Reagent for inducing retinol-like action and use thereof

Abstract

Provided is a reagent which has reduced inhibition of differentiation of epidermal keratinocytes, is capable of inducing a retinol-like effect, and is mainly applicable to human skin or the like. The reagent for inducing a retinol-like action according to the present disclosure contains bakuchiol (4-[(1E, 3S)-3-vinyl-3, 7-dimethyl octyl-1, 6-dienyl] phenol).

Description

Technical Field

[0001] The present disclosure relates to an agent for exerting a retinol-like effect in the skin of humans, etc., and uses thereof. Background Art

[0002] It is known that retinoic acid, which is a retinol, controls the expression of retinoic acid receptors (RARs) in epidermal keratinocytes and the like when applied to the skin. Non-patent document 1 describes that retinoic acid weakly induces (enhances) the expression of RARs in RARs. β Genes and RAR γ Gene expression.

[0003] The retinoic acid activates the metabolism of the skin on one hand, and inhibits the differentiation of epidermal keratinocytes on the other hand, thereby causing side effects such as skin erythema and scaling, which is a problem.

[0004] Prior art literature Non-patent literature Non-patent document 1: Ding-Dar Lee et al., "Retinoid-Responsive Transcriptional Changes in Epidermal Keratinocytes", J Cell Physiol. 2009 August; 220 (2): pp. 427-439 Summary of the invention

[0005] Technical problem to be solved by the invention Therefore, an object of the present disclosure is to provide an agent that reduces inhibition of epidermal keratinocyte differentiation and can induce a retinol-like effect and can be applied mainly to human skin and the like.

[0006] Technical solutions for solving technical problems In order to achieve the above object, the agent for inducing a retinol-like effect (hereinafter, also referred to as a "retinol-like effect inducer") disclosed herein comprises bakuchiol (4-[(1E,3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol).

[0007] The agent for inducing the expression of the epidermal keratinocyte maturation-promoting gene of the present disclosure (hereinafter, also referred to as “maturation-promoting gene expression inducer”) contains bakuchiol.

[0008] The agent for inducing the expression of the ceramide synthase 1 (CERS1) gene of the present disclosure (hereinafter, also referred to as “the CERS1 gene expression inducer”) contains bakuchiol.

[0009] The agent for promoting the proliferation and / or maturation of epidermal keratinocytes disclosed herein (hereinafter, also referred to as a “maturation promoting agent”) comprises bakuchiol.

[0010] Effects of the Invention According to the present disclosure, it is possible to provide an agent that reduces inhibition of epidermal keratinocyte differentiation and can induce a retinol-like effect and can be applied mainly to human skin and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 (A) and (B) represent the RAR in Example 1. α Gene expression chart, Figure 1 (A) shows the results after 48 hours of culture. Figure 1 (B) shows the results after 72 h of culture.

[0012] Figure 2 (A) and (B) represent the RAR in Example 1. β Gene expression chart, Figure 2 (A) shows the results after 48 hours of culture. Figure 2 (B) shows the results after 72 h of culture.

[0013] Figure 3 (A) and (B) represent the RAR in Example 1. γ Gene expression chart, Figure 3 (A) shows the results after 48 hours of culture. Figure 3 (B) shows the results after 72 h of culture.

[0014] Figure 4 (A) and (B) are graphs showing the expression of the filaggrin (FLG) gene in Example 1. Figure 4 (A) shows the results after 48 hours of culture. Figure 4 (B) shows the results after 72 h of culture.

[0015] Figure 5 (A) and (B) are graphs showing the expression of the involucrin (IVL) gene in Example 1. Figure 5 (A) shows the results after 48 hours of culture. Figure 5 (B) shows the results after 72 h of culture.

[0016] Figure 6 (A) and (B) are graphs showing the expression of the CERS1 gene in Example 1. Figure 6 In the figure, (A) shows the results after 48 hours of culture, and (B) shows the results after 72 hours of culture.

[0017] Figure 7 This is a graph showing the amount of melanin produced in Example 2. DETAILED DESCRIPTION

[0018] Hereinafter, the present disclosure will be specifically described by giving examples. Unless otherwise specified, each disclosure may refer to the description of other disclosures.

[0019] <Agent or composition for inducing retinol-like effect> In a certain embodiment, the present disclosure provides an agent or composition capable of inducing a retinol-like effect. The agent for inducing a retinol-like effect of the present disclosure includes bakuchiol (4-[(1E, 3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol). In addition, the composition for inducing a retinol-like effect of the present disclosure (hereinafter, also referred to as a "retinol-like effect inducing composition") includes bakuchiol (4-[(1E, 3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol). In the following description, unless otherwise specified, the description of each agent of the present disclosure can be cited for the description of each corresponding composition.

[0020] As a result of intensive research conducted by the present inventors, the following findings were obtained: Bakuchiol has a retinol-like effect in controlling the expression of retinoic acid receptors (RARs) in epidermal keratinocytes, that is, an effect similar to retinol (vitamin A), namely ATRA (all-trans retinoic acid). In addition, as a result of further research conducted by the present inventors, it was found that in Bakuchiol, the differentiation inhibition effect of epidermal keratinocytes observed in ATRA was reduced, while on the other hand, the RARs observed in ATRA were exerted. β Gene expression induction and RAR γ As described later, it is presumed that, for example, ATRA inhibits the expression of RAR α Therefore, according to the retinol-like effect inducer disclosed in the present invention, for example, it is expected that the occurrence of side effects such as erythema and flaking of the skin caused by retinol, which are caused by the inhibitory effect of retinol on the differentiation of epidermal keratinocytes, can be suppressed, and the wrinkle improvement effect observed in retinol can be obtained.

[0021] The “bakuchiol” is 4-[(1E,3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol, and may also be referred to as a compound represented by the following formula (1). The bakuchiol may be, for example, a phenoxy anion. In addition, the bakuchiol may be, for example, esterified.

[0022] [Chemistry 1]

[0023] The bakuchiol may be an isolated or purified compound or a composition comprising bakuchiol. Examples of the composition comprising bakuchiol include an extract comprising bakuchiol, a crude purified product of the extract, a dried product of the extract, a freeze-dried product of the extract, a processed product of the extract such as spray drying, and the like.

[0024] The extract containing bakuchiol can be produced, for example, by subjecting a plant containing bakuchiol to solvent extraction. The plant containing bakuchiol can be, for example, Psoralea corylifolia ( Psoralea corylifolia )、 Otholobium pubescens The plant may be used alone or in combination. The plant material used for the extraction may be a plant individual or a plant part. Examples of the plant part include roots, rhizomes, leaves, stems, flowers, or mixtures thereof. The material may be the collected plant itself or a processed product that has been dried and / or pulverized.

[0025] The solvent used in the extraction of bakuchiol can be, for example, water, buffer and other aqueous solvents; methanol, ethanol, propanol, isopropanol, butanol, isobutanol and other lower alcohols or water-containing lower alcohols; propylene glycol, 1,3-butanediol, 1,2-butanediol, 1,4-butanediol, 1,5-pentanediol, 1,2-pentanediol, 1,3-pentanediol, 1,4-pentanediol, 1,3,5-pentanetriol, glycerol, polyethylene glycol (e.g., molecular weight 100 to 100,000) and other polyols or water-containing polyols; acetone, ethyl acetate, diethyl ether, dimethyl ether, ethyl methyl ether, dioxane, hexane, acetonitrile, xylene, benzene, chloroform, carbon tetrachloride, phenol, toluene and other organic solvents; acids (hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, etc.) or bases (sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia, etc.) with appropriately adjusted equivalent concentrations; etc. The above solvents may be used alone or in combination of two or more.

[0026] The treatment of the treated material may include, for example: decomposition based on the addition of acid (hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, organic acid, etc.) or alkali (sodium hydroxide, calcium hydroxide, ammonia, etc.); fermentation or metabolic conversion based on microorganisms; component adsorption based on ion exchange resins, activated carbon, diatomaceous earth, etc.; separation using chromatography with various separation modes (ion exchange, hydrophilic adsorption, hydrophobic adsorption, size exclusion, ligand exchange, affinity, etc.); filtration using filter paper, membrane filter or ultrafiltration membrane, etc.; pressurization or decompression; heating or cooling: drying or freeze drying; pH adjustment; deodorization; decolorization; long-term static storage; etc. The treatment may be implemented alone or in combination.

[0027] The "retinol-like effect" refers to a compound or composition that exhibits at least one of the effects exhibited by retinoic acid ((2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid), especially ATRA. The retinol-like effect may be, for example, an effect on the skin or cells constituting the skin, or an effect on gene expression in the cells, i.e., induction or inhibition of gene expression. The retinol-like effect inducer disclosed herein exerts one or more retinol-like effects.

[0028] When the retinol-like action is an action on the skin or cells constituting the skin, examples of the retinol-like action include strengthening of the basal layer of the skin, stabilization of the basal layer of the skin, and promotion of proliferation of epidermal keratinocytes.

[0029] The “strengthening of the basal layer of the skin” means that when there is an external stimulus on the skin, the cells of the basal layer are difficult to be destroyed (resistance to external stimulus). The strengthening of the basal layer of the skin against the external stimulus can be evaluated, for example, by a marker (basal layer marker) expressed in the basal layer. Examples of the basal layer marker include hyaluronan synthase 3 (HAS3), integrin α 6 (ITG α 6) Integrin β 1(ITG β 1) etc.

[0030] The “stabilization of the basal layer of the skin” refers to the suppression of the fragmentation of the basal layer that occurs with aging. The stabilization of the basal layer of the skin can be evaluated, for example, using the basal layer marker.

