Peptides having hair growth promoting and hair loss suppressing activity and their uses

Abstract

The present invention relates to a peptide having the activity of promoting hair growth or preventing or suppressing alopecia. The peptide of the present invention has the activity of promoting the proliferation of hair follicle dermal papilla cells (HFDPCs), activating cell proliferation-related signaling proteins and β-catenin in human dermal papilla cells, increasing the expression levels of β-catenin subordinate genes, down-regulating the expression level of the hair loss protein DKK-1, increasing the expression of keratin proteins in outer root sheath cells (HORSCs), and increasing the expression of transcription factors involved in cell activation in hair matrix cells (HHGMCs).

Description

Technical Field

[0001] The present invention relates to a peptide having hair growth promoting and hair loss suppressing activities and uses thereof.

Background Art

[0002] Alopecia is a phenomenon in which the telogen phase becomes longer than normal in the hair growth cycle, or the number of hair follicles in the telogen phase increases and excessive hair loss occurs, and refers to the fact that hair is excessively lost due to stress, nutritional deficiency, local blood flow disorder, hormones, genetic factors, etc. and does not recover.

[0003] As hair loss treatment agents, 5α-reductase inhibitors that act to convert testosterone, a male hormone, into dihydrotestosterone (DHT), an androgenic hormone, such as finasteride or dutasteride, have been developed and commercially available, and minoxidil, a drug that has the effect of stimulating hair follicles and increasing blood flow to promote hair growth, has also been approved and used.

[0004] However, in the case of 5α-reductase inhibitors, it has been reported that side effects such as sexual dysfunction, depression, anxiety, and breast hypertrophy occur relatively frequently, and in the case of minoxidil, it has also been reported that cardiovascular side effects such as electrocardiogram abnormalities, tachycardia, and endocarditis occur. In addition, minoxidil is known to cause hair loss again when drug administration is interrupted.

[0005] Peptides have high biocompatibility, and when used as a single active ingredient in drugs or cosmetics, they have fewer side effects compared to extracts containing various components. After locally suppressing hair loss, they can be easily decomposed and removed by proteases in the body. Therefore, unlike existing therapeutic agents, there is less fear of side effects.

[0006] PCT International Patent WO2005-082395 discloses a peptide that promotes hair growth by accelerating the progression from the resting stage to the growth stage in the hair growth cycle, and Korean Registered Patent No. 10-2387764 discloses a dimeric peptide derivative that promotes the proliferation of hair follicle cells. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] WO2005-082395 [Patent Document 1] Korean Registered Patent Publication No. 10-2387764 [Overview of the project] [Problems that the invention aims to solve]

[0008] The inventors have made research efforts to develop a peptide with improved activity that is effective in promoting hair growth and inhibiting hair loss with fewer side effects. As a result, the inventors have experimentally demonstrated that the novel peptide they developed promotes the proliferation of human dermal papilla cells (HHFDPCs), activates cell proliferation-related signaling proteins in human dermal papilla cells, activates β-catenin, increases the expression levels of β-catenin subfactors LEF-1, c-Myc, and Cyclin D1, lowers the expression level of the hair loss protein DKK-1, increases the expression of keratin protein in outer root sheath cells (HORSCs), and increases the expression of cell activity-involved transcription factors MSX2, HOXC13, and FOXN1 in hair matrix cells (HHGMCs), thereby completing the present invention.

[0009] Therefore, the object of the present invention is to provide a novel peptide having hair growth promoting and hair loss suppressing activity.

[0010] Another object of the present invention is to provide a composition for promoting hair growth or suppressing, preventing, or improving alopecia, which contains the aforementioned active peptide as an active ingredient.

[0011] Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of alopecia.

[0012] Another object of the present invention is to provide a cosmetic composition for promoting hair growth or preventing or improving alopecia. [Means for solving the problem]

[0013] In order to achieve the aforementioned objective, One aspect of the present invention is to provide a peptide containing the amino acid sequence of SEQ ID NO: 1.

[0014] Another aspect of the present invention is to provide a composition for promoting hair growth or suppressing, preventing, or improving alopecia, which contains the peptide as an active ingredient.

[0015] Another aspect of the present invention is to provide a pharmaceutical composition for the prevention or treatment of alopecia, comprising the peptide as an active ingredient.

[0016] Another aspect of the present invention is to provide a cosmetic composition for promoting hair growth or preventing or improving alopecia, comprising the peptide as an active ingredient.

[0017] The present invention will be described in detail below.

[0018] 1. Peptides and their activity According to one aspect of the present invention, a peptide comprising the amino acid sequence disclosed in Sequence ID No. 1 is provided.

[0019] In this specification, the term "peptide" means a linear molecule formed by the bonding of amino acid residues to each other via peptide bonds.

[0020] The peptide containing the amino acid sequence of SEQ ID NO: 1 of the present invention may be used without modification, but within the range that does not affect the original activity of the peptide, such as hair growth promotion or alopecia suppression activity, variants or fragments of amino acids having different sequences due to deletion, insertion, substitution, or combinations thereof of amino acid residues may be used.

[0021] The peptide of the present invention can be modified by phosphorylation, sulfation, acrylation, glycosylation, methylation, farnesylation, etc. within the range that does not change its activity.

[0022] The peptide of the present invention includes peptides containing an amino acid sequence substantially identical to the peptide containing the amino acid sequence of SEQ ID NO: 1, variants thereof, or active fragments thereof. The substantially identical amino acid sequence means an amino acid sequence having a sequence identity of 75% or more, for example, 80% or more, 85% or more, 90% or more, 95% or more, 97% or more with the amino acid sequence of SEQ ID NO: 1. Further, the peptide may additionally contain a targeting sequence, a tag, a labeled residue, a half-life, or an amino acid sequence produced for a specific purpose to increase peptide stability.

[0023] The peptide of the present invention may be one in which a partial site of the amino acid sequence is selected and N-terminal and / or C-terminal modifications are induced to increase its activity. Such N-terminal and / or C-terminal modifications can significantly improve the stability of the peptide of the present invention, for example, increase the half-life during in vivo administration of the peptide. The term "stability" includes not only in vivo stability that protects the peptide of the present invention from the attack of proteolytic enzymes in the body, but also storage stability (for example, room temperature storage stability).

