WO2023002851A1 - Obp促進剤 - Google Patents
Obp促進剤 Download PDFInfo
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- WO2023002851A1 WO2023002851A1 PCT/JP2022/026895 JP2022026895W WO2023002851A1 WO 2023002851 A1 WO2023002851 A1 WO 2023002851A1 JP 2022026895 W JP2022026895 W JP 2022026895W WO 2023002851 A1 WO2023002851 A1 WO 2023002851A1
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- obp
- extract
- skin
- expression
- substance
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9783—Angiosperms [Magnoliophyta]
- A61K8/9789—Magnoliopsida [dicotyledons]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9783—Angiosperms [Magnoliophyta]
- A61K8/9794—Liliopsida [monocotyledons]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6897—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids involving reporter genes operably linked to promoters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/70—Biological properties of the composition as a whole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/74—Biological properties of particular ingredients
- A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
Definitions
- the present invention relates to a screening method for an OBP (odorant binding protein) expression promoter and a substance that promotes or suppresses OBP expression.
- OBP odorant binding protein
- the nose is a sensor that senses harmful substances by smell, and also has a defense function that traps harmful substances by nasal mucus that covers the mucous membranes in the nasal cavity.
- a runny nose contains a protein substance called OBP (odorant binding protein), and it has been suggested that OBP may prevent harmful substances from entering the body from the outside by capturing harmful substances. ing. Furthermore, it has been reported that OBP is contained in tears, prostate, mammary glands, etc. (Non-Patent Documents 1 to 3).
- the barrier function of the stratum corneum prevents large molecules from entering the skin.
- small molecules and the like that are captured by OBP may pass through keratinocytes. Little is known about the details of how such molecules can defend against the skin.
- One of the purposes of the present invention is to provide a substance that promotes the expression of OBP (odorant binding protein).
- Another object of the present invention is to provide a screening method for a substance that promotes or suppresses OBP expression.
- the present inventors found that substances such as rose extract, cherry blossom extract, and lily extract promote the expression of OBP. Based on these findings, the present inventors have conducted extensive studies and have completed the present invention relating to OBP expression promoters.
- An OBP (odorant binding protein) expression promoter characterized by containing, as an active ingredient, a substance selected from the group consisting of lily extract, rose extract and cherry blossom extract.
- the OBP expression promoter according to item 1 which is used for promoting OBP expression in epidermal cells and/or keratinocytes.
- the OBP expression promoter according to item 1 or 2 which is used for promoting OBP expression in skin with reduced OBP activity.
- the OBP expression promoter according to any one of items 1 to 3 which is used for improving skin moisturizing function and/or barrier function.
- the OBP expression promoter according to any one of items 1 to 4 which is used for reducing skin damage caused by harmful substances.
- a cosmetic method or a non-therapeutic method comprising applying an OBP expression promoter containing, as an active ingredient, a substance selected from the group consisting of lily extract, rose extract, and cherry blossom extract.
- a skin harmful substance inhibitor containing, as an active ingredient, a substance selected from the group consisting of lily extract, rose extract and cherry blossom extract.
- a method of screening for a substance that promotes or suppresses OBP expression comprising the steps of: contacting a cell with the substance; A method comprising the step of determining.
- an OBP expression promoter is provided.
- This OBP expression promoter can be used, for example, to promote the expression of OBP in skin (epidermal cells and/or keratinocytes) with reduced OBP activity, reduce skin damage caused by harmful substances, It can be used to improve moisturizing and/or barrier function.
- substances useful as OBP expression promoters can be identified by the screening method of the present invention.
- FIG. 1 is a graph showing that transcription of OBP (OBP2A and OBP2B) is observed in keratinocytes and 3D skin models.
- FIG. 2 is a graph showing the effect of t-2-nonenal on the survival rate of OBP2A/OBP2B knockdown keratinocytes.
- FIG. 3 is a graph showing the effect of oleic acid on the survival rate of OBP2A/OBP2B knockdown keratinocytes.
- FIG. 4 is a graph showing the effect of palmitoleic acid on the viability of OBP2A/OBP2B knockdown keratinocytes.
- FIG. 5 shows simulation results showing how OBP captures t-2-nonenal.
- FIG. 1 is a graph showing that transcription of OBP (OBP2A and OBP2B) is observed in keratinocytes and 3D skin models.
- FIG. 2 is a graph showing the effect of t-2-nonenal on the survival
- FIG. 6 is a diagram showing simulation results showing how OBP traps oleic acid.
- FIG. 7 is a diagram showing simulation results showing how OBP captures palmitoleic acid.