[0031] The “promotion of proliferation of epidermal keratinocytes” refers to promoting or enhancing the proliferation of epidermal keratinocytes, particularly human epidermal keratinocytes. The promotion of proliferation of epidermal keratinocytes can be performed, for example, by evaluating the proliferation of the epidermal keratinocytes.

[0032] The "epidermal keratinocyte" refers to a keratinocyte produced by cell division in the basal layer of the epidermis. It is known that the epidermal keratinocyte further differentiates in the epidermis and finally differentiates into keratinocytes that form the stratum corneum.

[0033] When the retinol-like effect is an effect on gene expression in the cell, the retinol-like effect may be, for example, the retinoic acid receptor (RAR). β Gene expression induction, RAR γ Gene expression inhibition, etc., preferably RAR β Gene expression induction and RAR γ Inhibition of gene expression.

[0034] As the RAR β An example of a gene, human RAR β Examples of mRNA encoded by a gene include a polynucleotide consisting of a base sequence registered with accession number NM_000965.5 in Genbank.

[0035] As the RAR γ An example of a gene, human RAR γ Examples of mRNA encoded by a gene include a polynucleotide consisting of a base sequence registered with accession number NM_000966.6 in Genbank.

[0036] The "RAR β "Induction of gene expression" refers to the RAR β The increase or enhancement of gene expression may also refer to the RAR β The gene changes from a non-expressed state to an expressed state. β The expression of the gene can be measured, for example, by measuring RAR according to Example 1 described below. β The expression level of the mRNA of the gene is evaluated. β Gene expression can be measured for any one or more RARs β The expression level of the isoforms of a gene may be measured, or the expression of all isoforms may be measured, but the latter is preferred.

[0037] The "RAR γ "Inhibition of gene expression" refers to the RAR γ The expression level of a gene is inhibited or reduced, and may also refer to the RAR γ The gene changes from an expressed state to a non-expressed state. γ The expression of the gene can be measured, for example, by measuring RAR according to Example 1 described below. γ The expression level of the mRNA of the gene is evaluated. γ Gene expression can be measured for any one or more RARs γ The expression level of the isoforms of a gene may be measured, or the expression of all isoforms may be measured, but the latter is preferred.

[0038] The "gene" can exist in the form of RNA (such as mRNA) or DNA (such as cDNA or genomic DNA). The DNA can be double-stranded or single-stranded. In this specification, the "gene" can include additional sequences such as the sequence of the untranslated region (UTR).

[0039] The retinol-like effect inducer disclosed herein can induce a retinol-like effect, for example, by administering it to a subject. The conditions for use (administration conditions) of the retinol-like effect inducer disclosed herein are not particularly limited, and for example, the administration method, administration period, and administration amount can be appropriately set according to the type of the subject to be administered.

[0040] The retinol-like effect inducer disclosed herein can be used, for example, in vivo ( in vivo ) can also be used in vitro ( in vitro )use.

[0041] The subject to which the retinol-like effect inducer of the present disclosure is administered is not particularly limited. in vivo ) When the retinol-like action inducer of the present disclosure is used, the administration subject may be, for example, a human or a non-human animal other than a human. Examples of the non-human animal include mammals such as mice, rats, rabbits, dogs, sheep, horses, cats, goats, monkeys, guinea pigs, and birds. In vitro ( in vitro ) When the retinol-like action inducer of the present invention is used, the administration object may include, for example, cells, tissues, organs, etc., the cells may include, for example, cells collected from a living body, cultured cells, etc., and the tissues or organs may include, for example, tissues (living tissues) or organs collected from a living body, etc.

[0042] In the following skin external preparation (e.g., a coating agent or composition for transdermal administration or to the skin) or the following oral administration agent or oral administration composition containing the inducer of the retinol-like effect of the present disclosure, the amount of bakuchiol incorporated is sufficient as long as it is within the range of exerting the retinol-like effect, that is, an effective amount. The amount of bakuchiol incorporated (upper and lower limits) is, for example, as follows. It should be noted that in the following examples, the upper limit and the lower limit can be arbitrarily combined.

[0043] Lower limit: 0.1 μ mol / l、1 μ mol / l, preferably 2.5 μ mol / l Upper limit: 200mmol / l, preferably 100mmol / l, preferably 50mmol / l, 10mmol / l, 1mmol / l, preferably 500mmol / l μ mol / l, more preferably 100 μ mol / l It should be noted that in this specification, "mol / l" is sometimes also indicated as "M". In addition, in the examples described below, the addition of bakuchiol 5 μ M (0.000125% (w / v%)) or 10 μ Experimental content of M (0.00025% (w / v%)).

[0044] The administration method of the retinol-like action inducer disclosed in the present invention may include oral administration or non-oral administration. The non-oral administration may include transdermal administration, application (contact) to the skin, etc. The application to the skin may include application to the oral mucosa, that is, application to or contact with epithelial cells in the oral cavity. In addition, the application to the skin may include administration or injection into the skin or subcutaneous via the skin surface in addition to or instead of application to the skin surface. Administration or injection into the skin via the skin surface may be implemented, for example, using microneedles.

[0045] The dosage form of the retinol-like effect inducer disclosed in the present invention is not particularly limited, and can be appropriately determined, for example, according to the administration method. The dosage form may be, for example, liquid or solid. The dosage form may also be, for example, in the form of oil gel (for example, an oil gel containing bakuchiol), oil gel particles (for example, an oil gel particle containing bakuchiol), liposomes (for example, a liposome containing bakuchiol), etc. In the case where the administration method is oral administration, the dosage form may be, for example, tablets, pills, capsules, granules, powders, liquids, etc.

[0046] The "oleogel" refers to a gel-like oil (oily component) thickened by a lipophilic gelling agent. The oleogel can be prepared, for example, by adding an oily gelling agent to an oil. The "oleogel particle" refers to one or more particles composed of an oleogel, in which a desired component is dissolved or dispersed in the oil of the oleogel. The "liposome" refers to a vesicle having a lipid bimolecular membrane dispersed in an aqueous solvent.

[0047] The retinol-like effect inducer disclosed in the present invention may include additives as needed. When used as a composition, the additives preferably include pharmaceutically acceptable additives or pharmaceutically acceptable carriers. The additives are not particularly limited, and for example, base raw materials, excipients, colorants, lubricants, adhesives, disintegrants, stabilizers, coating agents, preservatives, flavoring agents such as spices, etc. can be cited. In the present disclosure, the amount of the additives is not particularly limited as long as it does not hinder the function of bakuchiol.

[0048] Examples of the excipient include: sugar derivatives such as lactose, lactose hydrate, saccharide, glucose, mannitol, sorbitol, etc.; corn starch, potato starch, αStarch derivatives such as starch and dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; organic excipients such as pullulan; silicate derivatives such as light silicic anhydride, synthetic aluminum silicate, calcium silicate, magnesium aluminosilicate; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; inorganic excipients such as sulfates such as calcium sulfate. Examples of the colorant include yellow ferric oxide, etc. Examples of the lubricant include metal stearates such as stearic acid, calcium stearate, magnesium stearate; talc; polyethylene glycol; silicon dioxide; solidified vegetable oil, etc. Examples of the flavoring and smelling agents include spices such as cocoa powder, menthol, aromatic powder, peppermint oil, borneol, cinnamon powder, sweeteners, acidulants, etc. Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, polyethylene glycol, etc. Examples of the disintegrant include: cellulose derivatives such as carboxymethyl cellulose and carboxymethyl cellulose calcium; chemically modified starches and chemically modified celluloses such as carboxymethyl starch, sodium carboxymethyl starch, cross-linked polyvinyl pyrrolidone, and sodium starch glycolate. Examples of the stabilizer include: parabens such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; sorbic acid, etc. Examples of the coating agent include: polyethylene glycols such as hypromellose and polyethylene glycol 6000, talc, and titanium oxide.

[0049] When the retinol-like action inducing composition of the present disclosure is an orally administered composition, specific examples of the orally administered composition include beverages, foods, pharmaceuticals (drugs), quasi-drugs (drugs), and the like.

[0050] When the retinol-like action inducer or composition of the present disclosure is a substance used for percutaneous administration or application to the skin (hereinafter, also referred to as "skin external preparation"), the forms of the skin external preparation may include ampoules, capsules, powders, granules, liquids, gels, foams, emulsions, tablets, mists, sprays, etc. according to the usage form. The usage forms may include, for example: pharmaceuticals; quasi-pharmaceuticals; topical or systemic skin external preparations; pharmaceutical and / or cosmetic preparations applied to the scalp and hair; bath agents placed in bath water for use; other preparations; etc. The topical or systemic skin external preparations may include, for example: basic cosmetics such as lotions, emulsions, creams, ointments, lotions, oils, face masks, etc., facial cleansers or skin cleansers such as solid soaps, liquid soaps, hand sanitizers, massage agents, cleaning agents, hair removal agents, depilatory agents, shaving treatment agents, aftershaves, pre-shaves, shaving creams, foundations, lipsticks, blushes, eyeshadows, eyeliners, mascaras, etc. color cosmetics, perfumes, nail cosmetics, nail polishes, nail polish removers, cataplasms, plaster agents, tape agents, sheet agents, patches, aerosol agents, mouthwashes such as toothpaste and mouthwash, etc. The pharmaceutical and / or cosmetic preparations applied to the scalp and hair may include, for example: shampoos, conditioners, hair care agents, hair pretreatment agents, permanent wave lotions, hair dyes, hair styling agents, hair packs, hair growth and nourishing agents, cataplasms, plaster agents, tape agents, sheet agents, aerosol agents, etc. The other preparations may include, for example: antiperspirants or deodorants, antiperspirants, sanitary products, sanitary pads, wet wipes, etc.