[0024] The N-terminal modification may involve attaching a protecting group selected from the group consisting of an acetyl group, a fluoreonylmethoxycarbonyl group, a formyl group, a palmitoyl group, a myristyl group, a stearyl group, and polyethylene glycol (PEG) to the N-terminus of the peptide. The C-terminal modification may involve attaching a hydroxyl group (-OH), an amino group (-NH2), to the C-terminus of the peptide. hydrazino group ( Hydazino Group It may be a combination of , -NHNH2, etc., but is not limited to this.

[0025] The peptides of the present invention can be produced by a variety of widely known methods in the art to which the present invention pertains. For example, the peptides of the present invention can be produced by chemical synthesis methods known in the art, particularly solid-phase synthesis techniques (Merrifield, J. Amer. Chem. Soc. 85:2149-54 (1963); Stewart, et al., Solid Phase Peptide Synthesis, 2nd ed., Pierce Chem. Co.: Rockford, 111 (1984)) or liquid-phase synthesis techniques (US Patent No. 5,516,891).

[0026] The peptide of the present invention has hair growth promoting activity or activity to prevent or suppress alopecia.

[0027] In one embodiment, the peptide of the present invention promotes the proliferation of hair follicle dermal papilla cells (HFDPCs).

[0028] In one embodiment, the peptide of the present invention activates the protein Akt or ERK, which is involved in signal transduction in hair follicle dermal papilla cells (HFDPCs).

[0029] In one embodiment, the peptide of the present invention activates β-catenin in hair follicle dermal papilla cells (HFDPCs) and promotes its translocation to the nucleus.

[0030] In one embodiment, the peptide of the present invention upregulates the gene expression of one or more factors selected from the group consisting of LEF-1, c-Myc, and Cyclin D1, which are subfactors of β-catenin in hair follicle dermal papilla cells (HFDPC).

[0031] In one embodiment, the peptide of the present invention lowers the expression level of DKK-1 (Dickkopf-1), a hair loss protein, in hair follicle dermal papilla cells (HFDPCs). Dihydrotestosterone (DHT) in hair follicles promotes the expression of DKK-1 (Dickkopf-1), and DKK-1 induced and produced by DHT is known to suppress the proliferation of keratinocytes in hair follicles, induce cell death (apoptosis), and promote hair loss (J of Invest Dermatolo. 2008, Feb., 128(2), pp.262-269). The expression level of the aforementioned hair loss protein, DKK-1, is increased by dihydrotestosterone (DHT), and the peptide of the present invention lowers the expression level of DKK-1, which is increased by DHT.

[0032] In one embodiment, the peptide of the present invention increases the gene expression of one or more proteins selected from the group consisting of Ha3-II, Keratin 5, Keratin 14, and Keratin 19 in human hair outer root sheath cells (HHORSCs).

[0033] In one embodiment, the peptide of the present invention increases the expression of one or more transcription factors selected from the group consisting of MSX2, HOXC13, and FOXN1 in human hair germinal matrix cells (HHGMCs).

[0034] The peptide of the present invention, as described above, has the activity described above and can therefore exert the efficacy of promoting hair growth or suppressing, preventing, or improving alopecia.

[0035] 2. Composition for promoting hair growth or preventing, treating, or improving alopecia In another aspect of the present invention, a composition for promoting hair growth or preventing, treating, or improving alopecia is provided, comprising a peptide containing the amino acid sequence of SEQ ID NO: 1 as an active ingredient.

[0036] The peptide containing the amino acid sequence of Sequence ID No. 1 of the present invention has hair growth promoting activity or activity to suppress or prevent alopecia, as described above.

[0037] In another aspect of the present invention, the present invention provides a pharmaceutical composition for the prevention or treatment of alopecia, comprising a peptide containing the amino acid sequence of SEQ ID NO: 1 as an active ingredient.

[0038] In this specification, the terms "hair loss" or "alopecia" mean a condition in which hair is absent in areas where hair should normally be present due to the loss of abnormal hair, or in which the number of hairs is reduced compared to a normal state. In one embodiment, hair loss or symptoms of hair loss in the present invention include hair loss on the scalp.

[0039] In the present invention, hair loss includes, but is not limited to, hereditary androgenic hair loss (male pattern hair loss), female pattern hair loss, telogen effluvium, anagen effluvium, alopecia areata, tinea capitis due to fungal infection, hair loss due to hypothyroidism or hyperthyroidism, hair loss due to inflammation (seborrheic scalp), hair loss due to malnutrition, hair loss due to diabetes, hair loss due to lupus, hair loss due to hair growth disorders, hair loss due to drugs (anticoagulants, antidepressants, discontinuation of oral contraceptives, chemotherapy), toxic folliculitis, lichen planus pilaris, hair loss due to burns or trauma, hair loss due to ultraviolet light, or hair loss due to contact with fine particulate matter in the air.

[0040] In one embodiment, a pharmaceutical composition containing the peptide of the present invention as an active ingredient promotes the proliferation of hair follicle dermal papilla cells (HFDPCs).

[0041] In one embodiment, a pharmaceutical composition containing the peptide of the present invention as an active ingredient activates the proteins Akt or ERK, which are involved in signal transduction in hair follicle dermal papilla cells (HFDPCs).

[0042] In one embodiment, a pharmaceutical composition containing the peptide of the present invention as an active ingredient activates β-catenin in hair follicle dermal papilla cells (HFDPCs) and promotes its translocation to the nucleus.

[0043] In one embodiment, a pharmaceutical composition containing the peptide of the present invention as an active ingredient upwardly regulates the gene expression of one or more factors selected from the group consisting of LEF-1, c-Myc, and Cyclin D1, which are subfactors of β-catenin in hair follicle dermal papilla cells (HFDPC).

[0044] In one embodiment, a pharmaceutical composition containing the peptide of the present invention as an active ingredient lowers the expression level of DKK-1 (Dickkopf-1), a hair loss protein, in hair follicle dermal papilla cells (HFDPC). The expression level of DKK-1, the hair loss protein, is increased by dihydrotestosterone (DHT), and the peptide of the present invention lowers the expression level of DKK-1, which is increased by DHT.

[0045] In one embodiment, a pharmaceutical composition containing the peptide of the present invention as an active ingredient increases the gene expression of one or more proteins selected from the group consisting of Ha3-II, Keratin 5, Keratin 14, and Keratin 19 in human hair outer root sheath cells (HHORSCs).

