JP2024004964A - APJ expression promoter - Google Patents
APJ expression promoter Download PDFInfo
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- JP2024004964A JP2024004964A JP2022104889A JP2022104889A JP2024004964A JP 2024004964 A JP2024004964 A JP 2024004964A JP 2022104889 A JP2022104889 A JP 2022104889A JP 2022104889 A JP2022104889 A JP 2022104889A JP 2024004964 A JP2024004964 A JP 2024004964A
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- apj
- expression
- skin elasticity
- extract
- present
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Abstract
Description
本発明は、APJ発現促進剤に関する。 The present invention relates to an APJ expression promoter.
皮膚弾力は、見た目の年齢や外観に影響が大きく、皮膚弾力を維持、改善することは、美容上の大きな課題である。皮膚弾力は、コラーゲン、エラスチン、ヒアルロン酸といった、真皮層のマトリックスに関する研究が多くなされている。例えば、真皮層のコラーゲンの量が大きく影響することはよく知られており、これまでに、コラーゲンの産生促進させることで皮膚の加齢変化を予防・改善する各種成分がみいだされている。また、線維芽細胞において発現するインテグリンなどの接着分子を介して、線維芽細胞が細胞外マトリクスと相互作用し、かかる相互作用がハリに関与することも知られている。 Skin elasticity has a large effect on apparent age and appearance, and maintaining and improving skin elasticity is a major cosmetic issue. Regarding skin elasticity, much research has been conducted on the matrix of the dermal layer, such as collagen, elastin, and hyaluronic acid. For example, it is well known that the amount of collagen in the dermal layer has a large effect, and various ingredients have been discovered that prevent and improve aging changes in the skin by promoting collagen production. It is also known that fibroblasts interact with extracellular matrix through adhesion molecules such as integrins expressed in fibroblasts, and that this interaction is involved in firmness.
更に、7回膜貫通型のGタンパク質共役型の受容体であるAPJ（AGTRL1：Angiotensin receptor like 1）の発現を増強させ血管を安定化することにより皮膚弾力を改善できることが本発明者らにより発見された。本発明者らはかかる発見に基づき、APJ発現を指標とした皮膚弾力改善剤のスクリーニング方法、並びにジュウヤクエキス、サクラリーフエキス、ニームリーフエキスを含むAPJ発現促進剤およびそれを含む皮膚弾力改善剤を報告している（特許文献１）。APJ発現を指標とした皮膚弾力を改善する物質の更なる探索が求められる。 Furthermore, the present inventors discovered that skin elasticity can be improved by stabilizing blood vessels by enhancing the expression of APJ (AGTRL1: Angiotensin receptor like 1), a seven-transmembrane G protein-coupled receptor. It was done. Based on these findings, the present inventors have developed a method for screening skin elasticity improving agents using APJ expression as an indicator, as well as APJ expression promoters containing Juyaku extract, cherry leaf extract, and neem leaf extract, and skin elasticity improving agents containing the same. reported (Patent Document 1). Further exploration of substances that improve skin elasticity using APJ expression as an indicator is required.
本発明は、新たなAPJ発現促進剤、それを含む皮膚弾力改善剤、及びそれを用いた皮膚弾力を改善するための方法を提供することを課題とする。 An object of the present invention is to provide a new APJ expression promoter, a skin elasticity improving agent containing the same, and a method for improving skin elasticity using the same.
本発明者らはAPJの発現を促進する新規な物質を探索すべく鋭意研究した結果、本発明に至った。 The present inventors conducted intensive research to search for a new substance that promotes the expression of APJ, and as a result, they arrived at the present invention.
本発明は、下記の発明に関する：
（1）ゲンノショウコエキスからなる、APJ発現促進剤。
（2）（1）に記載のAPJ発現促進剤を含む、皮膚弾力改善剤。
（3）（2）に記載の皮膚弾力改善剤を対象に投与することによりAPJ発現促進を介して対象の皮膚弾力を改善するための美容目的の方法。
The present invention relates to the following inventions:
(1) An APJ expression promoter consisting of Gennoshoko extract.
(2) A skin elasticity improving agent containing the APJ expression promoter described in (1).