[0051] The skin external preparation can be arbitrarily selected and / or used in combination with the following exemplified components and / or additives within the range that does not interfere with the action of bakuchiol as needed.

[0052] (1) Various oils Avocado oil, almond oil, anise oil, perilla oil, olive oil, orange oil, orange roughy oil, sesame oil, cocoa butter, chamomile oil, carrot oil, cucumber oil, tallow fatty acid, candlenut oil, safflower oil, shea butter, liquid shea butter, soybean oil, camellia oil, corn oil, rapeseed oil, peach kernel oil, castor oil, cottonseed oil, peanut oil, turtle oil, mink oil, egg yolk oil, palm oil, palm kernel oil, Japan wax, coconut oil, beef tallow, lard, squalene, squalane, shark liver alkane or hydrogenated products (hardened oils, etc.) of these oils, etc.

[0053] (2) Waxes Beeswax, carnauba wax, cetyl wax, lanolin, liquid lanolin, reduced lanolin, hard lanolin, candelilla wax, lignite wax, shellac wax, rice bran wax, etc.

[0054] (3) Mineral oils Liquid paraffin, vaseline, paraffin, ozokerite, ceresin, microcrystalline wax, etc.

[0055] (4) Fatty acids Natural fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, linolenic acid, docosahexaenoic acid, eicosapentaenoic acid, 12-hydroxystearic acid, undecylenic acid, tall oil, lanolin fatty acid, and synthetic fatty acids such as isononanoic acid, caproic acid, 2-ethylbutyric acid, isovaleric acid, 2-methylvaleric acid, 2-ethylhexanoic acid, and isovaleric acid.

[0056] (5) Alcohols Natural alcohols such as ethanol, isopropyl alcohol, lauryl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, lanolin alcohol, cholesterol, phytosterols, phenoxyethanol, and synthetic alcohols such as 2-hexyldecanol, isostearyl alcohol, and 2-octyldodecanol.

[0057] (6) Polyols Ethylene oxide, ethylene glycol, diethylene glycol, triethylene glycol, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, polyethylene glycol, propylene oxide, propylene glycol, polypropylene glycol, 1,3-butylene glycol, pentylene glycol, glycerol, pentaerythritol, threitol, arabitol, xylitol, ribitol, galactitol, sorbitol, mannitol, lactitol, maltitol, etc.

[0058] (7) Esters Isopropyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, oleyl oleate, decyl oleate, octyldodecyl myristate, hexyl decyl dimethyl octanoate, cetyl lactate, myristyl lactate, diethyl phthalate, dibutyl phthalate, lanolin acetate, ethylene glycol monostearate, propylene glycol monostearate, propylene glycol dioleate, etc.

[0059] (8) Metal soaps Aluminum stearate, magnesium stearate, zinc stearate, calcium stearate, zinc palmitate, magnesium myristate, zinc laurate, zinc undecylenate, etc.

[0060] (9) Gum, sugar or water-soluble polymer compounds Arabic gum, benzoin gum, dammar gum, guaiac, Irish moss, karaya gum, tragacanth gum, carob bean gum, quince seed, agar, casein, lactose, fructose, sucrose or its esters, trehalose or its derivatives, dextrin, gelatin, pectin, starch, carrageenan, carboxymethyl chitin or chitosan, hydroxyalkyl (C2-C4) chitin or chitosan with alkylene (C2-C4) oxide added by ethylene oxide, low molecular weight chitin or chitosan, chitosan salt, chitosan sulfate or chitosan, phosphorylated chitosan cellulose or chitosan, alginic acid or its salt, hyaluronic acid or its salt, chondroitin sulfate or its salt, heparin, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, carboxyethyl cellulose, sodium carboxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, nitrocellulose, crystalline cellulose, polyvinyl alcohol, polyvinyl methyl ether, polyvinyl pyrrolidone, polyvinyl methacrylate, polyacrylate, polyalkylene oxide such as polyethylene oxide or polypropylene oxide or their cross-linked polymers, carboxyvinyl polymers, polyethylene imine, etc.

[0061] (10) Surfactants Anionic surfactants (alkyl carboxylates, alkyl sulfonates, alkyl sulfate ester salts, alkyl phosphate ester salts), cationic surfactants (alkyl amine salts, alkyl quaternary ammonium salts), amphoteric surfactants: carboxylic acid type amphoteric surfactants (amino type, betaine type), sulfate type amphoteric surfactants, sulfonic acid type amphoteric surfactants, phosphate type amphoteric surfactants, nonionic surfactants (ether type nonionic surfactants, ether ester type nonionic surfactants, ester type nonionic surfactants, block polymer type nonionic surfactants, nitrogen-containing nonionic surfactants), other surfactants (natural surfactants, protein hydrolyzate derivatives, polymer surfactants, titanium and silicon-containing surfactants, fluorinated carbon surfactants), etc.

[0062] (11) Various vitamins Vitamin B family: Thiamine hydrochloride, Thiamine sulfate (vitamin B1), Riboflavin (vitamin B2), Pyridoxine (vitamin B6), Cyanocobalamin (vitamin B12), Folic acid, Niacin, Pantothenic acid, Biotin, Choline, Inositol, Vitamin C family: Vitamin C acid or its derivatives, Vitamin D family: Ergocalciferol (vitamin D2), Cholecalciferol (vitamin D3), Dihydrotachysterol, Vitamin E family: Vitamin E or its derivatives, Ubiquinones, Vitamin K family: Phytomenadione (vitamin K1), Menaquinone (vitamin K2), 2-Menadione (vitamin K3), Hydrogenated Menadione (vitamin K4), Other essential fatty acids (vitamin F), Carnitine, Ferulic acid, γ - Oryzanol, orotic acid, vitamin P (rutin, erythritol, hesperidin), vitamin U, etc.

[0063] (12) Various amino acids Valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, lysine, glycine, alanine, asparagine, glutamine, serine, cysteine, cystine, tyrosine, proline, hydroxyproline, aspartic acid, glutamic acid, hydroxylysine, arginine, ornithine, histidine, and their sulfates, phosphates, nitrates, citrates, or amino acid derivatives such as pyrrolidonecarboxylic acid, etc.

[0064] (13) Additives The skin topical preparation may further contain various additives derived from animals or plants. The additives may be processed by conventional methods according to the type and form of the product to be added, and may be arbitrarily selected and added from various raw materials. The processing may be, for example, arbitrarily selected and / or combined treatments such as crushing, milling, washing, hydrolysis, fermentation, purification, squeezing, extraction, fractionation, filtration, drying, powdering, granulation, dissolution, sterilization, pH adjustment, deodorization, and decolorization.

[0065] The solvent used in the extraction can be selected based on the purpose of use, type, or subsequent processing of the product provided. The extraction solvent is preferably selected from, for example, water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol and other lower alcohols or aqueous lower alcohols, propylene glycol, 1,3-butanediol, glycerol and other polyols or aqueous polyols, acetone, ethyl acetate and other organic solvents, or a mixture of one or more thereof. However, in the case where the extraction solvent does not preferably contain an organic solvent according to the purpose, water alone may be used, or ethanol that is easily removed after extraction may be used alone or in any mixture with water, or the solvent after squeezing extraction may be used.

[0066] When the additives derived from plant or animal raw materials are used in external preparations or cosmetics for systemic or local use, the external preparations for skin, for example, protect the skin and hair, and in addition to the beauty effects such as moisturizing, improvement of touch and feel, imparting softness, relieving irritation, relieving stress caused by fragrance, cell activation (prevention of cell aging), inhibition of inflammation, improvement of skin quality and hair quality, prevention of skin roughness and its improvement, hair growth, hair growth, prevention of hair loss, imparting gloss, cleansing effect, relief of fatigue, promotion of blood flow, warm bath effect, etc., can also be expected to have fragrance, deodorizing, thickening, antiseptic, buffering and the like.

[0067] The skin external preparation can expect various cosmetic and medicinal effects of various raw materials known so far in addition to the above, and by combining them, the effect aimed at by the present disclosure can be enhanced, and a product expected to have multifunctional effects can be made.

[0068] <Agent or composition for inducing expression of epidermal keratinocyte maturation-promoting gene> In another embodiment, the present disclosure provides an agent or composition capable of inducing maturation-promoting genes of epidermal keratinocytes, particularly human epidermal keratinocytes. The agent disclosed herein for inducing the expression of maturation-promoting genes of epidermal keratinocytes comprises bakuchiol. In addition, the composition disclosed herein for inducing the expression of maturation-promoting genes of epidermal keratinocytes comprises bakuchiol. According to the inducer or composition for the expression of maturation-promoting genes disclosed herein, the maturation of epidermal keratinocytes can be promoted, thereby achieving effects such as strengthening the skin barrier function and moisturizing effects. In addition, the inducer or composition for the expression of maturation-promoting genes disclosed herein, for example, can be expected to suppress the side effects of ATRA, and thus can be expected to suppress the side effects caused by retinol while obtaining the wrinkle improvement effect observed in retinol.

[0069] The maturation promoting gene of epidermal keratinocytes refers to a gene whose maturation of epidermal keratinocytes is promoted when the gene is expressed. The maturation promoting gene may include, for example, FLG gene, IVL gene, etc., preferably FLG gene, or a combination of FLG gene and IVL gene. The FLG gene is known to be a gene expressed during differentiation and maturation of epidermal keratinocytes, such as inducing keratinization of epidermal keratinocytes, contributing to the maturation of epidermal keratinocytes, etc. The IVL gene is known to be a gene expressed in the early stages of differentiation and maturation of epidermal keratinocytes, such as contributing to the differentiation of epidermal keratinocytes, etc.