[0046] In one embodiment, a pharmaceutical composition containing the peptide of the present invention as an active ingredient increases the expression of one or more transcription factors selected from the group consisting of MSX2, HOXC13, and FOXN1 in human hair germinal matrix cells (HHGMCs).

[0047] The pharmaceutical composition of the present invention may contain a therapeutically effective amount of the peptide of the present invention.

[0048] The term "therapeutically effective amount" refers to an amount sufficient to achieve the activity or efficacy of the peptide, which is the active ingredient of the pharmaceutical composition of the present invention, for example, an amount sufficient to achieve the efficacy of treating or preventing alopecia.

[0049] In this specification, the term “prevention” means reducing the risk of contracting a disease or disability, and includes all actions that suppress or delay the onset of a disease by preventing the progression of a disease or one or more of its clinical symptoms.

[0050] In this specification, the term “treatment” means alleviating a disease or disorder, and includes all actions that improve or modify the symptoms of a disease by preventing or reducing the progression of the disease or one or more of its clinical symptoms.

[0051] In the present invention, the prevention or treatment of hair loss may involve removing the cause of hair loss or suppressing the progression of hair loss, or it may involve suppressing hair shedding or promoting hair formation to promote hair growth.

[0052] The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier.

[0053] The aforementioned pharmaceutically acceptable carriers include, but are not limited to, those commonly used in formulation, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, fine crystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoic acid, propylhydroxybenzoic acid, talc, magnesium stearate, and mineral oil.

[0054] The pharmaceutical composition of the present invention may further contain, but is not limited to, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspension agents, preservatives, and the like, in addition to the above-mentioned components.

[0055] Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington: The Science and Practice of Pharmacy (19th ed., 1995, Williams & Wilkins).

[0056] The pharmaceutical composition of the present invention may be administered via any suitable route for treating alopecia, for example, orally or parenterally. In the case of parenteral administration, it may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, topical administration, or transdermal administration. Since the pharmaceutical composition of the present invention has prophylactic or therapeutic activity for alopecia, it may be applied by topical administration, such as to the scalp.

[0057] The dosage of the pharmaceutical composition may be 0.0001 ug to 100 mg, 0.001 ug to 100 mg, 0.01 ug to 100 mg, 0.1 ug to 100 mg, or 1.0 ug to 1000 mg per day, but is not limited thereto, and can be prescribed in various ways depending on factors such as the formulation method, administration method, patient's age, weight, sex, medical condition, diet, administration time, route of administration, excretion rate, and response sensitivity.

[0058] The pharmaceutical compositions of the present invention may be manufactured in unit volume form or contained in multi-dose containers by formulation using pharmaceutically acceptable carriers and / or excipients by a method readily available to a person with ordinary skill in the art to which the invention pertains. The dosage form may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or in the form of an extract, powder, granules, tablet or capsule, and may further contain a dispersant or stabilizer.

[0059] The pharmaceutical composition of the present invention may be a topical skin preparation. The topical skin preparation is a formulation that can be applied to the outside of the skin, and when the pharmaceutical composition of the present invention is used as a topical skin preparation, it may be applied to the scalp, specifically to the scalp in the area where hair loss has occurred or to the scalp in the area where hair growth is to be promoted. The topical skin preparation may be a cream, gel, ointment, skin emulsifier, skin suspension, transdermal patch, drug-containing bandage, lotion, or a combination thereof, and the topical skin preparation may be appropriately formulated with ingredients commonly used in topical skin preparations such as cosmetics and pharmaceuticals, for example, aqueous components, oily components, powder components, alcohols, humectants, thickeners, UV absorbers, whitening agents, preservatives, antioxidants, surfactants, fragrances, colorants, various skin nutrients, or combinations thereof as needed. The aforementioned topical skin preparation may also contain, as appropriate, chelating agents such as disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, and gluconic acid; drugs such as caffeine, tannins, licorice extract, glabridin, various herbal medicines, tocopherol acetate, glycyrrhizin, tranexamic acid, and their derivatives or salts; and sugars such as vitamin C, magnesium ascorbate phosphate, ascorbate glucoside, arbutin, kojic acid, glucose, fructose, and trehalose.

[0060] In another aspect of the present invention, the present invention provides a cosmetic composition for promoting hair growth or preventing or improving alopecia, comprising a peptide containing the amino acid sequence of SEQ ID NO: 1 as an active ingredient.

[0061] In this specification, the term "improvement" means any action that causes the symptoms of a disease or disorder to improve or get better.

[0062] In one embodiment, a cosmetic composition containing the peptide of the present invention as an active ingredient promotes the proliferation of hair follicle dermal papilla cells (HFDPCs).

[0063] In one embodiment, a cosmetic composition containing the peptide of the present invention as an active ingredient activates the proteins Akt or ERK, which are involved in signal transduction in hair follicle dermal papilla cells (HFDPCs).

[0064] In one embodiment, a cosmetic composition containing the peptide of the present invention as an active ingredient activates β-catenin in hair follicle dermal papilla cells (HFDPCs) and promotes its translocation to the nucleus.

[0065] In one embodiment, a cosmetic composition containing the peptide of the present invention as an active ingredient upwardly regulates the gene expression of one or more factors selected from the group consisting of LEF-1, c-Myc, and Cyclin D1, which are subfactors of β-catenin in hair follicle dermal papilla cells (HFDPC).

[0066] In one embodiment, a cosmetic composition containing the peptide of the present invention as an active ingredient lowers the expression level of DKK-1 (Dickkopf-1), a hair loss protein, in hair follicle dermal papilla cells (HFDPC). The expression level of DKK-1, the hair loss protein, is increased by dihydrotestosterone (DHT), and the peptide of the present invention lowers the expression level of DKK-1, which is increased by DHT.

[0067] In one embodiment, a cosmetic composition containing the peptide of the present invention as an active ingredient increases the gene expression of one or more proteins selected from the group consisting of Ha3-II, Keratin 5, Keratin 14, and Keratin 19 in human hair outer root sheath cells (HHORSCs).

[0068] In one embodiment, a cosmetic composition containing the peptide of the present invention as an active ingredient increases the expression of one or more transcription factors selected from the group consisting of MSX2, HOXC13, and FOXN1 in human hair germinal matrix cells (HHGMC).

