WO2022210296A1 - オキシトシンシグナル増強剤及びオキシトシン誘発性角化細胞増殖促進剤 - Google Patents
オキシトシンシグナル増強剤及びオキシトシン誘発性角化細胞増殖促進剤 Download PDFInfo
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- WO2022210296A1 WO2022210296A1 PCT/JP2022/014125 JP2022014125W WO2022210296A1 WO 2022210296 A1 WO2022210296 A1 WO 2022210296A1 JP 2022014125 W JP2022014125 W JP 2022014125W WO 2022210296 A1 WO2022210296 A1 WO 2022210296A1
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- Prior art keywords
- oxytocin
- extract
- ginger
- keratinocyte proliferation
- addition
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Definitions
- the present invention provides an oxytocin signal enhancer and an oxytocin-induced keratinocyte proliferation promoter.
- Oxytocin is a peptide hormone, also known as the "love hormone” or “happiness hormone”, and it works as a neurohormone, neurotransmitter, or neuroregulator. Its known effects include anti-anxiety, stress relief, bond formation, appetite suppression, and analgesia. Oxytocin receptors are confirmed to be expressed in various tissues throughout the body, such as the central nervous system, uterus, mammary gland, skin, fat, kidney, heart, thymus, and pancreas, and play physiological roles in various parts of the body.
- Non-Patent Document 1 Non-Patent Document 1
- Patent Document 2 Regarding the direct action of oxytocin on the skin, it has the effect of improving wrinkles and skin flexibility (Patent Document 2), and increases the production of ingredients that increase elasticity by acting on fibroblasts (Patent Document 3).
- Patent Document 4 As for the indirect action, it has been reported that an increase in the amount of oxytocin in the body improves the texture of the skin (Patent Document 4). From these findings, it can be speculated that enhancing the action of oxytocin in the skin will bring about skin improvement.
- Patent Document 2 discloses an oxytocin production accelerator containing rose oil, ethyltrimethylcyclopentenylbutenol, methyltrimethylcyclopentenylpentanol, and hexahydrohexamethylcyclopentabenzopyran.
- Patent Document 1 discloses that stimulation such as massage increases the amount of skin oxytocin.
- Patent Document 3 discloses that cinnamon bark extract increases the number of oxytocin receptors in fibroblasts. However, nothing provides a means to amplify the oxytocin response.
- An object of the present invention is to provide an oxytocin signal enhancer and an oxytocin-induced keratinocyte proliferation promoter.
- shell ginger leaf extract and/or ginger extract have a high oxytocin signal enhancing effect and oxytocin-induced keratinocyte proliferation promoting effect, and completed the following invention.
- rice field (1) An oxytocin signal enhancer containing as an active ingredient an shell ginger leaf extract and/or a ginger extract.
- An oxytocin-induced keratinocyte proliferation-promoting agent containing shell ginger leaf extract and/or ginger extract as active ingredients.
- a drug containing an oxytocin signal enhancer and/or an oxytocin-induced keratinocyte proliferation promoter can be provided. If the proliferation of oxytocin-induced keratinocytes can be promoted by enhancing the oxytosy signal, it is expected to prevent or improve conditions and diseases in various tissues including the skin.
- FIG. 1 shows the change in the fluorescence intensity ratio when the Alpinia speciosa leaf extract was added in Experiment 3.
- FIG. A change in the fluorescence intensity ratio value represents a change in the intracellular calcium ion concentration.
- the horizontal axis indicates time (seconds), and the vertical axis indicates the fluorescence intensity ratio (f340 nm/f380 nm).
- the first addition of oxytocin alone was carried out for 2 minutes (1st OT was applied for 2 minutes), and after the reaction due to the addition of 1st OT was completed, the shell ginger leaf extract (extract) was added. Two minutes after the addition of the extract, the second oxytocin addition was performed for 2 minutes (2 nd OT applied for 2 minutes).
- FIG. 2 is a graph showing changes in the fluorescence intensity ratio when the Alpinia speciosa leaf extract was added in Experiment 3.
- 3 is a graph showing changes in fluorescence intensity ratio when ginger extract was added in Experiment 3.
- FIG. 4 is a graph showing changes in fluorescence intensity ratio when shell ginger leaf extract and ginger extract were added in Experiment 3.
- FIG. 5 is a graph showing changes in the fluorescence intensity ratio when no candidate sample was added in Experiment 3;
- the amount of change in the fluorescence intensity ratio (f340 nm/f380 nm) in the case of the first addition of oxytocin alone was assumed to be 100% (change due to 1 st OT), and the second addition of oxytocin was performed for 2 minutes without adding the candidate sample.