- FIG. 8 is a graph showing that plant extracts increase the amount of transcription of OBP.
- FIG. 9 is a graph showing that cherry blossom extract increases the amount of filaggrin transcription.
- FIG. 10 is a graph showing that cherry blossom extract increases the amount of kallikrein 10 transcription.
- FIG. 11 is a graph showing that cherry blossom extract increases the transcription level of caspase-14.
- FIG. 12 is a graph showing that lily extract increases the amount of filaggrin transcription.
- FIG. 13 is a graph showing that lily extract increases the amount of kallikrein 10 transcription.
- FIG. 14 is a graph showing that lily extract increases the transcription level of caspase-14.
- FIG. 15 is a graph showing that cherry blossom extract and lily extract improve TEWL.
- OBP odorant binding protein
- OBP odorant binding protein
- OBP2A is present in nasal mucus, etc., and has a high affinity for fatty acids and aldehydes.
- OBP2B is present in the prostate and mammary glands, and LCN1 is present in tears.
- Non-Patent Document 1 Although the function of OBP is not well established, it functions as a scavenger for 4-hydroxy-2-nonenal in the nasal mucosa of mammals (Non-Patent Document 1), and overexpression of the bovine OBP monomeric form catalyzed E. coli. It protects against oxidative stress by substances (Non-Patent Document 2), human tear lipocalin functions as an oxidative stress-induced scavenger of lipid peroxidation products that are potentially harmful substances in cell culture systems (Non-Patent Document 2). Since Patent Document 3) and the like have been reported, it has been suggested that it may have a role in protection from external harmful substances.
- OBP is also present in the skin.
- Hazardous substances with a large molecular weight can be prevented from entering the skin by the stratum corneum and the like, but substances with a small molecular weight may penetrate the stratum corneum and enter the skin.
- OBP present in the skin is thought to play a protective role against such small molecules.
- OBP odorant binding protein expression promoter
- OBP expression promoter can contain, as an active ingredient, a substance selected from the group consisting of rose extract, cherry blossom extract, and lily extract. Promotion of OBP expression refers to increasing the amount of transcripts and/or the amount of protein of OBP.
- a substance that can be used as an active ingredient of the OBP expression promoter can be a plant extract selected from the group consisting of rose extract, cherry blossom extract, and lily extract. In some embodiments, a combination of multiple types of plant extracts may be blended.
- plant extract used in the invention, whole plants, leaves, flower parts, stems, roots, grains, etc. can be used.
- the flowering time, size, etc. are not particularly limited, and a flower containing petals, calyx, or all of them can be used.
- Plant extracts can be extracted from plant raw materials by methods known to those skilled in the art. Plant extracts can be obtained using any method known to those skilled in the art, such as, for example, an extraction method using a solvent, a method including a grinding or pressing step.
- the part of the plant to be extracted is washed with water in advance to remove foreign matter, then it is left as it is or dried, then cut into small pieces or pulverized as necessary, and then brought into contact with the extraction solvent for extraction.
- Extraction can be carried out by contacting with an extraction solvent according to a conventional method such as immersion, but supercritical extraction or steam distillation may also be used.
- extraction solvents include water; lower alcohols such as methanol, ethanol and propanol; higher alcohols such as oleyl alcohol, stearyl alcohol and octyldodecanol; ethylene glycol, 1,3-propanediol, 1,3-butylene glycol, polyhydric alcohols such as glycerin; esters such as ethyl acetate, butyl acetate, methyl propionate and glyceryl trioctanoate; ketones such as acetone and methyl ethyl ketone; ethers such as ethyl ether, isopropyl and ether; , chloroform and other hydrocarbon solvents, and the like, which can be used alone or in combination of two or more.
- lower alcohols such as methanol, ethanol and propanol
- higher alcohols such as oleyl alcohol, stearyl alcohol and octyldodecanol
- the mixing ratio is, for example, a mixed solvent of water and ethyl alcohol in the range of 1:1 to 25:1 in volume ratio (the same applies hereinafter); a mixed solvent of water and glycerin. In the range of 1:1 to 15:1; or in the case of a mixed solvent of water and 1,3-propanediol or 1,3-butylene glycol, the range is preferably in the range of 1:1 to 15:1.
- the pH is not particularly limited, but it is generally preferred to be in the range of pH 3-9.
- the extraction solvent is blended with an alkalinity adjuster such as sodium hydroxide, sodium carbonate, potassium hydroxide, or an acidity adjuster such as citric acid, hydrochloric acid, phosphoric acid, sulfuric acid, etc. to obtain a desired pH.
