening effects on the skin.
  • non-human animals include non-human mammals such as apes and other primates.
  • Sites of the skin to which the formulation of the present invention is administered or used include, for example, the face, neck, arms, backs of hands, fingers and the like.
  • cDNA library was prepared from the RNA obtained in (2) by reverse transcription using a reverse transcriptase and an oligo dT primer with an adapter sequence.
  • SMARTer RACE cDNA Amplification kit (Takara Bio Inc.) was used as a reaction reagent, and the reaction conditions were performed according to the protocol described in the manual.
  • CpGDH full-length GDH gene derived from the Colletotrichum plurivorum MAFF305790GDH strain was elucidated by the 5'RACE method and the 3'RACE method.
  • the clarified CpGDH gene sequence optimized for Aspergillus oryzae codon frequency is shown in SEQ ID NO: 1. Furthermore, the amino acid sequence predicted from the gene sequence is shown in SEQ ID NO:2.
  • a plasmid vector was prepared using an improved promoter of the amylase system from Oryzae. First, using the cDNA library obtained in (3) as a template, a PCR product containing the CpGDH gene was obtained. Next, using the PCR product as a template, a CpGDH gene for vector insertion was prepared.
  • the prepared CpGDH gene was linked downstream of the promoter to prepare a plasmid vector capable of expressing the gene.
  • the prepared expression plasmid vector was introduced into Escherichia coli JM109 strain for transformation.
  • the resulting transformant was cultured, and a plasmid vector was extracted from the collected cells using illustra plasmid Prep Midi Flow Kit (GE Healthcare). Sequence analysis of the insert in the plasmid vector confirmed a nucleotide sequence containing the CpGDH gene.
  • the transformant obtained in (6) was inoculated into the cooled liquid medium and cultured with shaking at 30°C for 120 hours. After the culture was completed, the supernatant was collected by centrifugation, and the GDH activity was measured by the GDH activity measurement method described later, and CpGDH activity was confirmed.
  • Glucose dehydrogenase (GDH) activity measurement method 100 mM potassium phosphate buffer (pH 6.0) 1.00 mL, 1 M D-glucose solution 1.00 mL, 3 mM 2,6-dichlorophenolindophenol (hereinafter referred to as "DCIP") 0.14 mL, 3 mM 1-methoxy-5 -Methylphenadium methylsulfate (hereinafter referred to as "1-m-PMS”) 0.20 mL and ultrapure water 0.61 mL are mixed, and after incubation at 37 ° C. for 10 minutes, 0.05 mL of the enzyme solution is added to react. started.
  • DCIP 2,6-dichlorophenolindophenol
  • 1-m-PMS 1-methoxy-5 -Methylphenadium methylsulfate
  • the amount of decrease in absorbance at 600 nm per minute ( ⁇ A600) accompanying the progress of the enzyme reaction was measured for 5 minutes from the start of the reaction, and the enzymatic activity was calculated from the linear portion according to the following equation. At this time, the enzymatic activity was defined as 1 U as the amount of enzyme that reduces 1 ⁇ mol of DCIP per minute at 37° C. and pH 6.0.
  • As the enzyme dilution solution a solution containing 50 mM potassium phosphate buffer (pH 6.0) and 1 mg/mL BSA as the final concentration was used.
  • 3.0 is the liquid volume (mL) of the reaction reagent + enzyme solution
  • 10.8 is the molar extinction coefficient of DCIP at pH 6.0
  • 1.0 is the optical path length of the cell (cm)
  • 0.05. is the volume (mL) of the enzyme solution
  • ⁇ A600blank is the amount of decrease in absorbance at 600 nm per minute when the reaction is started by adding a diluted solution of the enzyme instead of the enzyme solution.
  • the collected culture supernatant was purified by removing contaminating proteins using a TOYOPEARL DEAE-650S (Tosoh Corporation) column. After concentrating the purified sample with an ultrafiltration membrane with a cutoff molecular weight of 10,000, water substitution was performed to obtain purified CpGDH. When the purified CpGDH was subjected to SDS-polyacrylamide electrophoresis, it was confirmed to exhibit a single band.