- the relative value of the amount of change in the fluorescence intensity ratio ( f340 nm/f380 nm) (change due to 2nd OT) is shown.
- the present inventors discovered that shell ginger leaf extract and/or ginger extract have a high oxytocin signal enhancing effect and an oxytocin-induced keratinocyte proliferation promoting effect. Based on these findings, the present invention provides an oxytocin signal-enhancing agent and an oxytocin-induced keratinocyte proliferation-promoting agent containing as an active ingredient an Alpinia alba extract and/or a ginger extract. In one aspect, the oxytocin-induced keratinocyte proliferation-promoting effect is achieved through oxytocin signal enhancement.
- Oxytocin (CAS number: 50-56-6) is a peptide hormone (Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly) consisting of 9 amino acids. It is one of the posterior pituitary hormones.
- Oxytocin signal enhancement is to enhance the response by oxytocin. You can check it by measuring it (https://www.dojindo.co.jp/technical/beginner/calcium1.pdf). It can be determined by measuring changes in intracellular calcium ion concentration using a microscope capable of measuring fluorescence intensity or a high-throughput calcium imaging method. For example, as described in Examples, when the oxytocin signal enhancer increases the oxytocin signal-enhancing intracellular calcium ion concentration compared to the state in which only oxytocin is applied (control), there is an oxytocin signal-enhancing effect. can be judged.
- the increase in calcium ion concentration is enhanced with a statistically significant difference (e.g., Student's t-test) with a significance level of 5% when the candidate drug is added, or, e.g., 5% or more, 10% 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, 200% or more, 300% or more, 400% or more, Or it can mean that it is enhanced by 500% or more.
- Calcium ion influx may be measured by any known technique, such as, but not limited to, another method such as intracellular calcium imaging.
- Such an oxytocin signal enhancement effect can be measured by various methods including in vivo, in vitro, ex vivo, etc. For example, by administering a test substance to cells such as skin cells such as keratinocytes or fibroblasts, central nerve cells, uterine cells, mammary gland cells, adipocytes, and determining changes in intracellular calcium ion concentration in the cells, oxytocin signals can be detected. Enhancement can be determined. Alternatively, for example, in vivo or ex vivo methods are employed such as measuring changes in intracellular calcium ion concentration in samples such as tissues/models such as skin, central nervous system, uterus, mammary gland, fat after administration to mammals. good too. However, the measuring method is not limited to the above method, and any other method may be adopted.
- Oxytocin-induced keratinocyte proliferation promotion refers to the promotion of keratinocyte proliferation by oxytocin.
- the oxytocin-induced keratinocyte proliferation-promoting effect is achieved through enhancement of oxytocin signals.
- Keratinocyte proliferation can be detected using, for example, proliferation markers such as BrdU, Ki67, MCM2, and PCNA, or using tetrazolium salts (such as MTT) that colorize by utilizing the reduction reaction of living cells.
- a proliferation marker may be used, for example, using an antibody against the proliferation marker such as a fluorescently-labeled anti-BrdU antibody, and the intensity of the signal emitted from the antibody may be measured.
- the signal intensity emitted from the antibody against the proliferation marker is higher than the state in which nothing is applied to the cultured epidermal cells or the state in which only oxytocin is applied (control) when an oxytocin signal enhancer is applied.
- the keratinocyte proliferation effect can be arbitrarily selected from an in vitro method using keratinocytes, an ex vivo method using a skin model or skin tissue, or an in vivo method.
- the shell ginger leaf extract used in the present invention is an extract obtained from shell ginger leaves.
- Alpinia zerumbet is a plant belonging to the family Zingiberaceae, genus Alpinia, which is distributed in tropical to subtropical Asia, and grows naturally in Okinawa Prefecture and Kagoshima Prefecture in Japan.
- Alpinia speciosa leaf extract it is also possible to use a commercially available one as a raw material for cosmetics or a raw material for health foods.
- Alpinia speciosa leaf extract is known to have a fibroblast proliferation-promoting effect (Patent Document 5), a collagen production-promoting effect (Patent Document 6), and the like.
- the ginger extract used in the present invention is an extract obtained from the rhizome of ginger.
- Ginger (Zingiber Officinale Roscoe) is native to tropical Asia and distributed all over the world, and is a plant of the Zingiberaceae family. Ginger extracts that are commercially available as raw materials for cosmetics or health foods can also be used. Ginger extract is known to have antipyretic analgesic, antitumor and other effects.