[0070] As an example of the FLG gene, mRNA encoded by the human FLG gene may be, for example, a polynucleotide consisting of a base sequence registered with accession number NM_002016.2 in Genbank.

[0071] As an example of the IVL gene, mRNA encoded by the human IVL gene may be, for example, a polynucleotide consisting of a base sequence registered with accession number NM_005547.4 in Genbank.

[0072] The "induction of FLG gene expression" refers to an increase or enhancement in the expression level of the FLG gene, and may also refer to a change in the FLG gene from a non-expressed state to an expressed state. The expression of the FLG gene can be evaluated, for example, by measuring the expression level of the mRNA of the FLG gene according to Example 1 described below.

[0073] The "induction of IVL gene expression" refers to an increase or enhancement in the expression level of the IVL gene, and may also refer to a change in the IVL gene from a non-expressed state to an expressed state. The expression of the FLG gene can be evaluated, for example, by measuring the expression level of the IVL gene mRNA according to Example 1 described below.

[0074] The inducing agent for expression of a maturation-promoting gene disclosed herein can, for example, induce the expression of a maturation-promoting gene by administering it to a subject. Thus, the inducing agent for expression of a maturation-promoting gene disclosed herein can, for example, achieve effects such as anti-wrinkle effects and strengthening of skin barrier function. The conditions for use (administration conditions) of the inducing agent for expression of a maturation-promoting gene disclosed herein can refer to the description of the conditions for use of the inducing agent for retinol-like effects disclosed above.

[0075] <Agent or composition for inducing expression of CERS1 gene> In another embodiment, the present disclosure provides an agent or composition capable of inducing the CERS1 gene. The agent for inducing the expression of the CERS1 gene disclosed herein comprises bakuchiol. The composition for inducing the expression of the CERS1 gene disclosed herein comprises bakuchiol. According to the CERS1 gene expression inducer or composition disclosed herein, the differentiation of epidermal keratinocytes can be promoted, thereby achieving effects such as strengthening the skin barrier function and moisturizing. In addition, the CERS1 gene expression inducer or composition disclosed herein, for example, can be expected to suppress the side effects of ATRA, and therefore can be expected to suppress the side effects caused by retinol while obtaining the wrinkle improvement effect observed in retinol.

[0076] The CERS1 gene is known to be a gene expressed in the early stage of differentiation of epidermal keratinocytes and contributes to the differentiation of epidermal keratinocytes and the strengthening of barrier function by, for example, synthesizing ceramide.

[0077] As an example of the CERS1 gene, the mRNA encoded by the human CERS1 gene can be, for example, a polynucleotide consisting of a base sequence registered with the registration number NM_021267.5 in Genbank, etc. As the expression level of the CERS1 gene, the expression level of any one or more isoforms of the CERS1 gene can be measured, or the expression of all isoforms can be measured.

[0078] The "induction of CERS1 gene expression" refers to an increase or enhancement in the expression level of the CERS1 gene, and may also refer to a change in the CERS1 gene from a non-expressed state to an expressed state. The expression of the FLG gene can be evaluated, for example, by measuring the expression level of the CERS1 gene mRNA according to Example 1 described below.

[0079] The CERS1 gene expression inducer disclosed in the present invention can, for example, induce the expression of the CERS1 gene by administering it to a subject. Thus, the CERS1 gene expression inducer disclosed in the present invention can, for example, induce the differentiation of epidermal keratinocytes, and can obtain effects such as anti-wrinkle effects and strengthening of skin barrier function. The conditions for use (administration conditions) of the CERS1 gene expression inducer disclosed in the present invention can refer to the description of the conditions for use of the inducer of the retinol-like effect disclosed above.

[0080] <Agent or composition for promoting proliferation and / or maturation of epidermal keratinocytes> In another embodiment, the present disclosure provides an agent or composition capable of promoting the proliferation and / or maturation of epidermal keratinocytes, particularly human epidermal keratinocytes. The agent disclosed herein for promoting the proliferation and / or maturation of epidermal keratinocytes comprises bakuchiol. The composition disclosed herein for promoting the proliferation and / or maturation of epidermal keratinocytes comprises bakuchiol. According to the maturation promoter or composition disclosed herein, the proliferation and / or maturation of epidermal keratinocytes can be promoted, thereby achieving effects such as wrinkle improvement and strengthening of skin barrier function. In addition, the maturation promoter or composition disclosed herein, for example, can be expected to suppress the side effects of ATRA, and thus can be expected to suppress the side effects caused by retinol while obtaining the wrinkle improvement effect observed in retinol.

[0081] The maturation promoter of the present invention can promote the proliferation and / or maturation of epidermal keratinocytes, for example, by administering it to a subject. As a result, the maturation promoter of the present invention can achieve effects such as anti-wrinkle effects and strengthening of skin barrier function. The conditions for use (administration conditions) of the maturation promoter of the present invention can refer to the description of the conditions for use of the inducer of the retinol-like effect of the present invention.

[0082] <Agent or composition for inhibiting melanin production> In another embodiment, the present disclosure provides an agent or composition capable of inducing melanin production. The agent for inhibiting melanin production disclosed herein (hereinafter, also referred to as a "melanin inhibitor") comprises bakuchiol. The composition for inhibiting melanin production disclosed herein comprises bakuchiol. The melanin inhibitor or composition disclosed herein can inhibit melanin production. Therefore, the melanin inhibitor or composition disclosed herein can be used, for example, as a whitening agent, etc.

[0083] The melanin inhibitor of the present disclosure can inhibit melanin production, particularly melanin production in the skin, by, for example, administering the melanin inhibitor to a subject. The conditions for use (administration conditions) of the melanin inhibitor of the present disclosure can refer to the conditions for use of the inducer of the retinol-like effect of the present disclosure.

[0084] <Method of inducing retinol-like effects> In another embodiment, the present disclosure discloses a method capable of inducing a retinol-like effect. The method for inducing a retinol-like effect disclosed herein uses the inducer or composition of the retinol-like effect disclosed above. According to the method for inducing a retinol-like effect disclosed herein, it is expected that, for example, the occurrence of side effects such as erythema and scaling of the skin caused by retinol, which are caused by the inhibitory effect of retinol on the differentiation of epidermal keratinocytes, can be suppressed, and effects such as the wrinkle improvement effect observed in retinol can be obtained.

[0085] The method for inducing retinol-like effects disclosed herein includes a step of using the inducer or composition of the retinol-like effects disclosed herein in a subject. The use may be, for example, contact with the skin or administration.

[0086] In the method for inducing retinol-like effects disclosed herein, the use step may be performed, for example, in vitro ( in vitro ) or in vivo ( in vivo The subject (administration subject) and administration conditions of the method for inducing the retinol-like effect of the present disclosure can refer to the description of the administration subject and administration conditions in the inducer or composition of the retinol-like effect of the present disclosure, for example.

[0087] <Method for inducing expression of epidermal keratinocyte maturation-promoting gene> In another embodiment, the present disclosure discloses a method capable of inducing the expression of a maturation-promoting gene of epidermal keratinocytes. The method for inducing the expression of a maturation-promoting gene of epidermal keratinocytes disclosed herein uses the above-mentioned expression inducer or composition of the maturation-promoting gene of epidermal keratinocytes disclosed herein. According to the method for inducing the expression of a maturation-promoting gene of epidermal keratinocytes disclosed herein, for example, the maturation of epidermal keratinocytes can be promoted, thereby achieving effects such as a strengthening effect of the skin barrier function and a moisturizing effect. In addition, the method for inducing the expression of a maturation-promoting gene disclosed herein, for example, can be expected to suppress the side effects of ATRA, and thus can be expected to suppress the side effects caused by retinol while obtaining the wrinkle improvement effect observed in retinol.

[0088] The method for inducing expression of epidermal keratinocyte maturation-promoting gene disclosed herein comprises a step of using the epidermal keratinocyte maturation-promoting gene expression inducer or composition disclosed herein in a subject. The use may be, for example, contact with the skin or administration.

[0089] In the method for inducing expression of epidermal keratinocyte maturation-promoting genes disclosed herein, the use step may be performed, for example, in vitro ( in vitro ) or in vivo ( in vivoThe subject (administration subject) and administration conditions of the method for inducing the expression of epidermal keratinocyte maturation-promoting gene disclosed in the present invention can refer to the description of the administration subject and administration conditions in the inducer or composition of the retinol-like effect disclosed in the present invention.

[0090] <Method for inducing expression of CERS1 gene> In another embodiment, the present disclosure discloses a method capable of inducing the expression of the CERS1 gene. The method for inducing the expression of the CERS1 gene disclosed herein uses the above-mentioned CERS1 gene expression inducer or composition disclosed herein. According to the method for inducing the expression of the CERS1 gene disclosed herein, the differentiation of epidermal keratinocytes can be promoted, thereby achieving effects such as strengthening the skin barrier function and moisturizing. In addition, the method for inducing the expression of the CERS1 gene disclosed herein, for example, can be expected to suppress the side effects of ATRA, and thus can be expected to suppress the side effects caused by retinol while obtaining the wrinkle improvement effect observed in retinol.

[0091] The method for inducing CERS1 gene expression disclosed herein includes a step of using the CERS1 gene expression inducer or composition disclosed herein in a subject. The use may be, for example, contact with the skin or administration.

[0092] In the method for inducing expression of the CERS1 gene disclosed herein, the use step may be performed, for example, in vitro ( in vitro ) or in vivo ( in vivo The subject (administration subject) and administration conditions of the method for inducing expression of the CERS1 gene disclosed herein can refer to the description of the administration subject and administration conditions in the inducer or composition for retinol-like action disclosed herein, for example.