- an alkalinity adjuster such as sodium hydroxide, sodium carbonate, potassium hydroxide
- an acidity adjuster such as citric acid, hydrochloric acid, phosphoric acid, sulfuric acid, etc.
- Extraction conditions such as extraction temperature and extraction time vary depending on the type and pH of the solvent used, and are not limited.
- water or 1,3-butylene glycol or a mixture of water and 1,3-butylene glycol When used as a solvent, the extraction temperature may be in the range of 0° C. to 90° C., and the extraction time may be in the range of 0.5 hours to 7 days.
- the extraction site Prior to the extraction process or in parallel with the extraction process, the extraction site may be subjected to hydrolysis treatment as necessary. As a result, there is a possibility that the extract can be used more effectively by improving the skin irritation, efficacy, storage stability, or the like of the extract.
- the OBP expression promoter of the present disclosure can be blended into compositions such as cosmetics, quasi-drugs, pharmaceuticals, and functional foods.
- cosmetics it can be blended in any cosmetics that are applied to the skin, such as, but not limited to, sunscreens, lotions, serums, milky lotions, beauty creams, and aftercare lotions.
- sunscreens lotions, serums, milky lotions, beauty creams, and aftercare lotions.
- the OBP expression promoter according to the present invention can be appropriately blended with arbitrary compounding ingredients used in cosmetics, pharmaceuticals, etc., as necessary, within a range that does not impair its effect.
- the optional ingredients include oils, surfactants, powders, colorants, water, alcohols, thickeners, chelating agents, silicones, antioxidants, UV absorbers, moisturizers, fragrances, and various medicinal effects.
- Other ingredients may include, for example, anti-inflammatory ingredients, whitening ingredients, and the like.
- a person skilled in the art can appropriately set the amount of the extract to be included in the OBP expression promoter.
- the OBP expression promoter can be used to promote OBP expression in skin tissue, particularly epidermal cells and/or keratinocytes.
- the OBP expression promoter according to the present disclosure By applying the OBP expression promoter according to the present disclosure to the skin, it can be used in a cosmetic method for promoting OBP expression in epidermal cells and/or keratinocytes.
- the usage and dosage of the external skin preparation according to the present disclosure in such a cosmetic method are not particularly limited, and are appropriately determined depending on the dosage form and the skin condition to be treated.
- An appropriate amount for example, 0.1 ml to 1 ml per 1 square cm 2 can be directly rubbed into the skin once to 5 times, or the appropriate amount can be impregnated into gauze or the like and then applied to the skin.
- an OBP expression promoter can be used to promote OBP expression in skin with reduced OBP activity.
- causes of decreased OBP activity include, for example, aging and fatigue.
- a decrease in OBP activity refers to a decrease in the amount, expression level, and/or function of OBP. Compared to the state without, for example, it is reduced with a statistically significant difference (e.g., Dunnett's test, etc.) with a significance level of 5%, or, for example, 5% or more, 10% or more, 20% or more , 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 100% reduction.
- a person skilled in the art can assess reduction of OBP activity using known methods.
- the OBP expression promoter can be used to improve the skin's moisturizing function and/or barrier function.
- the stratum corneum which is the outermost layer, is the outermost layer of the skin.
- the index of skin barrier function includes, for example, transepidermal water loss (TEWL) and skin penetration using index substances such as pigments. Skin TEWL can be measured using a device such as a Vapometer.
- OBP expression promoters can be used to reduce skin damage caused by harmful substances.
- Skin damage refers to deterioration of the skin condition due to harmful substances, and includes, for example, thinning of the skin of animals including humans, conspicuous pores, enlargement of pore conical parts, disordered texture, and/or parakeratosis. be done. However, skin damage is not limited because it varies depending on the type of skin harmful substance.
- Toxic substances can be, for example, aldehydes, fatty acids, and air pollutants.
- Aldehydes are, for example, n-hexanal, n-heptanal, n-nonanal, n-decanal, undecanal, n-dodecanal, benzaldehyde, ⁇ -methyl-3,4-(methylenedioxy)-hydrocinnamaldehyde, or 2 -methyl-3-(4-tert-butylphenyl)-propanal, but is not limited to these.
- Fatty acids are, for example, octanoic acid (caprylic acid), decanoic acid (capric acid), dodecanoic acid (lauric acid), tetradecanoic acid (myristic acid), hexadecanoic acid (palmitic acid), 12-bromododecanoic acid (BrC12-Ac) , or 15-bromopentadecanoic acid (BrC15-Ac), but is not limited to these.