- extracts can be easily dried, purified, and extracted from the above plants by known methods, and are readily available commercially. It can be used raw or dried, but it can also be used as an extract, dried product, dried powder, raw material powder, squeezed liquid, etc., and it is possible to appropriately select which form to use. and may be subjected to treatment such as sterilization as necessary.
- the extraction method of the above extract can be performed, for example, by solvent extraction.
- solvent extraction the whole or part of the plant is optionally dried and optionally chopped or ground before being treated with an aqueous extractant, water, such as cold water, hot water, or boiling point or below.
- Hot water, anhydrous or water-containing organic solvents, organic solvents such as ethanol, methanol, ether, 1,3-butylene glycol, propylene glycol, etc. are appropriately selected according to the properties of the raw material and the application of the composition, and the solvent is heated at room temperature. Or it is extracted by heating and using.
- the extraction method is not limited to solvent extraction, and may be a conventional method known in the art.
- the form of the above-mentioned extract is not limited to the liquid extract itself, but may be one obtained by diluting or concentrating it by a conventional technique. good too.
- the extraction solvent used in the present invention is preferably a polar solvent such as water, a lower alcohol, or a liquid polyhydric alcohol. , particularly water, or lower alcohols such as methanol, ethanol or 1,3-butylene glycol are preferred.
- the lower alcohol may be, for example, a hydrous lower alcohol, in which case the water content is, for example, 0-10 v/v%, 10-40 v/v%, 20-30 v/v%, 30-50 v/v%. , 50 to 80 v/v%, 80 to 99.5 v/v%, and the like.
- the lower alcohol may be, for example, a C1-C5 lower alcohol.
- the oxytocin signal-enhancing agent and/or oxytocin-induced keratinocyte proliferation-promoting agent of the present invention can be in any form such as a transdermal agent or an oral agent.
- transdermal agents are preferred from the viewpoint of enhancing oxytocin signals in the skin.
- the agent of the present invention can be administered by various administration routes such as transdermal and oral administration. can be appropriately determined according to their types, purposes, forms, usage methods, and the like.
- the present application also provides a composition containing the agent of the present invention.
- the composition of the invention may be a cosmetic composition or a food composition.
- the composition of the present invention may be, for example, a composition for enhancing oxytocin signaling and/or promoting oxytocin-induced keratinocyte proliferation, or improving skin condition via such actions. .
- the present application aims to enhance the oxytocin signal and/or promote the proliferation of oxytocin-induced keratinocytes by administering the agent or composition of the present invention to a subject, or to treat skin conditions mediated by such actions.
- a cosmetic method for improvement is also provided.
- the method of the present invention may be a cosmetic method and not a treatment by a doctor or medical practitioner.
- the agent or composition of the present invention can be administered by any route such as external administration or oral administration.
- the form of external administration can be arbitrarily selected, for example, cream, milky lotion, liquid, sheet, spray, gel, and the like.
- Oral administration forms can be arbitrarily selected, for example, tablets, supplements, beverages, powders, and the like.
- the cosmetic composition of the present invention may be various cosmetics such as milky lotions, creams, serums, lotions, packs, facial cleansers, soaps, body soaps, shampoos, etc., and may be in the form of liquids, milky lotions, creams, solids, and sheets. It may be in various forms such as a form, spray form, gel form, foam form, and powder form.
- the food composition of the present invention may be powder, beverage, or tablet, and may be in various forms such as powder, liquid, solid, granules, granules, paste, and gel.
- the frequency of administration is once every 4 weeks, once every 2 weeks, once a week, once every 3 days, once every 2 days, once a day, twice a day, and 3 times a day. , 4 times a day, 5 times a day, each time administration, etc. can be arbitrarily selected, but are not limited to these.
- the amount of shell ginger leaf extract and/or ginger extract in the agent or composition of the present invention can be appropriately determined according to their type, purpose, form, method of use, and the like.
- the amount of shell ginger leaf extract and/or ginger extract is 0.0001 to 100% by weight, 0.0001 to 90% by weight, 0.001 to 50% by weight, 0.01 to 5% by weight, based on the total weight of the agent or composition of the present invention. 0.01-1% by weight, 0.01-0.5% by weight, 0.05-0.2% by weight, 0.1-0.15% by weight, 0.15% by weight, 0.1% by weight, etc., but limited if the effect of the present invention is exhibited not.
- the agent and composition of the present invention can be produced using a conventional method in a formulation that appropriately combines excipients, carriers and/or diluents and other ingredients according to the dosage form.
- Additives can be arbitrarily selected and used together as needed. Additives include excipients, colorants, preservatives, thickeners, binders, disintegrants, dispersants, stabilizers, gelling agents, antioxidants, surfactants, preservatives, pH adjusters, etc. As for, known ones can be appropriately selected and used.