[0093] <Method for promoting proliferation and / or maturation of epidermal keratinocytes> In another embodiment, the present disclosure discloses a method capable of promoting the proliferation and / or maturation of epidermal keratinocytes, particularly human epidermal keratinocytes. The method for promoting the proliferation and / or maturation of epidermal keratinocytes disclosed herein uses the above-mentioned epidermal keratinocyte proliferation and / or maturation promoter or composition disclosed herein. According to the method for promoting the proliferation and / or maturation of epidermal keratinocytes disclosed herein, the proliferation and / or maturation of epidermal keratinocytes can be promoted, thereby achieving effects such as wrinkle improvement effects and strengthening effects of skin barrier function. In addition, the method for promoting the proliferation and / or maturation of epidermal keratinocytes disclosed herein, for example, can be expected to suppress the side effects of ATRA, and thus can be expected to suppress the side effects caused by retinol while obtaining the wrinkle improvement effects observed in retinol.

[0094] The method for promoting the proliferation and / or maturation of epidermal keratinocytes disclosed herein comprises a step of using the above-mentioned agent or composition for promoting the proliferation and / or maturation of epidermal keratinocytes disclosed herein in a subject. The use may be, for example, contact with the skin or administration.

[0095] In the method for promoting the proliferation and / or maturation of epidermal keratinocytes disclosed herein, the use step may be performed, for example, in vitro ( in vitro ) or in vivo ( in vivo The subject (administration subject) and administration conditions of the method for promoting proliferation and / or maturation of epidermal keratinocytes disclosed herein can refer to the description of the administration subject and administration conditions in the inducer or composition of the retinol-like effect disclosed herein.

[0096] <Methods to inhibit melanin production> In another embodiment, the present disclosure discloses a method capable of inhibiting melanin production. The method for inhibiting melanin production disclosed herein uses the inhibitor or composition of melanin production disclosed above. According to the method for inhibiting melanin production disclosed herein, melanin production can be inhibited. Therefore, according to the method for inhibiting melanin production disclosed herein, for example, it can be applied to the induction of whitening effects, etc.

[0097] The method for inhibiting melanin production disclosed herein includes a step of using the above-mentioned inhibitor or composition of melanin production disclosed herein on a subject. The use may be, for example, contact with the skin or the like, or administration.

[0098] In the method for inducing melanin production disclosed herein, the use step may be performed, for example, in vitro ( in vitro ) or in vivo ( in vivo The subject (administration subject) and administration conditions of the method for inducing melanin production disclosed herein can refer to the description of the administration subject and administration conditions in the inducer or composition of the retinol-like effect disclosed herein, for example.

[0099] <Uses of Bakuchiol> The present disclosure is the use of bakuchiol, the retinol-like effect inducer or the retinol-like effect inducing composition for inducing retinol-like effect. The present disclosure is the use of bakuchiol, the expression inducer of epidermal keratinocyte maturation promoting gene or the expression inducing composition of epidermal keratinocyte maturation promoting gene for inducing the expression of epidermal keratinocyte maturation promoting gene. The present disclosure is the use of bakuchiol, the expression inducer of CERS1 gene or the expression inducing composition of CERS1 gene for inducing the expression of CERS1 gene. The present disclosure is the use of bakuchiol, the proliferation and / or maturation promoter of epidermal keratinocytes or the proliferation and / or maturation promoting composition of epidermal keratinocytes for promoting the proliferation and / or maturation of epidermal keratinocytes. The present disclosure is the use of bakuchiol, the inhibitor of melanin production or the inhibitory composition of melanin production for inhibiting melanin production.

[0100] The present disclosure is the use of bakuchiol in the manufacture of an agent for inducing a retinol-like effect, or a composition for inducing a retinol-like effect. The present disclosure is the use of bakuchiol in the manufacture of an agent for inducing the expression of a maturation-promoting gene of epidermal keratinocytes, or a composition for inducing the expression of a maturation-promoting gene of epidermal keratinocytes. The present disclosure is the use of bakuchiol in the manufacture of an agent for inducing the expression of a CERS1 gene, or a composition for inducing the expression of a CERS1 gene. The present disclosure is the use of bakuchiol in the manufacture of an agent for promoting the proliferation and / or maturation of epidermal keratinocytes, or a composition for promoting the proliferation and / or maturation of epidermal keratinocytes. The present disclosure is the use of bakuchiol in the manufacture of an agent for inhibiting the production of melanin, or a composition for inhibiting the production of melanin.

[0101] Example Next, examples of the present invention will be described. However, the present invention is not limited to the following examples. Commercially available reagents were used based on their protocols unless otherwise specified. It should be noted that "mol / l" is sometimes also indicated as "M".

[0102] [Example 1] It was confirmed that bakuchiol exhibits a retinol-like effect in controlling the expression of RAR. In addition, it was confirmed that bakuchiol has a lower inhibitory effect on epidermal keratinocyte differentiation than retinol, and exhibits an effect of promoting the differentiation and maturation of epidermal keratinocytes.

[0103] (1) Sample preparation ATRA was prepared by dissolving it in DMSO to a concentration of 1 mmol / l, and bakuchiol (manufactured by BIB Corporation) was prepared by dissolving it in DMSO to a concentration of 20 mmol / l.

[0104] (2) Culture of epidermal keratinocytes In a 12-well plate, 2.1 × 10 4 Normal human epidermal keratinocytes derived from newborns (NBNHEK, purchased from Kurabo Co., Ltd.) were inoculated in a cells / well manner. The culture medium used was KBM (trademark) Gold Keratinocyte Growth Medium BulletKit (trademark) (KGM all+, manufactured by Lonza). After the above inoculation, the NBMNHEK were cultured until they were confluent. After the above culture, the culture medium of each well was replaced with a culture medium (KGM EGF+ / BPE+) in which only EGF (epidermal growth factor), BPE (bovine pituitary extract) and an additional antibiotic (GA-1000) were added to KBM (trademark) Gold Basal Medium. Subsequently, after culturing the NBMNHEK for 6 hours, the culture medium was replaced with a sample-added culture medium (ATRA: final concentration 1 μ mol / l, Bakuchiol: 5 or 10 μ The control group (nt) without sample addition was replaced with medium supplemented with DMSO so that the final concentration was equal to that of the sample addition group.

[0105] (3) Expression of RAR genes and differentiation marker genes After culturing for a predetermined time (48 or 72 hours) in the above medium, total RNA was extracted using QIAshredder (manufactured by QIAGEN) and RNeasy mini kit (manufactured by QIAGEN). Based on the value of the measured total RNA concentration, cDNA was synthesized using PrimeScript (manufactured by Takara). Furthermore, quantitative analysis of gene expression was performed by Realtime PCR using SYBR Premix Ex Taq (manufactured by Takara) from the obtained cDNA. The target gene was RAR α Gene, RAR β Genes and RAR γ Gene. In addition, the target genes of epidermal keratinocyte differentiation and maturation markers are FLG gene, CERS1 gene, and IVL gene. In addition, the housekeeping gene (internal standard gene) used is RPS18 gene. The expression level of each gene is set as a relative value relative to the gene expression level of RPS18 gene. Each group was implemented with 3 samples (n=3). It should be noted that statistical analysis was implemented by Dunnett's test. These results are shown in Figure 1 to Figure 6 .

[0106] Figure 1 Is for RARα Graph of gene expression. Figure 1 In the figure, (A) shows the results after 48 hours of culture, and (B) shows the results after 72 hours of culture. Figure 1 In (A) and (B), the horizontal axis represents the type of sample and the vertical axis represents RAR α The expression level of the gene.

[0107] Figure 1 The numerical values ​​of the ordinates in (A) and (B) represent the values ​​of each group when the value of the nt group is set to 1.0 (1.00).

[0108] Figure 1 The numerical values ​​of the ordinate of (A) are as follows.

[0109] ATRA-added group: 1.52, bakuchiol 5 μ M added group: 1.16, bakuchiol 10 μ M added group: 1.11 Figure 1 The numerical values ​​of the ordinate of (B) are as follows.

[0110] ATRA-added group: 1.61, bakuchiol 5 μ M added group: 1.03, bakuchiol 10 μ M added group: 1.06 like Figure 1 As shown in (A) and (B), in the ATRA-added group, RAR α On the other hand, if Figure 1 As shown in (A) and (B), in the group supplemented with bakuchiol, RAR α The expression of genes did not change significantly.

[0111] then, Figure 2 Is for RAR β Graph of gene expression. Figure 2 In the figure, (A) shows the results after 48 hours of culture, and (B) shows the results after 72 hours of culture. Figure 2 In (A) and (B), the horizontal axis represents the type of sample and the vertical axis represents RAR β The expression level of the gene.

[0112] Figure 2 The numerical values ​​of the ordinates in (A) and (B) represent the values ​​of each group when the value of the nt group is set to 1.0 (1.00).

[0113] Figure 2 The numerical values ​​of the ordinate of (A) are as follows.

[0114] ATRA-added group: 3.98, bakuchiol 5 μ M added group: 1.76, bakuchiol 10 μ M added group: 2.20 Figure 2 The numerical values ​​of the ordinate of (B) are as follows.

[0115] ATRA-added group: 3.48, bakuchiol 5 μ M added group: 1.31, bakuchiol 10 μ M added group: 1.69 like Figure 2 As shown in (A) and (B), in the ATRA-added group, RAR β Gene expression is induced. Figure 2 As shown in (A) and (B), in the group supplemented with bakuchiol, RAR β The expression of genes was also significantly induced.

[0116] then, Figure 3 Is for RAR γ Graph of gene expression. Figure 3 In the figure, (A) shows the results after 48 hours of culture, and (B) shows the results after 72 hours of culture. Figure 3 In (A) and (B), the horizontal axis represents the type of sample and the vertical axis represents RAR γ The expression level of the gene.