  • FIG. 1 shows the results of 1 H-NMR analysis and 13 C-NMR analysis of resveratrol glucuronide obtained.
  • Example 1 Water/octanol partition coefficient of resveratrol glucuronide
  • LogP Water / octanol partition coefficient
  • sample for analysis The sample was dissolved in methanol filtered through a 0.45 ⁇ m filter to prepare a sample solution with a final concentration of 1 mM. Of the prepared sample solution, 0.1 mL was accurately weighed and concentrated to dryness under reduced pressure. °C for 30 minutes. After heating, 0.2 mL of 1-octanol was further added and suspended, and the suspension was separated into two phases by centrifugation at 2,900 ⁇ g for 5 minutes under room temperature conditions, and then the aqueous phase and the octanol phase were separated. and used as a sample for analysis.
  • Hyaluronidase inhibitory activity of resveratrol glucuronide was evaluated by the following method.
  • Hyaluronidase inhibition rate (%) (1-[(absorbance of sample - absorbance of sample blank) / (absorbance of control - absorbance of control blank)]) x 100
  • resveratrol glucuronide has a higher hyaluronidase inhibitory activity than resveratrol and piceid, and is effective in suppressing aging phenomena (wrinkles, sagging, etc.) associated with hyaluronic acid degradation, and hyaluronidase is involved. It can be expected to be effective against allergies and inflammation.
  • Example 3 Collagenase inhibitory activity of resveratrol glucuronide
  • FIG. 3 shows the resulting collagenase inhibition rate of resveratrol glucuronide.
  • the IC50 of resveratrol glucuronide was about 60 ⁇ M as the final concentration of the sample.
  • IC50 of collagenase inhibitory activity of resveratrol is about 440 ⁇ M (Non-Patent Document 8). From these results, resveratrol glucuronide has a high collagenase inhibitory activity and can be expected to have an effect of suppressing aging phenomena (wrinkles, sagging, etc.) associated with collagen degradation in the skin.
  • Example 4 Antioxidant activity of resveratrol glucuronide
  • the antioxidant activity of resveratrol glucuronide was measured using DPPH (2,2-diphenyl-1-picrylhydrazyl, Fujifilm Wako Pure Chemical Industries, Ltd.) by the following method.
  • a premixed solution was prepared by mixing 10 mL of 400 ⁇ M DPPH solution, 10 mL of 0.2 M MES buffer (pH 6.0), and 10 mL of 20% ethanol.
  • a sample solution resveratrol, piceid, resveratrol glucuronide, and Trolox standard (Fujifilm Wako Pure Chemical Industries, Ltd.) are each dissolved in 80% ethanol, and diluted with 80% ethanol. Concentration sample solutions were prepared in 0.3 mL portions.
  • Example 5 (Tyrosinase inhibitory activity of resveratrol glucuronide) Tyrosinase inhibitory activity of resveratrol glucuronide was evaluated by the following method.
  • Tyrosinase inhibition rate (%) [1-((absorbance of sample after standing for 30 minutes - absorbance of sample immediately after preparation) - (absorbance of sample blank after standing for 30 minutes - absorbance of sample blank immediately after preparation) ) / (absorbance of control after standing for 30 minutes - absorbance of control immediately after preparation)] ⁇ 100
  • FIG. 4 shows the tyrosinase inhibition rate of resveratrol glucuronide.
  • Example 6 Solubility of resveratrol glucuronide in water
  • resveratrol glucuronide was suspended in ultrapure water under room temperature conditions and dissolved by shaking for 1 hour. After shaking, it was confirmed that resveratrol glucuronide was completely dissolved in ultrapure water at a final concentration of 10 mM.

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JP2013526505A (ja) * 2010-05-11 2013-06-24 イケルケム、エセ エレ 多置換ベンゾフランおよびその医学的応用
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JP2016506925A (ja) * 2013-01-22 2016-03-07 キョンプク ナショナル ユニバーシティ インダストリー−アカデミック コーポレーション ファウンデーション レスベラトロール誘導体の皮膚美白用途

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JP2011084472A (ja) * 2009-10-13 2011-04-28 Nippon Menaade Keshohin Kk 皮膚外用剤
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