- Experiment 1 Selection of Samples
- Candidate samples were a 1,3-butylene glycol dilution of shell ginger (trade name: shell ginger extract BG) purchased from Maruzen Pharmaceutical from the cosmetic material library, and ginger purchased from Ichimaru Falcos.
- 300 types of candidate samples were selected, including naturally-derived and synthetic components such as ethanol-diluted Ginger extract (trade name: ginger extract E) and other plant extracts.
- the sample was adjusted to 20% by weight using DMSO, and diluted to the following concentrations using extracellular fluid during the experiment. As a control, an extracellular solution containing the same amount of DMSO was used.
- Experiment 2 Cell Culture Normal human epidermal keratinocytes purchased from Kurabo were used. Addition factors (hydrocortisone 0.67 mg/mL, bovine pituitary extract 0.4%, insulin 10 mg/mL, EGF 0.1 ⁇ g/ mL) (HumediaGG growth factor set, etc. (Kurabo)) was added, and these cells were cultured according to the operating procedure.
- Experiment 3 Screening for Oxytocin Signal-Enhancing Substances by Calcium Imaging Method Screening for oxytocin signal-enhancing substances was performed by measuring the intracellular calcium ion concentration of the epidermal keratinocytes cultured by the method described above. After attaching cells to a glass chamber surface-treated with collagen, Fura-2AM (Sigma-Aldrich, etc.), a calcium-sensitive fluorescent dye, was added to the extracellular solution (NaCl 150 mM, KCl 5 mM, CaCl 2 1.8 mM, MgCl 2 ).
- Fura-2AM Sigma-Aldrich, etc.
- the chamber was placed on the stage of a phase-contrast microscope (manufactured by Olympus), and the cells were irradiated alternately with near-ultraviolet excitation light of 340 nm and 380 nm using ORCA-ER manufactured by Hamamatsu Photonics. Fluorescence intensity was measured by measuring and calculating the fluorescence ratio (510 nm) of the amount of light emitted from one cell according to the excitation wavelength using HCImage analysis software. A 20% solution was prepared using DMSO with the concentration of each sample of the active ingredient being stored as 100% (stored at -40°C). The extracellular solution was used to dissolve the final concentration of 0.1%, and the test solution was freshly prepared.
- Extracellular fluid containing the same amount of DMSO was used as a control.
- Oxytocin (CAS number: 50-56-6) was purchased from Peptide Institute, dissolved in ultrapure water, and diluted to a concentration of 1 ⁇ M using extracellular fluid.
- Fig. 1 shows the state of the reaction when shell ginger leaf extract is added.
- the amount of change in the fluorescence intensity f340/f380 ratio obtained in response to the first addition of oxytocin alone was taken as 100%, and the second addition of oxytocin after applying or not applying each candidate sample.
- the addition of oxytocin alone increased the intracellular calcium ion concentration
- the addition of shell ginger leaf extract and then oxytocin further increased the intracellular calcium ion concentration (Figs. 1 and 2).
- addition of ginger extract Fig.
- FIG. 4 shows the results when oxytocin alone was applied twice at the same time points (about 300 seconds and about 700 seconds after the start of measurement) as when the candidate sample was added without adding the candidate drug. There was almost no change in the second oxytocin reaction compared to the first oxytocin reaction.
- Experiment 4 Oxytocin-Induced Keratinocyte Proliferation Promoting Action by Alpinia speciosa Leaf Extract
- Alpinia speciosa leaf extract which was determined to have an oxytocin signal enhancement effect in Experiment 3, promotes keratinocyte proliferation through oxytocin signal enhancement.
- keratinocyte proliferation was measured when stimulated with shell ginger leaf extract in the presence or absence of oxytocin.
- FIG. 6 is a graph showing the absorbance (A450 nm) when the shell ginger extract was added with or without the addition of oxytocin in Experiment 4.
- FIG. 6 The addition of oxytocin alone significantly promoted the proliferation of keratinocytes compared to the case of no oxytocin addition (FIG. 6, left).
- no significant increase in the proliferation of keratinocytes was observed in the absence of oxytocin even when the Alpinia speciosa leaf extract alone was added (the right gray bar in FIG. 6).
- the Alpinia speciosa leaf extract was added in addition to oxytocin, the proliferation of keratinocytes significantly increased compared to the case of oxytocin alone (open bar on the right in FIG. 6).
- shell ginger leaf extract has the effect of promoting oxytocin-induced keratinocyte proliferation.