[0117] Figure 3 The numerical values ​​of the ordinates in (A) and (B) represent the values ​​of each group when the value of the nt group is set to 1.0 (1.00).

[0118] Figure 3 The numerical values ​​of the ordinate of (A) are as follows.

[0119] ATRA-added group: 0.89, bakuchiol 5 μ M added group: 0.83, bakuchiol 10 μ M added group: 0.54 Figure 3 The numerical values ​​of the ordinate of (B) are as follows.

[0120] ATRA-added group: 0.70, bakuchiol 5 μ M added group: 0.95, bakuchiol 10 μ M added group: 0.71 like Figure 3 As shown in (A) and (B), in the ATRA-added group, RAR γ Gene expression is inhibited. Figure 3 As shown in (A) and (B), in the group supplemented with bakuchiol, RAR γThe expression of genes was also significantly suppressed.

[0121] then, Figure 4 It is a graph showing the expression of FLG gene. Figure 4 In the figure, (A) shows the results after 48 hours of culture, and (B) shows the results after 72 hours of culture. Figure 4 In (A) and (B), the abscissa represents the type of sample, and the ordinate represents the expression level of the FLG gene.

[0122] Figure 4 The numerical values ​​of the ordinates in (A) and (B) represent the values ​​of each group when the value of the nt group is set to 1.0 (1.00).

[0123] Figure 4 The numerical values ​​of the ordinate of (A) are as follows.

[0124] ATRA-added group: 0.42, bakuchiol 5 μ M added group: 2.69, bakuchiol 10 μ M added group: 2.07 Figure 4 The numerical values ​​of the ordinate of (B) are as follows.

[0125] ATRA-added group: 0.03, bakuchiol 5 μ M added group: 1.59, bakuchiol 10 μ M added group: 1.19 like Figure 4 As shown in (A) and (B), in the ATRA-added group, the expression of FLG gene was significantly suppressed. Figure 4 As shown in (A) and (B), in the bakuchiol-supplemented group, the expression of FLG gene was significantly increased.

[0126] then, Figure 5 This is a graph showing the expression of IVL gene. Figure 5 In the figure, (A) shows the results after 48 hours of culture, and (B) shows the results after 72 hours of culture. Figure 5 In (A) and (B), the abscissa represents the type of sample, and the ordinate represents the expression level of the IVL gene.

[0127] Figure 5 The numerical values ​​of the ordinates in (A) and (B) represent the values ​​of each group when the value of the nt group is set to 1.0 (1.00).

[0128] Figure 5 The numerical values ​​of the ordinate of (A) are as follows.

[0129] ATRA-added group: 1.69, bakuchiol 5 μM added group: 2.72, bakuchiol 10 μ M added group: 3.22 Figure 5 The numerical values ​​of the ordinate of (B) are as follows.

[0130] ATRA-added group: 0.72, bakuchiol 5 μ M added group: 2.72, bakuchiol 10 μ M added group: 3.29 like Figure 5 As shown in (A) and (B), in the ATRA-added group, the expression of IVL genes increased (after 48 hours) or remained the same (after 72 hours). Figure 5 As shown in (A) and (B), in the bakuchiol-supplemented group, the expression of IVL gene was significantly increased.

[0131] then, Figure 6 This is a graph showing the expression of CERS1 gene. Figure 6 In the figure, (A) shows the results after 48 hours of culture, and (B) shows the results after 72 hours of culture. Figure 6 In (A) and (B), the abscissa represents the type of sample, and the ordinate represents the expression level of the CERS1 gene.

[0132] Figure 6 The numerical values ​​of the ordinates in (A) and (B) represent the values ​​of each group when the value of the nt group is set to 1.0 (1.00).

[0133] Figure 6 The numerical values ​​of the ordinate of (A) are as follows.

[0134] ATRA-added group: 4.79, bakuchiol 5 μ M-added group: 3.07, bakuchiol 10 μ M added group: 9.74 Figure 6 The numerical values ​​of the ordinate of (B) are as follows.

[0135] ATRA-added group: 2.36, bakuchiol 5 μ M added group: 1.71, bakuchiol 10 μ M added group: 3.21 like Figure 6 As shown in (A) and (B), the expression of CERS1 gene increased in the ATRA-added group. Figure 6 As shown in (A) and (B), in the bakuchiol-supplemented group, the expression of CERS1 gene was significantly increased.

[0136] (4) Cytotoxicity In a 96-well plate, 1.8 × 10 3 NBNHEK were inoculated in cells / well format and cultured in the same manner as in Example 1 (2) above. After replacing the culture medium with the sample addition medium, the culture was further cultured for 24 hours or 48 hours. After the above culture, cells were recovered from each well and the number of viable cells was evaluated using Cell Counting Kit-8 (DOJINDO). Each group was implemented with 6 samples (n=6). It should be noted that statistical analysis was performed using Dunnett's test. As a result, when any sample was used, there was no difference in the proportion of viable cells compared with the control. In other words, no cytotoxicity was confirmed by the addition of bakuchiol.

[0137] In addition, in the bakuchiol group, RAR α Gene, RAR β Genes and RAR γ In the gene, RAR β Genes and RAR γ The behavior of gene expression control was the same as that of the ATRA group, confirming that bakuchiol exerts a retinol-like effect. Tazarotene, a selective retinoid, acts on RAR β Genes and RAR γ Genes were expressed in retinoic acid, and the aforementioned side effects were suppressed compared with retinoic acid. Therefore, it is suggested that the side effects of retinoic acid are dependent on RAR. α Therefore, bakuchiol can induce the expression of RAR β Genes and RAR γ gene expression and showed retinol-like effects, but on the other hand, RAR α The expression of the gene is inhibited, so the side effects observed with retinoic acid can be expected to be suppressed.

[0138] In addition, in the ATRA group, the expression of the FLG gene as a maturation marker of epidermal keratinocytes was significantly suppressed, confirming the inhibition of differentiation of epidermal keratinocytes as the cause of the side effect. On the other hand, in the bakuchiol group, the expression of marker genes related to the differentiation and maturation of epidermal keratinocytes such as FLG gene, IVL gene and CERS1 gene was induced. It is thus believed that bakuchiol, by promoting the differentiation and maturation of epidermal keratinocytes, suppresses the side effects in retinoic acid and shows the wrinkle improvement effect and the strengthening effect of skin barrier function.

[0139] [Example 2] It was confirmed that bakuchiol exerts an inhibitory effect on melanin production.

[0140] (1) Sample preparation Bakuchiol (manufactured by BIB Corporation) was added to the culture medium at a predetermined final concentration (5 μ mol / l or 10 μ mol / l) was dissolved in 100% ethanol.

[0141] (2) Culture of melanoma cells In a 60 mm culture dish, 1.75 × 10 5 B16 cells (B16 mouse melanoma cells, distributed by RIKEN BRC, Lot. RCB1283, passage number 20) were inoculated in a cells / dish format and cultured overnight at 5% CO2 and 37°C. The culture medium used was E-MEM culture medium (5% FBS / E-MEM culture medium, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) containing 5% fetal bovine serum (FBS, manufactured by Sigma-Aldrich). After removing the culture medium in the culture dish by suction, the prepared bakuchiol was added in such a manner as to achieve the final concentration, and the B16 cells were cultured at 5% CO2 and 37°C for 72 hours. At this time, an untreated (NT) group cultured only with 5% FBS / E-MEM culture medium and a group with arbutin (manufactured by LKT Laboratories, Inc.) added (final concentration 200 μ g / ml) and a negative control (NC) group in which 100% ethanol was added for culture. In addition, considering the effect of 100% ethanol used in the dilution of the sample, the ethanol concentration was set to 0.05% in all treatment groups except the NT group. After the culture medium in the culture dish was removed by suction, the B16 cells were recovered by trypsin treatment and centrifuged to remove the supernatant.

[0142] To the obtained precipitate, add a mixture of ethanol and diethyl ether = 3:1 (volume ratio) and centrifuge to remove the supernatant to obtain a melanin precipitate. Dry it overnight and dissolve the obtained melanin in a 1N NaOH / 10% DMSO mixture at 400 °C. μ l. The absorbance at 420 nm was measured as the amount of melanin produced. Three samples were used for each group (n=3). It should be noted that statistical analysis was performed using Dunnett's test ( :p<0.05, : p < 0.001 vs NC). These results are shown in Figure 7 .

[0143] Figure 7 This is a graph showing the amount of melanin produced. Figure 7 In the graph, the horizontal axis represents the type of sample, and the vertical axis represents the relative value of the amount of melanin produced.

[0144] Figure 7 The numerical values ​​of the ordinate in represent the values ​​of each group with the value of the NC group being 100 (%).

[0145] Figure 7 The values ​​of the ordinate are as follows.

[0146] NT group: 32.63, PC group: 64.27, bakuchiol 5 μ M-added group: 75.90, bakuchiol 10 μ M added group: 17.78 like Figure 7 As shown, the amount of melanin production decreased depending on the concentration of bakuchiol.

[0147] (3) Cytotoxicity In a 96-well plate, 7 × 10 3 B16 cells were inoculated in cells / well format and cultured overnight at 5% CO2 and 37°C. The culture medium was the same as that in Example 2 (2). After removing the culture medium from each well, the sample was added in the same manner as in the melanin production inhibition test, and cultured for 72 hours at 5% CO2 and 37°C. After the culture, an MTT assay was performed for each well using Thiazolyl Blue Tetrazolium Bromide (Sigma-Aldrich). The sample was measured by measuring the absorbance at a target absorbance of 570nm and a reference at 620nm to evaluate cell survival rate. The amount of melanin produced in each group is a relative value with NC as 100. Six samples were used for each group (n=6). It should be noted that statistical analysis was performed using Dunnett's test ( : p<0.001 vs NC). As a result, when any sample was used, there was no significant difference in the proportion of live cells from the control. In other words, no cytotoxicity was observed by adding bakuchiol.