- Air pollutants are, for example, sulfur oxides (SOx), nitrogen oxides (NOx), photochemical oxidants (Ox), particulate matter (PM), suspended particulate matter (SPM), or fine particulate matter (PM2. 5), but is not limited to these. Examples of hazardous materials are also described elsewhere herein.
- One aspect of the present invention relates to cosmetic or non-therapeutic methods comprising applying an OBP expression-promoting agent.
- the OBP expression promoter can contain, as an active ingredient, a substance selected from the group consisting of rose extract, cherry blossom extract, and lily extract.
- Such a method is a cosmetic method and is not a method used for treatment by a doctor or a medical worker.
- Subjects of application are, for example, mammals, especially humans.
- the application site can be, for example, the skin of the face, neck, scalp, arms, legs, and the like.
- Application can be in any manner, including application by hand, applicator, and the like. The number, frequency, amount, etc., of application are appropriately set according to the desired effect and the like.
- One aspect of the present invention relates to the use of a substance selected from the group consisting of rose rose extract, cherry blossom extract, and lily extract in promoting expression of OBP.
- one aspect of the present invention relates to a substance selected from the group consisting of rose rose extract, cherry blossom extract, and lily extract, for use in promoting expression of OBP.
- the data disclosed herein demonstrate that substances selected from the group consisting of rose extract, cherry blossom extract, and lily extract are useful for promoting the expression of OBP.
- the plant extracts described above can be used to prepare compositions for use in promoting OBP expression.
- One aspect of the present invention relates to an external preparation for skin containing an OBP expression promoter containing, as an active ingredient, a substance selected from the group consisting of rose extract, cherry blossom extract, and lily extract.
- the OBP expression promoter can be formulated as an external skin preparation that can be directly applied to the skin.
- external skin preparations include external solids, external powders, external liquids, liniments, sprays, external aerosols, pump sprays, ointments, creams, gels, patches, tapes, poultices, etc. It can be prepared in any form.
- the dosage form of the external preparation for skin according to the present disclosure is not particularly limited. , ointment, gel, aerosol and the like. Also, the form of use is not particularly limited, and can be in any form such as lotion, milky lotion, cream, essence, jelly, gel, ointment, pack, mask, foundation, and the like.
- One aspect of the present invention relates to a skin harmful substance inhibitor containing, as an active ingredient, a substance selected from the group consisting of rose extract, cherry blossom extract, and lily extract.
- a skin toxic substance refers to a substance that damages the skin, but whose activity is suppressed by OBP such as OBP2A and OBP2B.
- Activity is inhibited by OBP means that when OBP is present, the amount of skin harmful substances, the expression level, and / or skin adverse effects are statistically higher than when OBP is not present, for example, with a significance level of 5% Reducing with a significant difference (e.g., Dunnett's test, etc.), or, for example, 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% 80% or more, 90% or more, or 100% reduction.
- OBP knockdown skin cells such substances can be detected as skin toxins if cell viability is lower than with non-knockdown skin cells.
- OBP knockdown skin cells refer to skin cells such as keratinocytes in which one or both of the OBP2A and OBP2B genes have been knocked down, resulting in impaired or reduced OBP expression.
- Knockdown treatment can use any known technique, such as described in Sci Rep. 2018 Oct23;8(1):15610.
- Non-knockdown skin cells refer to skin cells in which the OBP gene, which is knocked down in the knockdown cells, has not been subjected to knockdown treatment and OBP expression is normal.
- OBP expression is impaired or reduced by knockdown treatment means that the OBP gene expression level and/or OBP protein level in knockdown-treated cells is, for example, 5 levels of significance compared to non-knockdown cells. % statistically significant difference (e.g.
- Dunnett's test etc.
- 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more It may refer to a reduction of 60% or more, 70% or more, 80% or more, 90% or more, or 100%.
- Harmful substances include, but are not limited to, formaldehyde, acetaldehyde, propionic acid, normal valeric acid, normal butyric acid, isovaleric acid, ethyl acetate, methyl isobutyl ketone, isobutanol, propionaldehyde, butyraldehyde, in addition to the above harmful substances. , isobutyraldehyde, valeraldehyde, isovaleraldehyde, nonenal and other aldehydes; stress odor substances such as allyl mercaptan and dimethyl trisulfide; High substances and substances known to be ligands of OBP as described, for example, in Biochemistry. 2002 Jun11;41(23):7241-52.