- results of Experiments 2 and 3 suggest that ginger extract also has the same oxytocin-induced keratinocyte proliferation-promoting effect as shell ginger extract.
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Abstract
Description
(1)月桃葉エキス及び/又はショウキョウエキスを有効成分として含有する、オキシトシンシグナル増強剤。
(2)月桃葉エキス及び/又はショウキョウエキスを有効成分として含有する、オキシトシン誘発性角化細胞増殖促進剤。
(3)オキシトシンシグナル増強を介し角化細胞増殖を促進する、(2)に記載のオキシトシン誘発性角化細胞増殖促進剤。
以下の実験1~3を行った。
実験1:試料の選択
候補試料として、化粧品素材ライブラリーの中から丸善製薬から購入した月桃葉の1,3-ブチレングリコール希釈物(商品名:月桃葉エキスBG)、一丸ファルコスより購入したショウキョウのエタノール希釈物(商品名;ショウキョウエキスE)、その他植物の抽出物といった天然由来成分や合成成分を含め、300種類の候補試料を選択した。試料はDMSOを用いて20重量%となるように調整し、実験時に細胞外液を用いて下記の濃度に希釈した。対照としてDMSOが同程度含まれる濃度の細胞外液を用いた。
クラボウより購入した正常ヒト表皮角化細胞を用いた。無血清基礎培地(Epilife(Thermo Fisher Scientific社)又はHumedia KG2(クラボウ社))に、添加因子(ハイドロコルチゾン0.67 mg/mL、ウシ脳下垂体エキス0.4%、インスリン 10 mg/mL、EGF 0.1 μg/mL)(HumediaGG増殖因子セットなど(クラボウ))を加え、操作手順書に従いこれらの細胞を培養した。
上述の方法で培養した表皮角化細胞の細胞内カルシウムイオン濃度を測定することによりオキシトシンシグナル増強物質のスクリーニングを行った。コラーゲンで表面処理したガラスチャンバーに細胞を付着させた後に、カルシウム感受性蛍光色素であるFura-2AM(Sigma-aldrich社等)を細胞外液(NaCl 150 mM, KCl 5 mM, CaCl2 1.8 mM, MgCl2 1.2 mM, D-glucose 10 mM, HEPES 25 mMを超純水に溶かし、NaOHでpHを7.4に調整した水溶液)に溶解し、細胞にウエル内で5μMとなるように添加した。添加後室温で60分間インキュベーションを行い、細胞内へ蛍光色素の取込みを行った。取込み終了後、細胞に非特異的に結合した蛍光色素を細胞外液で洗浄後、新しい細胞外液を添加し15分間静置した。静置後、チャンバーを位相差顕微鏡(オリンパス社製)のステージ上に載せ、浜松ホトニクス社製ORCA-ERを用いて340 nmおよび380 nmの近紫外励起光を交互に細胞を照射し、各々の励起波長に応じ一つの細胞から放出される光量の蛍光比(510 nm)をHCImage解析ソフトにより、測定・算出することで蛍光強度を測定した。保存している原体各試料濃度を100%としDMSOを用いて20%溶液を作製した(-40℃保存)。最終濃度が0.1%となるように細胞外液を用いて溶解し、試験溶液を用事調整した。対照として同量のDMSOを含む細胞外液を用いた。オキシトシン(CAS番号:50-56-6)は、ペプチド研究所より購入し、超純水で溶解後、細胞外液を用いて、濃度1μMに希釈した。
次に、実験3でオキシトシンシグナル増強作用があると判断された月桃葉エキスがオキシトシンシグナル増強を介して角化細胞増殖を促進することを確認するために、オキシトシン存在又は非存在下で月桃葉エキスで刺激した場合の角化細胞増殖を測定した。
Claims (3)
- 月桃葉エキス及び/又はショウキョウエキスを有効成分として含有する、オキシトシンシグナル増強剤。
- 月桃葉エキス及び/又はショウキョウエキスを有効成分として含有する、オキシトシン誘発性角化細胞増殖促進剤。
- オキシトシンシグナル増強を介し角化細胞増殖を促進する、請求項2に記載のオキシトシン誘発性角化細胞増殖促進剤。
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BUSNELLI, M. ; RIMOLDI, V. ; VIGANO, P. ; PERSANI, L. ; DI BLASIO, A.M. ; CHINI, B.: "Oxytocin-induced cell growth proliferation in human myometrial cells and leiomyomas", FERTILITY AND STERILITY, ELSEVIER, AMSTERDAM, NL, vol. 94, no. 5, 1 October 2010 (2010-10-01), NL , pages 1869 - 1874, XP027321374, ISSN: 0015-0282 * |
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