[0148] The above results suggest that bakuchiol can inhibit the production of melanin in melanin-producing cells and can inhibit the production of melanin in the skin.

[0149] In addition, information such as the sequences of the primers used in the above-mentioned Examples 1 and 2 is shown in Table 1 below.

[0150] [Table 1]

[0151] [Example 3] Through a cell test (a test using epidermal keratinocytes), it was confirmed whether bakuchiol has the effect of promoting hyaluronic acid synthesis in the epidermis and strengthening the basement membrane.

[0152] (1) Sample preparation ATRA was prepared by dissolving it in DMSO to a concentration of 1 mmol / l, and bakuchiol (manufactured by BIB Corporation) was prepared by dissolving it in DMSO to a concentration of 20 mmol / l.

[0153] (2) Culture of epidermal keratinocytes In a 12-well plate, 2.1 × 10 4 Normal human epidermal keratinocytes derived from newborns (NBNHEK, purchased from Kurabo Co., Ltd.) were inoculated in a cells / well manner. The culture medium used was KBM (trademark) Gold Keratinocyte Growth Medium BulletKit (trademark) (KGM all+, manufactured by Lonza). After the above inoculation, the NBMNHEK were cultured until they were confluent. After the above culture, the culture medium of each well was replaced with a culture medium (KGM EGF+ / BPE+) in which only EGF (epidermal growth factor), BPE (bovine pituitary extract) and an additional antibiotic (GA-1000) were added to KBM (trademark) Gold Basal Medium. Subsequently, after culturing the NBMNHEK for 6 hours, the culture medium was replaced with a sample-added culture medium (ATRA: final concentration 1 μ mol / l, bakuchiol: final concentration 2.5, 5 or 10 μ The control group (nt) without sample addition was replaced with medium supplemented with DMSO so that the final concentration was equal to that of the sample addition group.

[0154] (3) Expression of marker genes The culture medium was used for a predetermined time (HAS3 gene expression level measurement sample and ITG β The gene expression level was measured in samples for 48 hours and ITG α6 After culturing the samples for gene expression measurement for 72 hours), total RNA was extracted using QIAshredder (manufactured by QIAGEN) and RNeasy mini kit (manufactured by QIAGEN). Based on the value of the measured total RNA concentration, cDNA was synthesized by PrimeScript (manufactured by Takara). Furthermore, quantitative analysis of gene expression levels was performed by Realtime PCR using SYBR Premix Ex Taq (manufactured by Takara) from the obtained cDNA. The target gene for epidermal hyaluronic acid synthesis is the HAS3 gene. The target gene for epidermal basement membrane reinforcement is the ITG α 6 genes, ITG β 1 gene. In addition, the RPS18 gene was used as the housekeeping gene (internal standard gene). The expression level of each gene was set as a relative value relative to the gene expression level of the RPS18 gene. Each group was implemented with 3 samples (n=3). It should be noted that statistical analysis was performed using Dunnett's test. The results of the measurement of the expression level of the gene are shown in the following Tables 2 to 4. It should be noted that the results shown in the following Tables 2 to 4 were calculated by calculating the average value of the 3 samples in each group, and the value (average value) of the control group (nt) was set to 1.00. The results shown in the following Tables 2 to 4 show that compared with the values ​​of the control group :p<0.001、 :p<0.01、 :p<0.05.

[0155] [Table 2]

[0156] [Table 3]

[0157] [Table 4]

[0158] As shown in Tables 2 to 4, it can be seen that in the group supplemented with a predetermined amount of ATRA and the group supplemented with a predetermined amount of bakuchiol, the expression of epidermal hyaluronic acid synthesis genes and epidermal basement membrane strengthening genes increased compared to the control group. It is therefore believed that the addition of bakuchiol can exert an effect similar to that of retinol ATRA, namely, an effect of promoting hyaluronic acid synthesis in the epidermis and an effect of strengthening the basement membrane.

[0159] In addition, information such as the sequences of the primers used in the above-mentioned Example 3 is shown in the following Table 5.

[0160] [Table 5]

[0161] The present disclosure has been described above with reference to the embodiments and examples, but the present disclosure is not limited to the above-described embodiments and examples. The structure and details of the present disclosure can be variously modified within the scope of the present disclosure that can be understood by those skilled in the art.

[0162] This application claims the benefit of priority based on Japanese patent application No. 2022-136384 filed on August 29, 2022 and Japanese patent application No. 2023-049423 filed on March 27, 2023, the disclosures of which are incorporated herein in their entirety.

[0163] <Note> A part or all of the above-mentioned embodiments and examples can be described as the following supplementary notes, but are not limited to the following.

[0164] <Agents for inducing retinol-like effects> (Note 1) An agent for inducing a retinol-like effect, comprising bakuchiol (4-[(1E,3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol).

[0165] (Note 2) The agent according to Supplementary Note 1, wherein the induction of the retinol-like action is strengthening of the skin basal layer, stabilization of the skin basal layer and / or promotion of proliferation of epidermal keratinocytes.

[0166] (Note 3) The reagent according to Appendix 1 or 2, wherein the retinol-like effect is retinoic acid receptor β (RAR β ) gene expression enhancement, and / or retinoic acid receptor γ (RAR γ ) inhibition of gene expression.

[0167] (Note 4) The reagent according to any one of Appendixes 1 to 3, wherein the bakuchiol is an extract containing bakuchiol.

[0168] (Note 5) An agent for application to the skin, comprising the agent according to any one of Supplementary Notes 1 to 4.

[0169] (Note 6) A reagent for oral administration, comprising the reagent according to any one of Appendix 1 to 4.

[0170] <Composition for inducing retinol-like effect> (Note 7) A composition for inducing a retinol-like effect, comprising bakuchiol (4-[(1E,3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol).

[0171] (Note 8) The composition according to Supplementary Note 7, wherein the induction of the retinol-like action is strengthening of the skin basal layer, stabilization of the skin basal layer and / or promotion of proliferation of epidermal keratinocytes.

[0172] (Note 9) The composition according to Appendix 7 or 8, wherein the retinol-like effect is retinoic acid receptor β (RAR β ) gene expression enhancement, and / or retinoic acid receptor γ (RAR γ ) inhibition of gene expression.

[0173] (Note 10) The composition according to any one of Appendix 7 to 9, wherein the bakuchiol is an extract containing bakuchiol.

[0174] (Note 11) A composition for application to the skin, comprising the composition according to any one of Appendix 7 to 10.

[0175] (Note 12) A composition for oral administration, comprising the composition according to any one of Appendix 7 to 10.

[0176] (Note 13) The composition according to any one of Supplements 7 to 12, comprising the agent for inducing a retinol-like effect according to any one of Supplements 1 to 6.

[0177] <Agent for inducing expression of epidermal keratinocyte maturation-promoting gene> (Note 14) An agent for inducing the expression of a maturation-promoting gene in epidermal keratinocytes, comprising bakuchiol (4-[(1E,3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol).

[0178] (Note 15) The reagent according to Supplementary Note 14, wherein the maturation-promoting gene includes a filaggrin gene.

[0179] (Note 16) The reagent according to Appendix 15, wherein the maturation-promoting gene further comprises an involucrin gene.

[0180] (Note 17) The reagent according to any one of Appendix 14 to 16, wherein the bakuchiol is an extract containing bakuchiol.

[0181] (Note 18) An agent for application to the skin, comprising the agent according to any one of Supplementary Notes 14 to 17.

[0182] (Note 19) An agent for oral administration, comprising the agent according to any one of Supplementary Notes 14 to 17.

[0183] <Composition for inducing expression of epidermal keratinocyte maturation-promoting gene> (Note 20) A composition for inducing the expression of a maturation-promoting gene in epidermal keratinocytes, comprising bakuchiol (4-[(1E, 3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol).

[0184] (Note 21) The composition according to Appendix 20, wherein the maturation-promoting gene comprises a filaggrin gene.

[0185] (Note 22) The composition according to Appendix 21, wherein the maturation-promoting gene further comprises an involucrin gene.

[0186] (Note 23) The composition according to any one of Appendix 20 to 22, wherein the bakuchiol is an extract containing bakuchiol.

[0187] (Note 24) A composition for application to the skin, comprising the composition according to any one of Appendix 20 to 23.

[0188] (Note 25) A composition for oral administration, comprising the composition according to any one of Appendix 20 to 23.

[0189] (Note 26) The composition according to any one of Supplements 20 to 25, comprising the agent according to any one of Supplements 14 to 19.

[0190] <Agents for inducing expression of CERS1 gene> (Note 27) An agent for inducing expression of a ceramide synthase 1 (CERS1) gene, comprising bakuchiol (4-[(1E,3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol).

[0191] (Note 28) The reagent according to Appendix 27, wherein the bakuchiol is an extract containing bakuchiol.

[0192] (Note 29) An agent for application to the skin, comprising the agent according to Appendix 27 or 28.

[0193] (Note 30) A reagent for oral administration, comprising the reagent according to Appendix 27 or 28.

[0194] <Composition for inducing expression of CERS1 gene> (Note 31) A composition for inducing the expression of a ceramide synthase 1 (CERS1) gene, comprising bakuchiol (4-[(1E,3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol).

[0195] (Note 32) The composition according to Appendix 31, wherein the bakuchiol is an extract containing bakuchiol.

[0196] (Note 33) A composition for application to the skin, comprising the composition according to Appendix 31 or 32.