- Nonenal (2-nonenal) in this specification refers to the trans form (t-2-nonenal) and is reported to be related to aging odor and skin yellowing (Patent Documents 1 to 3). The inventors have found that nonenal exerts adverse skin effects, including skin thinning (see Examples).
- the screening method of the present invention relates to a screening method for a substance that promotes or suppresses OBP expression.
- the screening method of the present invention may comprise the steps of contacting cells with a substance, measuring the OBP expression level in the cells, and determining changes in the OBP expression level due to the presence or absence of the substance.
- the cells can be, for example, epidermal cells or keratinocytes. Contacting the cells with the test substance may be accomplished, for example, by adding the test substance to the culture medium of the cells.
- the OBP expression level can be measured by any method known to those skilled in the art. For example, the amount of OBP mRNA can be quantified by RT-PCR or the like, or the amount of OBP protein can be quantified by ELISA or Western blotting. When a change in the OBP expression level was observed depending on the presence or absence of the substance, if the expression level increased, the test substance was evaluated to promote OBP expression, and if the expression decreased, the test substance was evaluated to promote OBP expression. is evaluated as suppressing
- Substances that promote or suppress OBP expression are, for example, substances contained in compound libraries and extract libraries of microorganisms, animals and plants, such as plant extracts, low-molecular-weight compounds, high-molecular polymers, proteins, peptides, and antibodies. , enzymes, nucleic acids, sugar chains, lipids, and compositions containing them.
- plant extract compositions include aloe extract, ginkgo biloba extract, oolong tea extract, turmeric extract, turmeric rhizome extract, rhizome/root extract, edelweiss extract, olive leaf extract, hydrolyzed silk powder, kawara mugwort extract, kawara mugwort flower.
- Example 1 Expression of OBP in Skin Human epidermal cells were prepared by culturing in Humedia-KG2 (Kurabo) medium at 37°C.
- human epidermis diluted in CnTPrime medium (CELLnTEC) solution was applied to a cell culture insert ( ⁇ 12 mm, average pore size of porous membrane: 0.4 ⁇ m) coated with CellStart (Invitrogen Life Technologies) solution diluted 50 times in DPBS.
- Cells (2.2 ⁇ 10 5 cells/500 ⁇ l) were seeded, 1 ml of CnT Prime medium (CELLnTEC) solution was added under the insert, and cultured at 37° C. for 3 days.
- the medium above the insert was replaced with 500 ⁇ l of CnT-PR-3D medium (CELLnTEC) supplemented with vitamin C (50 ⁇ g/ml), and the medium below the insert was replaced with 1 ml, followed by culturing at 37° C. for 1 day.
- the medium above the insert was aspirated, the medium below the insert was replaced with 500 ⁇ l of CnT-PR-3D medium (CELLnTEC) supplemented with vitamin C (50 ⁇ g/ml), and cultured at 37° C. for 1 day.
- CELLnTEC CnT-PR-3D medium
- Example 2 Analysis of the effect of knockdown of OBP on cell viability 10 ⁇ M of OBP2A and OBP2B siRNAs were added to a mixed solution of Lipofectamine RNAiMAX Transfection Reagent (Thermo Fisher Scientific) and Opti-MEM I Reduced Serum Media (Thermo Fisher Scientific). , was added to the epidermal cells cultured by the above method and cultured for 24 hours to prepare OBP2A and OBP2B double knockdown cells. Control cells were cultured and differentiated for 24 hours under the same conditions except that the above knockdown treatment was not performed.
- Lipofectamine RNAiMAX Transfection Reagent Thermo Fisher Scientific
- Opti-MEM I Reduced Serum Media Thermo Fisher Scientific
- OBP protein was determined by ELISA using Human odorant binding protein 2A ELISA Kit (MYBioSource) and Human odorant binding protein 2B ELISA Kit (MYBioSource). Measurements confirmed that 47% of OBP2A and 60% of OBP2B protein levels were reduced.
- aldehydes such as nonenal
- fatty acids such as oleic acid and palmitoleic acid.
- Example 3 Analysis of the capture of skin harmful substances by OBP Structural analysis of OBP and three substances (nonenal, oleic acid, palmitoleic acid) by simulation using Autodock (4.2.6) and Pymol (2.2.0) did The results are shown in Figures 5-7. Figures 5-7 show that all of these substances are trapped in the binding pocket of OBP.
- Example 4 Evaluation of enhancement of OBP expression by plant extracts Several plant extracts, ie rose extract, cherry blossom extract, and lily extract, were examined in cells for the effect of promoting OBP transcription.