[0069] The cosmetic composition may be manufactured in any dosage form commonly produced in the art to which the present invention belongs, and may be a topical skin preparation. For example, it may be formulated in the form of a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleanser, oil, powder foundation, emulsion foundation, wax foundation, and spray, but is not limited thereto.

[0070] The aforementioned cosmetic composition may be manufactured in various forms such as solutions, sol-gels, emulsions, oils, waxes, and aerosols, including softening lotions, nourishing lotions, nourishing creams, massage creams, essences, eye creams, cleansing creams, cleansing foams, cleansing waters, packs, sprays, powders, hair tonics, hair creams, hair lotions, hair shampoos, hair rinses, hair conditioners, hair sprays, hair aerosols, pomades, and gels, but is not limited thereto.

[0071] The cosmetic composition of the present invention may contain excipients, carriers, and other additives, and it is possible to apply and incorporate ordinary ingredients commonly used in general skin cosmetics in the necessary amounts.

[0072] If the dosage form of the cosmetic composition is a paste, cream, or gel, animal oils, vegetable oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc, or zinc oxide may be used as the carrier component.

[0073] When the dosage form of the cosmetic composition is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder may be used as a carrier component, and in particular in the case of a spray, propellants such as chlorofluorohydrocarbon, propane / butane, or dimethyl ether may be further included, but are not limited thereto.

[0074] When the dosage form of the cosmetic composition is a solution or emulsion, a solvent, solubilizer, or emulsifier may be used as the carrier component. For example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol, or fatty acid ester of sorbitan may be used.

[0075] If the dosage form of the cosmetic composition is a suspension, the carrier component may be a liquid diluent such as water, ethanol, or propylene glycol, a suspension agent such as ethoxylated isostearyl alcohol, polyoxyethyl sorbitol ester, or polyoxyethylene sorbitan ester, or microcrystalline cellulose, aluminum metahydroxyl, bentonite, aga, or tragacanth.

[0076] If the dosage form of the cosmetic composition is a surfactant-containing cleanser, then the carrier component may be an aliphatic alcohol sulfate, an aliphatic alcohol ether sulfate, a sulfosuccinate monoester, isethionic acid, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid amide ether sulfate, alkylamide betaine, aliphatic alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, or ethoxylated glycerol fatty acid ester.

[0077] If the dosage form of the cosmetic composition is a hair shampoo, the peptide of the present invention may be mixed with base components for forming the shampoo, such as a thickener, surfactant, viscosity modifier, humectant, pH adjuster, preservative, and essential oil. CDE may be used as the thickener, LES, an anionic surfactant, and cocobetaine, an amphoteric surfactant, as the surfactant, polyquartz may be used as the viscosity modifier, glycerin may be used as the humectant, and citric acid and sodium hydroxide may be used as the pH adjuster. Grapefruit extract may be used as the preservative, and essential oils such as cedarwood, peppermint, and rosemary, as well as silk amino acids, pentaol, or vitamin E may also be added.

[0078] The components included in the cosmetic composition may, but are not limited to, components commonly used in cosmetic compositions, such as antioxidants, stabilizers, solubilizers, vitamins, pigments, and fragrances, in addition to the peptide and carrier component of the present invention as active ingredients.

[0079] The peptide of the present invention may be included in the aforementioned composition at a concentration of 0.01 μM to 1000 μM. Specifically, the peptide of the present invention may be present at concentrations of 0.01 μM to 1000 μM; 0.05 μM to 800 μM, 0.05 μM to 700 μM, 0.05 μM to 600 μM, 0.05 μM to 500 μM, 0.05 μM to 300 μM, 0.05 μM to 200 μM; 0.1 μM to 800 μM, 0.1 μM to 700 μM, 0.1 μM to 600 μM, and 0.1 μM to 500 μM. It may be contained in concentrations of uM, 0.1uM~300uM, 0.1uM~200uM; 0.3uM~800uM, 0.3uM~700uM, 0.3uM~600uM, 0.3uM~500uM, 0.3uM~300uM, 0.3uM~200uM; 0.3uM~150uM, 0.3uM~100uM, 0.3uM~90uM, 0.3uM~80uM, 0.3uM~70uM, or 0.3uM~60uM, but is not limited to these.

[0080] 3. Uses of the peptide of the present invention In another aspect of the present invention, the present invention provides applications for using a peptide containing the amino acid sequence of SEQ ID NO: 1 to promote hair growth or to suppress, prevent, treat, or improve alopecia.

[0081] In another aspect of the present invention, the present invention provides a method for promoting hair growth or preventing, suppressing, treating, or improving alopecia, comprising administering a peptide containing the amino acid sequence of SEQ ID NO: 1 or a composition containing the peptide to a subject that needs to be stimulated to promote hair growth or to suppress, prevent, treat, or improve alopecia.

[0082] In another aspect of the present invention, the present invention provides applications for peptides comprising the amino acid sequence of SEQ ID NO: 1 for the manufacture of pharmaceuticals or cosmetics for promoting hair growth or preventing, treating, or improving alopecia. [Effects of the Invention]

[0083] The peptide of the present invention has hair growth promoting activity or activity to prevent, suppress, or treat alopecia.

[0084] The peptide of the present invention has the activity of promoting the proliferation of hair follicle dermal papilla cells (HFDPCs), activating the cell proliferation-related signaling proteins Akt or ERK in human dermal papilla cells, activating β-catenin, increasing the expression levels of β-catenin subgenes LEF-1, c-Myc, and Cyclin D1, decreasing the expression level of the hair loss protein DKK-1, increasing the expression of keratin protein in outer root sheath cells (HORSCs), and increasing the expression of cell activation-involved transcription factors MSX2, HOXC13, and FOXN1 in hair matrix cells (GMCs). The peptide of the present invention can be used as a hair growth promoter, or as an agent for preventing, suppressing, or treating alopecia, and as an active ingredient in cosmetics. [Brief explanation of the drawing]