[0197] (Note 34) A composition for oral administration, comprising the composition according to Appendix 31 or 32.

[0198] (Note 35) The composition according to any one of Supplements 31 to 34, comprising the agent according to any one of Supplements 27 to 30.

[0199] <Agents for promoting the proliferation and maturation of epidermal keratinocytes> (Note 36) An agent for promoting the proliferation and / or maturation of epidermal keratinocytes, comprising bakuchiol (4-[(1E, 3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol).

[0200] (Note 37) The reagent according to Supplementary Note 36, wherein the bakuchiol is an extract containing bakuchiol.

[0201] (Note 38) An agent for application to the skin, comprising the agent according to Appendix 36 or 37.

[0202] (Note 39) A reagent for oral administration, comprising the reagent according to Appendix 36 or 37.

[0203] <Composition for promoting proliferation and maturation of epidermal keratinocytes> (Note 40) A composition for promoting the proliferation and / or maturation of epidermal keratinocytes, comprising bakuchiol.

[0204] (Note 41) The composition according to Appendix 40, wherein the bakuchiol is an extract containing bakuchiol.

[0205] (Note 42) A composition for application to the skin, comprising the composition according to Appendix 40 or 41.

[0206] (Note 43) A composition for oral administration, comprising the composition of Appendix 40 or 41.

[0207] (Note 44) The composition according to any one of Supplements 40 to 43, comprising the agent according to any one of Supplements 36 to 39.

[0208] <Agents for inhibiting melanin production> (Note 45) An agent for inhibiting melanin production, comprising bakuchiol (4-[(1E,3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol).

[0209] (Note 46) The reagent according to Supplementary Note 45, wherein the bakuchiol is an extract containing bakuchiol.

[0210] (Note 47) An agent for application to the skin, comprising the agent according to Appendix 45 or 46.

[0211] (Note 48) A reagent for oral administration, comprising the reagent according to Appendix 45 or 46.

[0212] <Composition for inhibiting melanin production> (Note 49) A composition for inhibiting melanin production, comprising bakuchiol (4-[(1E, 3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol).

[0213] (Note 50) The composition according to Appendix 49, wherein the bakuchiol is an extract containing bakuchiol.

[0214] (Note 51) A composition for application to the skin, comprising the composition according to Appendix 49 or 50.

[0215] (Note 52) A composition for oral administration, comprising the composition according to Appendix 49 or 50.

[0216] (Note 53) The composition according to any one of Supplements 49 to 52, comprising the agent for inhibiting melanin production according to any one of Supplements 45 to 48.

[0217] <Method of inducing retinol-like effects> (Note 54) A method for inducing a retinol-like effect, comprising using the agent for inducing a retinol-like effect described in any one of Appendixes 1 to 6 and / or the composition for inducing a retinol-like effect described in any one of Appendixes 7 to 13.

[0218] (Note 55) The induction method according to Supplementary Note 54, comprising the following use step: using the agent for inducing a retinol-like effect and / or the composition for inducing a retinol-like effect in a subject.

[0219] (Note 56) The induction method according to Appendix 54 or 55, which is used in vitro or in vivo.

[0220] <Method for inducing expression of epidermal keratinocyte maturation-promoting gene> (Note 57) A method for inducing the expression of a maturation-promoting gene for epidermal keratinocytes, which uses the reagent for inducing the expression of a maturation-promoting gene for epidermal keratinocytes described in any one of Appendixes 14 to 19 and / or the composition for inducing the expression of a maturation-promoting gene for epidermal keratinocytes described in any one of Appendixes 20 to 26.

[0221] (Note 58) The induction method according to Supplementary Note 57, comprising the following use step: using the reagent for inducing the expression of the maturation-promoting gene of epidermal keratinocytes and / or the composition for inducing the expression of the maturation-promoting gene of epidermal keratinocytes in a subject.

[0222] (Note 59) The induction method according to Appendix 57 or 58, which is used in vitro or in vivo.

[0223] <Method for inducing expression of CERS1 gene> (Note 60) A method for inducing expression of a CERS1 gene, comprising using the reagent for inducing expression of a CERS1 gene described in any one of Supplements 27 to 30 and / or the composition for inducing expression of a CERS1 gene described in any one of Supplements 31 to 35.

[0224] (Note 61) The induction method according to Supplementary Note 60, comprising the following use step: using the reagent for inducing the expression of the CERS1 gene and / or the composition for inducing the expression of the CERS1 gene in a subject.

[0225] (Note 62) The induction method according to Supplementary Note 60 or 61, which is used in vitro or in vivo.

[0226] <Method for promoting proliferation and / or maturation of epidermal keratinocytes> (Note 63) A method for promoting the proliferation and / or maturation of epidermal keratinocytes, which uses the agent for promoting the proliferation and / or maturation of epidermal keratinocytes described in any one of Appendixes 36 to 39 and / or the composition for promoting the proliferation and / or maturation of epidermal keratinocytes described in any one of Appendixes 40 to 44.

[0227] (Note 64) The induction method according to Supplementary Note 63 comprises the following use step: using the agent for promoting the proliferation and / or maturation of epidermal keratinocytes and / or the composition for promoting the proliferation and / or maturation of epidermal keratinocytes in a subject.

[0228] (Note 65) The induction method according to Supplementary Note 63 or 64, which is used in vitro or in vivo.

[0229] <Methods to inhibit melanin production> (Note 66) A method for inhibiting melanin production, comprising using the agent for inhibiting melanin production described in any one of Supplements 45 to 48 and / or the composition for inhibiting melanin production described in any one of Supplements 49 to 53.

[0230] (Note 67) The induction method according to Supplementary Note 66, comprising the following use step: using the agent for inhibiting melanin production and / or the composition for inhibiting melanin production in a subject.

[0231] (Note 68) The induction method according to Supplement 66 or 67, which is used in vitro or in vivo.

[0232] <Application> (Note 69) Use of the agent for inducing a retinol-like effect according to any one of Supplements 1 to 6 or the composition for inducing a retinol-like effect according to any one of Supplements 7 to 13 for inducing a retinol-like effect.

[0233] (Note 70) Use of the reagent for inducing the expression of epidermal keratinocyte maturation-promoting gene described in any one of Supplements 14 to 19 or the composition for inducing the expression of epidermal keratinocyte maturation-promoting gene described in any one of Supplements 20 to 26 for inducing the expression of epidermal keratinocyte maturation-promoting gene.

[0234] (Supplementary Note 71) Use of the agent for inducing the expression of the CERS1 gene according to any one of Supplements 27 to 30 or the composition for inducing the expression of the CERS1 gene according to any one of Supplements 31 to 35 for inducing the expression of the ceramide synthase 1 (CERS1) gene.

[0235] (Note 72) Use of the agent for promoting the proliferation and / or maturation of epidermal keratinocytes as described in any one of Notes 36 to 39 or the composition for promoting the proliferation and / or maturation of epidermal keratinocytes as described in any one of Notes 40 to 44 for promoting the proliferation and / or maturation of epidermal keratinocytes.

[0236] (Note 73) Use of the agent for suppressing melanin production according to any one of Supplementary Notes 45 to 48 or the composition for suppressing melanin production according to any one of Supplementary Notes 53 for suppressing melanin production.

[0237] Industrial Applicability As described above, according to the present invention, it is possible to provide an agent that reduces inhibition of epidermal keratinocyte differentiation and can induce a retinol-like effect, and is mainly applicable to human skin, etc. Therefore, it can be said that the present invention is extremely useful in the fields of pharmaceuticals, quasi-drugs, and external skin preparations, for example.

Claims

1. An agent for inducing a retinol-like effect, characterized in that Contains bakuchiol, i.e. 4-[(1E,3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol.

2. The reagent according to claim 1, wherein The induction of the retinol-like effect is strengthening of the skin basal layer, stabilization of the skin basal layer, and / or promotion of proliferation of epidermal keratinocytes.

3. The reagent according to claim 1 or 2, wherein The retinol-like effect is retinoic acid receptor β (RAR β ) gene expression enhancement, and / or, retinoic acid receptor γ (RAR γ ) inhibition of gene expression.

4. A reagent for application to the skin, characterized in that The method comprises the reagent according to any one of claims 1 to 3.

5. A composition for inducing a retinol-like effect, characterized in that: An agent for inducing a retinol-like effect according to any one of claims 1 to 4.

6. A reagent for inducing the expression of a maturation-promoting gene in epidermal keratinocytes, characterized in that: Contains bakuchiol, i.e. 4-[(1E,3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol.

7. The reagent according to claim 6, wherein The maturation-promoting gene comprises a filaggrin gene.

8. The reagent according to claim 6 or 7, wherein The maturation-promoting gene further comprises an involucrin gene.

9. A composition for inducing the expression of a maturation-promoting gene in epidermal keratinocytes, characterized in that: An agent for inducing the expression of a maturation-promoting gene in epidermal keratinocytes according to any one of claims 6 to 8.

10. A reagent for inducing the expression of ceramide synthase 1 (CERS1) gene, characterized in that Contains bakuchiol, i.e. 4-[(1E,3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol.

11. A reagent for inducing the expression of ceramide synthase 1 (CERS1) gene, characterized in that Contains the reagent according to claim 10.

12. An agent for promoting the proliferation and / or maturation of epidermal keratinocytes, characterized in that: Contains bakuchiol, i.e. 4-[(1E,3S)-3-vinyl-3,7-dimethylocta-1,6-dienyl]phenol.

13. A composition for promoting the proliferation and / or maturation of epidermal keratinocytes, characterized in that: The invention comprises the agent for promoting the proliferation and / or maturation of epidermal keratinocytes according to claim 12.

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