- rose rose extract extracts extracted from rose flowers (ROSA CENTIFOLIA FLOWER EXTRACT, BUTYLENE GLYCOL, WATER) were purchased from Maruzen Pharmaceutical Co., Ltd. and used (trade name: rose extract BG).
- 1,3-butylene glycol was added to the filtrate obtained by water extraction from the flowers of Satozakura (Prunus lannesiana Wils. cv. Sekiyama (Rosaceae)). used (trade name: CosmeHerbest (registered trademark) Sakura).
- This product is made by adding ethanol to the flowers of Prunus lannesiana Wils. cv. Glycol is added and filtered to obtain a product.
- microwave extracted Chinese White Lily extract (Glycerin, Butylene Glycol, Water, Lilium Candidum Flower Extract) was purchased from CRODA and used (trade name: Phytofleur (trademark) Lily NP). .
- these plant extracts increased the transcription of the OBP gene compared to the control. Therefore, these plant extracts can be used as OBP expression promoters.
- Example 5 Improvement of Skin Barrier Function by Cherry Blossom Extract The effect of cherry blossom extract on genes known as marker genes for skin barrier function was investigated. Marker genes include filaggrin (see, e.g., "Filaggrin and Skin Barrier Function” doi: 10.1159/000441539), kallikrein 10 (see, e.g., "Epidermal Barriers” doi: 10.1101/cshperspect.a018218), caspase 14 (see e.g. "Phospho- ⁇ Np63 ⁇ regulates AQP3, ALOX12B, CASP14 and CLDN1 expression through transcription and microRNA modulation” doi: 10.1016/j.febslet.2013.09.023) was selected.
- cherry blossom extract promotes transcription of these genes and improves skin barrier function. Therefore, an OBP expression promoter containing a cherry blossom extract can be used to improve the skin barrier function. In addition, the cherry blossom extract can be used as an active ingredient of a skin barrier function improving agent.
- Example 6 Improvement of Skin Barrier Function by Lily Extract The same experiment as in Example 5 was performed using lily extract instead of cherry blossom extract. The results are shown in Figures 12-14. Values are relative values when the control is set to 1.
- lily extract promotes the transcription of filaggrin, kallikrein 10, and caspase 14 and improves skin barrier function. Therefore, an OBP expression promoter containing a lily extract can be used to improve the skin barrier function. In addition, the lily extract can be used as an active ingredient of a skin barrier function improving agent.
- Example 7 Improvement of transepidermal water loss (TEWL) by cherry blossom extract and lily extract
- the barrier function of the skin can be evaluated by suppressing transepidermal water loss, and the transepidermal water loss (TEWL) is small. It can be considered that the more excellent the barrier function is.
- Cell culture inserts coated with CellStart (Invitrogen Life Technologies) diluted 50-fold in DPBS were inoculated with human epidermal cells diluted in CnT Prime medium solution, and the CnT Prime medium solution was added to the bottom of the insert and kept at 37°C for 3 days. cultured. After that, the medium on the insert was replaced with CnT-PR-3D medium supplemented with vitamin C, and cultured at 37°C for 1 day. After 1 day, the medium on the insert was aspirated, the medium below the insert was replaced with CnT-PR-3D medium supplemented with vitamin C, and cultured at 37°C for 1 day. A 3D skin model was constructed by doing this work for eight days.
- an OBP expression promoter containing the above substance.
- This OBP expression promoter can be used, for example, to promote the expression of OBP in skin (epidermal cells and/or keratinocytes) with reduced OBP activity, reduce skin damage caused by harmful substances, It can be used to improve moisturizing and/or barrier function.
- substances useful as OBP expression promoters can be identified by the screening method of the present invention.