[0085] [Figure 1]These experimental results show that treating HHFDPC cells with the peptide of the present invention at concentrations of 500 nM, 5 uM, and 50 uM promotes the proliferation of HHFDPC cells. [Figure 2] These experimental results show that when HHFDPC cells were treated with the peptide of the present invention at concentrations of 500 nM, 5 μM, and 50 μM, the phosphorylation of Akt and ERK (extracellular-regulated kinase), which are signaling molecules related to cell proliferation, increased. [Figure 3] These experimental results show that when HHFDPC cells were treated with the peptide of the present invention at concentrations of 500 nM, 5 μM, and 50 μM, β-catenin was activated and its translocation to the nucleus increased. [Figure 4] These experimental results show that when HHFDPC cells are treated with the peptide of the present invention at concentrations of 500 nM, 5 μM, and 50 μM, the expression of LEF-1, Cyclin D1, and c-Myc, which are subfactors of β-catenin, increases. [Figure 5] This experimental result shows that when HHFDPC cells were treated with the peptide of the present invention at concentrations of 500 nM, 5 μM, and 50 μM, the expression of DKK-1, a hair loss protein induced by DHT treatment, decreased in a concentration-dependent manner. [Figure 6] Experimental results show that when HHORSC cells were treated with the peptide of the present invention at concentrations of 500 nM, 5 μM, and 50 μM, cell activity increased and the expression of cytokeratin proteins Ha3-II, Keratin 5, Keratin 14, and Keratin 19 increased. [Figure 7] These experimental results show that when HHGMC cells were treated with the peptide of the present invention at concentrations of 500 nM, 5 μM, and 50 μM, the expression of transcription factors MSX2, HOXC13, and FOXN1, which are involved in cell activity, increased. [Modes for carrying out the invention]

[0086] The present invention will be described in detail below with reference to examples. However, the following examples are merely illustrative of the present invention, and the content of the present invention is not limited to the following examples.

[0087] Manufacturing Example 1: Production of Peptides and Peptide Complexes Peptides having the amino acid sequence of SEQ ID NO: 1, as shown in Table 1 below, were synthesized using an automated peptide synthesizer (Milligen 9050, Millipore, USA). These synthesized peptides were then separated into pure molecules using C18 reversed-phase high-performance liquid chromatography (HPLC) (Waters Associates, USA). The column used was ACQUITY UPLC BEH300 C18 (2.1 mm x 100 mm, 1.7 μm, Waters Co, USA).

[0088] [Table 1]

[0089] The efficacy of the peptide of Sequence ID No. 1, which was manufactured as described above, was evaluated through the following experiment.

[0090] Experimental Example 1: Promoting the proliferation of human dermal papilla cells (HHFDPCs) We conducted experiments to investigate the effect of the peptide produced in Production Example 1 on the proliferation of human hair follicle dermal papilla cells (HHFDPCs).

[0091] HHFDPC 4x10 3Cells were seeded into 96-well cell culture plates at a density of cells / well and cultured for 24 hours under mesenchymal stem cell complete media conditions. Next, the cultures were switched to serum-free mesenchymal stem cell medium and cultured for another 24 hours. The cultured cell cultures were treated with the peptides prepared in Production Example 1 at concentrations of 500 nM, 5 μM, and 50 μM, respectively. A positive control group was treated with 1 μM of VEGF, and an untreated group was used as the negative control group (con). These groups were then cultured at 37°C for 72 hours. Next, 10 μL of 5 mg / ml MTT solution was added, and the cultures were incubated in a 37°C CO2 incubator for 4 hours. After removing the medium, 100 μL of DMSO was added, and the cultures were shaken for 10 minutes. Finally, the absorbance at a wavelength of 540 nm was measured using a spectrophotometer (Molecular Devices (USA, CA), SpectraMax iD3).

[0092] The experimental results, as shown in Figure 1, confirmed that when HHFDPC was treated with the peptide from Production Example 1 at concentrations of 500 nM, 5 μM, and 50 μM, the proliferation of HHFDPC was promoted compared to the negative control group (con).

[0093] Experimental Example 2: Activation of proliferation-related signaling molecules in human dermal papilla cells The effect of the peptide produced in Production Example 1 on the activation of proliferation-related signaling molecules in human dermal papilla cells (HHFDPCs) was confirmed by Western blot.

[0094] HHFDPC 4x10 5Cells were seeded into a 6-well cell culture plate at a density of cells / well and cultured for 24 hours in mesenchymal stem cell complete medium. Next, the cultures were switched to serum-free mesenchymal stem cell medium and cultured for another 24 hours. The cultured cell cultures were treated with the peptides prepared in Production Example 1 at concentrations of 500 nM, 5 μM, and 50 μM, respectively. A positive control group was treated with 1 μM minoxidil (MNX), and an untreated group was used as the negative control group (con). The cell cultures treated with the aforementioned substances were further cultured at 37°C for 24 hours. After washing the cultures with PBS, the cells were lysed with lysis buffer to obtain cell lysates. Protein samples of the same volume were prepared by quantification of the cell lysates using BCA. The prepared protein samples were subjected to electrophoresis using 10% SDS-PAGE. Proteins separated by SDS-PAGE were transferred to a PVDF membrane and blocked with 5% skim milk at room temperature for 30 minutes. Antibodies against phospho-AKT and phospho-ERK (Cell signaling, USA) were diluted 1:1000 in 3% BSA and reacted with the membrane at 4°C for 16 hours. The membrane was washed three times for 15 minutes each with 0.1% PBS-T (0.1% Tween-20 in PBS), and the secondary antibody was diluted 1:2000 in 5% skim milk and reacted at room temperature for 1 hour. The membrane was washed three times for 15 minutes each with 0.1% PBS-T (0.1% Tween-20 in PBS), treated with ECL solution (GE Healthcare, USA), and then detected on film.

[0095] As shown in Figure 2, the experimental results confirmed that when HHFDPC was treated with the peptide from Production Example 1 at concentrations of 500 nM, 5 μM, and 50 μM, the phosphorylation of Akt and ERK (extracellular-regulated kinase), which are signaling molecules related to cell proliferation, increased.

[0096] Experimental Example 3: Activation of β-catenin in human dermal papilla cells The effect of the peptide produced in Production Example 1 on the activation of β-catenin in human dermal papilla cells (HHFDPCs) was confirmed by Western blot.