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Abstract
Description
(1)百合エキス、セイヨウバラエキス、および桜の花エキスから成る群より選択される物質を有効成分として含有することを特徴とする、OBP(odorant binding protein)発現促進剤。
(2)表皮細胞および/またはケラチノサイトにおけるOBPの発現を促進するために用いられる、項目1に記載のOBP発現促進剤。
(3)OBP活性が低下した皮膚におけるOBPの発現を促進するために用いられる、項目1または2に記載のOBP発現促進剤。
(4)皮膚の保湿機能および/またはバリア機能を向上させるために用いられる、項目1~3のいずれか1項に記載のOBP発現促進剤。
(5)有害物質による皮膚へのダメージを低減させるために用いられる、項目1~4のいずれか1項に記載のOBP発現促進剤。
(6)有害物質が、アルデヒド、脂肪酸、ならびに大気汚染物質から成る群より選択される、項目5に記載のOBP発現促進剤。
(7)百合エキス、セイヨウバラエキス、および桜の花エキスから成る群より選択される物質を有効成分として含有するOBP発現促進剤を適用することを含む、美容方法または非治療的方法。
(8)OBPの発現の促進における百合エキス、セイヨウバラエキス、および桜の花エキスから成る群より選択される物質の使用。
(9)百合エキス、セイヨウバラエキス、および桜の花エキスから成る群より選択される物質を有効成分として含有するOBP発現促進剤を含有する皮膚外用剤。
(10)百合エキス、セイヨウバラエキス、および桜の花エキスから成る群より選択される物質を有効成分として含有する皮膚有害物質抑制剤。
(11)OBPの発現を促進または抑制する物質のスクリーニング方法であって、細胞と該物質を接触させる工程、該細胞におけるOBP発現量を測定する工程、該物質の有無によるOBP発現量の変化を決定する工程を含む方法。
OBP(odorant binding protein;オドラント結合タンパク質)は、多くの動物や昆虫に存在することが知られており、その構造は種によって様々であるものの、3つのジスルフィド結合により結合された6つのシステインが保存されたαヘリックス構造を有する10~30kDaのタンパク質である。脊椎動物では、OBPはリポカリンファミリーの一部であり、逆平行βシートで構成されるβバレルモチーフを有する。ヒトはOBP2A、OBP2B、LCN1の3種類のOBPを有する。OBP2Aは鼻水等に存在し、脂肪酸やアルデヒドに高い親和性を有する。OBP2Bは、前立腺や乳腺に存在し、LCN1は涙に存在する。
本発明の一つの側面は、OBP(odorant binding protein)発現促進剤に関する。いくつかの実施態様において、OBP発現促進剤は、セイヨウバラエキス、桜の花エキス、および百合エキスから成る群より選択される物質を有効成分として含有することができる。OBPの発現促進とは、OBPの転写産物の量、及び/又はタンパク質の量を増加させることを指す。
本発明の一つの側面は、OBP発現促進剤を適用することを含む、美容方法または非治療的方法に関する。いくつかの実施態様において、OBP発現促進剤は、セイヨウバラエキス、桜の花エキス、および百合エキスから成る群より選択される物質を有効成分として含有することができる。かかる方法は、美容を目的とする方法であり、医師や医療従事者による治療に用いられる方法ではない。適用の対象は例えば哺乳動物、特にヒトである。適用部位は例えば、顔、首、頭皮、腕、脚などの皮膚でありうる。適用は、手や塗布具等によってする塗布など、任意の様式で行うことができる。適用の回数、頻度、量等は、所望の効果等に応じて適宜設定される。
本発明の一つの側面は、OBPの発現の促進におけるセイヨウバラエキス、桜の花エキス、および百合エキスから成る群より選択される物質の使用に関する。別の観点から言えば、本発明の一つの側面は、OBPの発現の促進に使用するための、セイヨウバラエキス、桜の花エキス、および百合エキスから成る群より選択される物質に関する。本明細書に開示のデータは、セイヨウバラエキス、桜の花エキス、および百合エキスから成る群より選択される物質がOBPの発現促進に有用であることを実証している。よって、上記の植物エキスを用いて、OBPの発現促進に使用するための組成物を調製することができる。すなわち、本発明の一つの態様は、OBPの発現を促進するための組成物(例えば、皮膚外用剤)の製造におけるセイヨウバラエキス、桜の花エキス、および百合エキスから成る群より選択される物質の使用にも関する。
本発明の一つの側面は、セイヨウバラエキス、桜の花エキス、および百合エキスから成る群より選択される物質を有効成分として含有するOBP発現促進剤を含有する皮膚外用剤に関する。
本発明の一つの側面は、セイヨウバラエキス、桜の花エキス、および百合エキスから成る群より選択される物質を有効成分として含有する皮膚有害物質抑制剤に関する。
本発明の一つの側面は、OBPの発現を促進または抑制する物質のスクリーニング方法に関する。いくつかの実施態様において、本発明に係るスクリーニング方法は、細胞と物質を接触させる工程、細胞におけるOBP発現量を測定する工程、物質の有無によるOBP発現量の変化を決定する工程を含みうる。