[0097] HHFDPC 4x10 5Cells were seeded into 6-well cell culture plates at a density of cells / well and cultured for 24 hours in mesenchymal stem cell complete media. Next, the cultures were switched to serum-free mesenchymal stem cell medium and cultured for another 24 hours. The cultured cell cultures were treated with the peptides prepared in Production Example 1 at concentrations of 500 nM, 5 μM, and 50 μM, respectively. A positive control group was treated with 10 ng / mL of rhWnt-3a (recombinant human Wnt-3a protein, R&D Systems (USA, MN)), and an untreated group was used as the negative control group (con). The cell cultures treated with the aforementioned substances were further cultured at 37°C for 24 hours. After washing the cultures with PBS, nucleoproteins were separated using a nucleoprotein extraction kit (Thermo Scientific, USA), and BCA quantification was performed to prepare the same volume of protein samples. The prepared protein samples were subjected to electrophoresis using 10% SDS-PAGE. Proteins separated by SDS-PAGE were transferred to a PVDF membrane and blocked with 5% skim milk at room temperature for 30 minutes. Antibodies against β-catenin (Cell signaling, USA) and HDAC1 (Santa Cruz, USA) were diluted in 3% BSA at a ratio of 1:1000 and reacted with the membrane at 4°C for 16 hours. The membrane was washed three times for 15 minutes each with 0.1% PBS-T (0.1% Tween-20 in PBS), and the secondary antibody was diluted in 5% skim milk at a ratio of 1:2000 and reacted at room temperature for 1 hour. The membrane was washed three times for 15 minutes each with 0.1% PBS-T (0.1% Tween-20 in PBS), treated with ECL solution (GE Healthcare, USA), and then detected on film.

[0098] As shown in Figure 3, the experimental results confirmed that when HHFDPC was treated with the peptide from Production Example 1 at concentrations of 500 nM, 5 μM, and 50 μM, β-catenin was activated and its translocation to the nucleus increased.

[0099] Experimental Example 4: Promotion of β-catenin subgene expression in human dermal papilla cells The effects of the peptide produced in Production Example 1 on the expression levels of LEF-1 (Lymphoid enhancer-binding factor 1), c-Myc, and Cyclin D1, which are subgenes of β-catenin, in human hair follicle dermal papilla cells (HHFDPC) were confirmed by RT-PCR.

[0100] HHFDPC 4x10 5 Cells were seeded into 6-well cell culture plates at a density of cells / well and cultured for 24 hours in mesenchymal stem cell complete media. Next, the cultures were switched to serum-free mesenchymal stem cell medium and cultured for another 24 hours. The cultured cell cultures were treated with the peptides prepared in Production Example 1 at concentrations of 500 nM, 5 μM, and 50 μM, respectively. A positive control group was treated with 10 ng / mL of rhWnt-3a (recombinant human Wnt-3a protein, R&D Systems (USA, MN)), and an untreated group was used as the negative control group (con). Each group was further cultured at 37°C for 24 hours. After washing the cultures with PBS, RNA was isolated by treating with 300 μL of eaay blue (Intron, South Korea). The isolated RNA was quantified using nanodrops, and cDNA synthesis was performed using a cDNA synthesis kit (Enzynomics, South Korea). Next, the PCR reaction was carried out using the primers and PCR premix (permix) shown in Table 2 below (Enzynomics, South Korea). The PCR reaction products were electrophoresed on a 1.5% agarose gel, and the bands were detected using the Bio-Rad Gel Image System.

[0101] [Table 2]

[0102] As shown in Figure 4, the experimental results confirmed that when HHFDPC was treated with the peptide from Production Example 1 at concentrations of 500 nM, 5 μM, and 50 μM, β-catenin, which affects cell proliferation and differentiation, was activated, and the gene expression of its subordinate factors, LEF-1, Cyclin D1, and c-Myc, increased.

[0103] Experimental Example 5: Suppression of DKK-1 expression in human dermal papilla cells Dihydrotestosterone (DHT) in hair follicles promotes the expression of DKK-1 (Dickkopf-1), and DKK-1, induced and produced by DHT, is known to suppress the proliferation of keratinocytes in hair follicles, inducing apoptosis and promoting hair loss (J of Invest Dermatolo. 2008, Feb., 128(2), pp.262-269). The effect of the peptide produced in Production Example 1 on the expression level of the hair loss-inducing protein DKK-1 in human dermal papilla cells (HHFDPC) was confirmed by Western blot.

[0104] HHFDPC 4x10 5Cells were seeded into a 6-well cell culture plate at a density of cells / well and cultured for 24 hours in mesenchymal stem cell complete medium. Next, the cultures were switched to serum-free mesenchymal stem cell medium and cultured for another 24 hours. The cultured cell cultures were treated with the peptides prepared in Production Example 1 at concentrations of 500 nM, 5 μM, and 50 μM, respectively. The positive control group was treated with 5 μM finasteride, and the untreated group was used as the negative control group (con). At the same time, DHT, an inducer of the hair loss protein DKK-1, was added at a concentration of 100 nM. The cell cultures treated with the aforementioned substances were further cultured at 37°C for 24 hours. After washing the cultures with PBS, the cells were lysed with lysis buffer to obtain cell lysates. The same amount of protein sample was prepared by quantification of the cell lysates with BCA. The prepared protein samples were subjected to electrophoresis using 10% SDS-PAGE. Proteins separated by SDS-PAGE were transferred to a PVDF membrane and blocked with 5% skim milk at room temperature for 30 minutes. An antibody against DKK-1 (Cell signaling, USA) was diluted 1:1000 with 3% BSA and reacted with the membrane at 4°C for 16 hours. The membrane was washed three times for 15 minutes each with 0.1% PBS-T (0.1% Tween-20 in PBS), and the secondary antibody was diluted 1:2000 with 5% skim milk and reacted at room temperature for 1 hour. The membrane was washed three times for 15 minutes each with 0.1% PBS-T (0.1% Tween-20 in PBS), treated with ECL solution (GE Healthcare, USA), and then detected on film.

[0105] As shown in Figure 5, the experimental results confirmed that when HHFDPC was treated with the peptide from Production Example 1 at concentrations of 500 nM, 5 μM, and 50 μM, the expression of DKK-1, a hair loss protein induced by DHT treatment, decreased in a concentration-dependent manner.

[0106] Experimental Example 6: Activation of Human Outer Root Sheath Cells (HHORSCs) The effect of the peptide produced in Production Example 1 on the activation of human outer root sheath cells (HHORSCs) was confirmed by measuring the gene expression of cytokeratins proteins.