角化細胞ヒト表皮細胞はHumedia-KG2(クラボウ)培地にて37℃で培養することにより調製した。三次元表皮モデルの構築では、DPBSに50倍希釈したCellStart(Invitrogen LifeTechnologies)液でコーティングしたセルカルチャーインサート(φ12mm,多孔膜の平均孔径:0.4μm)にCnTPrime培地(CELLnTEC)溶液に希釈したヒト表皮細胞(2.2×105個/500μl)を播種し、CnTPrime培地(CELLnTEC)溶液1mlをインサート下に加えて37℃で3日間培養した。その後、インサート上の培地をビタミンC(50μg/ml)が加えられたCnT-PR-3D培地(CELLnTEC)で500μl、インサート下の培地を1mlに置換し、37℃で1日間培養した。1日後、インサート上の培地を吸い取り、インサート下の培地をビタミンC(50μg/ml)が加えられたCnT-PR-3D培地(CELLnTEC)500μlに置換し、37℃で1日間培養した。この作業を8日間行うことで三次元表皮モデルを構築した。
10μMのOBP2AとOBP2BのsiRNAをLipofectamine RNAiMAX Transfection Reagent(Thermo FisherScientific)とOpti-MEM I Reduced SerumMedia(Thermo FisherScientific)の混合溶液に加え、それを上記方法で培養した表皮細胞に添加し24時間培養することでOBP2A及びOBP2Bのダブルノックダウン細胞を作製した。対照細胞は、前述のノックダウン処理を行わない以外は同じ条件で培養し24時間分化させた。
Autodock(4.2.6)、Pymol(2.2.0)を用いたシミュレーションによりOBPおよび3種の物質(ノネナール、オレイン酸、パルミトレイン酸)の構造解析を行った。結果を図5~7に示す。図5~7は、これらの物質がいずれもOBPの結合ポケットに捕捉されることを示している。
いくつかの植物エキス、すなわち、セイヨウバラエキス、桜の花エキス、百合エキスについて、OBPの転写を促進する効果を細胞で調べた。
皮膚バリア機能のマーカー遺伝子として公知の遺伝子に対して、桜の花エキスが与える効果を調べた。マーカー遺伝子としては、フィラグリン(例えば、「Filaggrin and Skin Barrier Function」doi: 10.1159/000441539を参照)、カリクレイン10(例えば、「Epidermal Barriers」doi: 10.1101/cshperspect.a018218を参照)、カスパーゼ14(例えば、「Phospho-ΔNp63α regulates AQP3, ALOX12B, CASP14 and CLDN1 expression through transcription and microRNA modulation」doi: 10.1016/j.febslet.2013.09.023を参照)を選択した。
桜の花エキスに代えて百合エキスを用いて、実施例5と同様な実験を行った。結果を図12~14に示す。値は対照を1とした際の相対値を示している。
皮膚のバリア機能は、経皮水分蒸散の抑制により評価することができ、経表皮水分蒸散量(TEWL)が小さいほどバリア機能に優れるとみなすことができる。
Claims (11)
- 百合エキス、セイヨウバラエキス、および桜の花エキスから成る群より選択される物質を有効成分として含有することを特徴とする、OBP(odorant binding protein)発現促進剤。
- 表皮細胞および/またはケラチノサイトにおけるOBPの発現を促進するために用いられる、請求項1に記載のOBP発現促進剤。
- OBP活性が低下した皮膚におけるOBPの発現を促進するために用いられる、請求項1または2に記載のOBP発現促進剤。
- 皮膚の保湿機能および/またはバリア機能を向上させるために用いられる、請求項請求項1~3のいずれか1項に記載のOBP発現促進剤。
- 有害物質による皮膚へのダメージを低減させるために用いられる、請求項1~4のいずれか1項に記載のOBP発現促進剤。
- 有害物質が、アルデヒド、脂肪酸、ならびに大気汚染物質から成る群より選択される、請求項5に記載のOBP発現促進剤。
- 百合エキス、セイヨウバラエキス、および桜の花エキスから成る群より選択される物質を有効成分として含有するOBP発現促進剤を適用することを含む、美容方法または非治療的方法。
- OBPの発現の促進における百合エキス、セイヨウバラエキス、および桜の花エキスから成る群より選択される物質の使用。
- 百合エキス、セイヨウバラエキス、および桜の花エキスから成る群より選択される物質を有効成分として含有するOBP発現促進剤を含有する皮膚外用剤。
- 百合エキス、セイヨウバラエキス、および桜の花エキスから成る群より選択される物質を有効成分として含有する皮膚有害物質抑制剤。
- OBPの発現を促進または抑制する物質のスクリーニング方法であって、
細胞と該物質を接触させる工程、
該細胞におけるOBP発現量を測定する工程、
該物質の有無によるOBP発現量の変化を決定する工程
を含む方法。
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