[0107] HHORSC 4x10 3 Cells were seeded into 96-well cell culture plates at a density of cells / well and cultured for 24 hours in mesenchymal stem cell complete media. Next, the cultures were switched to serum-free mesenchymal stem cell medium and cultured for another 24 hours. The cultured cell cultures were treated with the peptides prepared in Production Example 1 at concentrations of 500 nM, 5 μM, and 50 μM, respectively. A positive control group was treated with 100 nM of EGF (epidermal growth factor), and an untreated group was used as the negative control group (con). The cultures were then cultured at 37°C for another 24 hours. After washing the cultures with PBS, RNA was isolated by treating with 300 μL of eaay blue (Intron, South Korea). The isolated RNA was quantified using nanodrops, and cDNA synthesis was performed using a cDNA synthesis kit (Enzynomics, South Korea). Next, the PCR reaction was carried out using the primers and PCR premix (permix) (Enzynomics, South Korea) shown in Table 3 below. The PCR reaction products were subjected to electrophoresis on a 1.5% agarose gel, and the bands were detected using the Bio-Rad Gel Image System.

[0108] [Table 3]

[0109] As shown in Figure 6, the experimental results confirmed that when HHORSCs were treated with the peptide from Production Example 1 at concentrations of 500 nM, 5 μM, and 50 μM, cell activity increased, and the expression of cytokeratin proteins Ha3-II, Keratin 5, Keratin 14, and Keratin 19, which are involved in the formation of the cytoskeleton and the composition of hair, increased.

[0110] Experimental Example 7: Activation of Human Hair Genetic Cells (HHGMCs) The effect of the peptide produced in Production Example 1 on the activation of human hair germinal matrix cells (HHGMCs) was confirmed by measuring the expression of the cell activation transcription factors MSX2, HOXC13 (Homeobox C13), and FOXN1 (Forkhead Box N1).

[0111] HHGMC 4x10 5Cells were seeded into 6-well cell culture plates at a density of cells / well and cultured for 24 hours in mesenchymal stem cell complete media. Next, the cultures were switched to serum-free mesenchymal stem cell medium and cultured for another 24 hours. The cultured cell cultures were treated with the peptides prepared in Production Example 1 at concentrations of 500 nM, 5 μM, and 50 μM, respectively. A positive control group was treated with 100 nM of EGF (epidermal growth factor), and an untreated group was used as the negative control group (con). The cultures were then cultured at 37°C for another 24 hours. After washing the cultures with PBS, RNA was isolated by treating with 300 μL of eaay blue (Intron, South Korea). After quantifying the isolated RNA using nanodrops, cDNA synthesis was performed using a cDNA synthesis kit (Enzynomics, South Korea). Next, the PCR reaction was carried out using the primers and PCR premix (permix) (Enzynomics, South Korea) shown in Table 4 below. The PCR reaction products were subjected to electrophoresis on a 1.5% agarose gel, and the bands were detected using the Bio-Rad Gel Image System.

[0112] [Table 4]

[0113] As shown in Figure 7, the experimental results confirmed that when HHGMC was treated with the peptide from Production Example 1 at concentrations of 500 nM, 5 μM, and 50 μM, the expression of transcription factors MSX2, HOXC13, and FOXN1, which are involved in cell activity, increased.

[0114] Manufacturing Example 2: Manufacturing of Pharmaceutical Compositions 2-1. Manufacturing of powdered medicines 2g of the peptide of the present invention Lactose 1g The aforementioned components were mixed and filled into airtight pouches to produce a powder.

[0115] 2-2. Manufacturing of Tablets 100 mg of the peptide of the present invention Corn starch 100mg Lactose 100mg Magnesium stearate 2mg After mixing the aforementioned components, tablets were manufactured by compressing them according to a standard tablet manufacturing method.

[0116] 2-3. Manufacturing of Capsules 100 mg of the peptide of the present invention Corn starch 100mg Lactose 100mg Magnesium stearate 2mg After mixing the aforementioned components, the mixture was filled into gelatin capsules according to a standard capsule manufacturing method to produce capsules.

[0117] 2-4. Manufacturing of the ball 1g of the peptide of the present invention Lactose 1.5g Glycerin 1g Xylitol 0.5g After mixing the aforementioned ingredients, the product was manufactured according to a standard method to produce 4g per pill.

[0118] 2-5. Granule production 150 mg of the peptide of the present invention Soybean extract 50mg Glucose 200mg Starch 600mg After mixing the aforementioned components, 100 mg of 30% ethanol was added and dried at 60°C to form granules, which were then filled into packets.

[0119] Manufacturing Example 3: Manufacturing of Cosmetic Compositions 3-1. Cream Manufacturing 4.6 parts by weight of the peptide of the present invention Cetostearyl alcohol 2.8 parts by weight Beeswax 2.6 parts by weight 1.4 parts by weight of stearic acid Lipophilic glyceryl monostearate 2 parts by weight PEG-100 stearate 1 part by weight 1.4 parts by weight of sorbital sesquioleate Jojoba oil 4 parts by weight Squalene 3.8 parts by weight Polysorbate 60 1.1 parts by weight Macadamia oil 2 parts by weight Tocopherol acetate 0.2 parts by weight Methylpolysiloxane 0.4 parts by weight Ethylparaben 0.1 parts by weight Propylparaben 0.1 parts by weight Euxyl K-400 0.1 parts by weight 1,3-Butylene glycol 7 parts by weight Methylparaben 0.05 parts by weight Glycerin 6 parts by weight d-Panthenol 0.2 parts by weight Triethanolamine 0.2 parts by weight pt41891 0.2 parts by weight p-H2O 46.05 parts by weight 3-2. Manufacturing of lotion 3.5 parts by weight of the peptide of the present invention Cetostearyl alcohol 1.6 parts by weight 1.4 parts by weight of stearic acid Lipophilic glyceryl monostearate 1.8 parts by weight PEG-100 stearate 2.6 parts by weight 0.6 parts by weight of sorbital sesquioleate Squalene 4.8 parts by weight Macadamia oil 2 parts by weight Jojoba oil 2 parts by weight Tocopherol acetate 0.4 parts by weight Methylpolysiloxane 0.2 parts by weight Ethylparaben 0.1 parts by weight Propylparaben 0.1 parts by weight 1,3-Butylene glycol 4 parts by weight Methylparaben 0.1 parts by weight Xanthan gum 0.1 parts by weight Glycerin 4 parts by weight d-Panthenol 0.15 parts by weight Allantoin 0.1 parts by weight Calcium carbonate (2% aq. Sol) 4 parts by weight Triethanolamine 0.15 parts by weight 3 parts by weight of ethanol pt41891 0.1 parts by weight p-H20 48.3 parts by weight 3-3. Manufacturing of softening lotion 0.2% by weight of the peptide of the present invention Ethanol 10.0% by weight Polyoxyethylene sorbitan polylaurate 1.0% by weight Methyl parahydroxybenzoate 0.2% by weight Glycerin 5.0% by weight 1,3-Butyl glycol 6.0% by weight Incense (appropriate amount) Dye appropriate amount Purified water (appropriate amount) Total 100 3-4. Manufacturing of nourishing lotion 0.1% by weight of the peptide of the present invention Vaseline 2.0% by weight Sorbitan sesquioleate 0.8% by weight Polyoxyethylene oleylethyl 1.2% by weight Methyl parahydroxybenzoate (appropriate amount) Propylene glycol 5.0% by weight Ethanol 3.2% by weight Carboxyvinyl polymer 18.0% by weight Dye appropriate amount Incense (appropriate amount) Purified water (appropriate amount) Total 100 3-5. Essence Manufacturing 5.0% by weight of the peptide of the present invention Propylene glycol 10.0% by weight Glycerin 10.0% by weight Sodium hyaluronate aqueous solution (1%) 5.0% by weight Ethanol 3.2% by weight Polyoxyethylene hydrogenated castor oil 1.0% by weight Methyl parahydroxybenzoate 0.1% by weight Incense (appropriate amount) Purified water (appropriate amount) Total 100 3-6. Pack manufacturing 0.5% by weight of the peptide of the present invention Glycerin 5.0% by weight Propylene glycol 4.0% by weight Polyvinyl alcohol 15.0% by weight Ethanol 8.0% by weight Polyoxyethylene oleylethyl 1.0% by weight Methyl parahydroxybenzoate 0.2% by weight Incense (appropriate amount) Dye appropriate amount Purified water (appropriate amount) Total 100 The aforementioned composition ratio is a mixture of preferred components as in the preferred example, but the components or blending ratio may be arbitrarily modified depending on regional and ethnic preferences such as the demand segment, the country of demand, and the intended use.

[0120] Although typical embodiments of this application have been described above, the scope of this application is not limited to such specific embodiments, and any person with ordinary skill in the art may modify the claims of this application as appropriate.

Claims

1. A peptide consisting of the amino acid sequence of SEQ ID NO:

1.

2. A composition for promoting hair growth or suppressing, preventing, or improving alopecia, comprising the peptide described in claim 1 as an active ingredient.

3. A pharmaceutical composition for the prevention or treatment of alopecia, comprising the peptide described in claim 1 as an active ingredient.

4. The pharmaceutically acceptable composition for the prevention or treatment of alopecia according to claim 3, wherein the peptide promotes the proliferation of hair follicle dermal papilla cells (HFDPCs).

5. The peptide is found in hair follicle dermal papilla cells (HFDPCs), (i) Activate Akt or ERK signaling proteins, (ii) Activate β-catenin, (iii) Upward regulation of the gene expression of one or more factors selected from the group consisting of β-catenin subfactors LEF-1, c-Myc, and Cyclin D1, or (iv) The pharmaceutical composition for the prevention or treatment of alopecia according to claim 3, which lowers the expression level of the hair loss protein DKK-1 (Dickkopf-1).

6. The pharmaceutically active ingredient in claim 3, wherein the peptide increases the expression of one or more proteins selected from the group consisting of Ha3-II, Keratin 5, Keratin 14, and Keratin 19 in outer root sheath cells (HORSCs).

7. The peptide is present in hair matrix cells (GMC), A pharmaceutical composition for the prevention or treatment of alopecia according to claim 3, which increases the expression of one or more transcription factors selected from the group consisting of MSX2, HOXC13, and FOXN1.

8. The pharmaceutical composition for the prevention or treatment of alopecia according to claim 3, wherein the pharmaceutical composition is a topical skin preparation.

9. A cosmetic composition for promoting hair growth or preventing or improving alopecia, comprising the peptide described in claim 1 as an active ingredient.

10. The aforementioned peptide promotes the proliferation of hair follicle dermal papilla cells (HFDPCs), as described in claim 9, for the cosmetic composition for promoting hair growth or preventing or improving alopecia.

11. The peptide is found in hair follicle dermal papilla cells (HFDPCs), (i) Activate Akt or ERK signaling proteins, (ii) Activate β-catenin, (iii) Upward regulation of the gene expression of one or more factors selected from the group consisting of β-catenin subfactors LEF-1, c-Myc, and Cyclin D1, or (iv) A cosmetic composition for promoting hair growth or preventing or improving alopecia, according to claim 9, which lowers the expression level of the hair loss protein DKK-1 (Dickkopf-1).

12. The peptide is found in outer root sheath cells (HORSCs), The cosmetic composition for promoting hair growth or preventing or improving alopecia according to claim 9, which increases the expression of one or more proteins selected from the group consisting of Ha3-II, Keratin 5, Keratin 14, and Keratin 19.

13. The peptide is present in hair matrix cells (GMC), The cosmetic composition for promoting hair growth or preventing or improving alopecia, as described in claim 9, which increases the expression of one or more transcription factors selected from the group consisting of MSX2, HOXC13, and FOXN1.

14. The cosmetic composition described above is a topical skin preparation, and is a cosmetic composition for promoting hair growth or preventing or improving alopecia according to claim 9.

15. The cosmetic composition according to claim 9, wherein the cosmetic composition is one or more dosage forms selected from the group consisting of a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleanser, oil, powder foundation, emulsion foundation, wax foundation, and spray.

16. The cosmetic composition for promoting hair growth or preventing or improving alopecia, as described in claim 9, wherein the cosmetic composition is one or more dosage forms selected from the group consisting of hair tonic, hair cream, hair lotion, hair shampoo, hair rinse, hair conditioner, hair spray, hair aerosol, pomade, and gel.

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