(3) A cosmetic method for improving the skin elasticity of a subject by promoting APJ expression by administering the skin elasticity improving agent according to (2) to the subject.
ゲンノショウコエキスによりAPJの発現を促進することができる。APJの発現が促進されると、血管の安定化が図られ、皮膚弾力が改善される。皮膚弾力を改善することにより、シワ、たるみといった肌の問題を改善することができる。 Expression of APJ can be promoted by Gennoshoko extract. When APJ expression is promoted, blood vessels are stabilized and skin elasticity is improved. By improving skin elasticity, skin problems such as wrinkles and sagging can be improved.
本発明は、ゲンノショウコエキスがAPJ発現促進作用を有するという発明者らの知見に基づくものであり、皮膚弾力を改善するためのAPJ発現促進剤に関する。一実施形態では、本発明のAPJ発現促進剤は、ゲンノショウコエキスからなる又は含む。 The present invention is based on the findings of the inventors that Gennoshoko extract has an effect of promoting APJ expression, and relates to an APJ expression promoter for improving skin elasticity. In one embodiment, the APJ expression promoter of the present invention consists of or contains Gennoshoko extract.
ゲンノショウコ（Geranium thunbergii）は、「現（験）之証拠」「玄草」「ロウカクソウ」「ミコシグサ」「ウメズル」等とも称され、日本各地、中国などのアジア地域に広く分布するフウロソウ科フウロソウ属の多年草である。ゲンノショウコは、内服による整腸、止瀉、胃弱、食欲不振、消化不良等に対する効果、塗布によるかぶれ、霜焼け，腫れ等に対する効果、抗光老化、グランザイムB抑制効果、JAK（ヤヌスキナーゼ）阻害効果等が知られている（特許文献２～４）。ゲンノショウコエキスは、ゲンノショウコの葉、茎、花、根などの植物体、特に地上部を抽出した抽出物をいう。 Geranium thunbergii, also known as ``experimental evidence,'' ``genso,'' ``geranium,'' ``geranium thunbergii,'' and ``geranium thunbergii,'' is a member of the genus Geranium of the family Geranium, which is widely distributed throughout Japan, China, and other Asian regions. It is a perennial plant. Gennoshoko has effects on intestinal regulation, antidiarrhea, stomach weakness, loss of appetite, indigestion, etc. when taken internally, effects on rashes, frostbite, swelling, etc. when applied, anti-photoaging, granzyme B inhibitory effects, JAK (Janus kinase) inhibitory effects, etc. are known (Patent Documents 2 to 4). Gennoshoko extract refers to an extract obtained from plants such as leaves, stems, flowers, roots, etc., especially the above-ground parts of Gennoshoko.
抽出物は、化粧品原料や健康食品材料として市販のものを使用してもよく、常法により得てもよい。抽出方法は特に限定されるものではないが、溶媒を用いた抽出法が好ましい。抽出を行う際には、原料植物を抽出溶媒とともに常温又は加熱して浸漬または加熱還流した後、濾過し、濃縮して得ることができる。植物体をそのまま使用することもできるが、顆粒状や粉末状に粉砕して抽出に供した方が、穏和な条件で短時間に高い抽出効率で有効成分の抽出を行うことができる。抽出温度は特に限定されるものではなく、粉砕物の粒径や溶媒の種類等に応じて適宜設定すればよい。通常は、室温から溶媒の沸点までの範囲内で設定される。また、抽出時間も特に限定されるものではなく、粉砕物の粒径、溶媒の種類、抽出温度等に応じて適宜設定すればよい。さらに、抽出時には、撹拌を行ってもよいし、撹拌せず静置してもよいし、超音波を加えてもよい。 The extract may be commercially available as a cosmetic raw material or health food material, or may be obtained by a conventional method. The extraction method is not particularly limited, but an extraction method using a solvent is preferred. When performing extraction, the raw material plant can be immersed or heated under reflux with an extraction solvent at room temperature or with heating, and then filtered and concentrated. Although it is possible to use the plant as it is, it is better to grind it into granules or powder and use it for extraction to extract the active ingredients in a short time and with high extraction efficiency under mild conditions. The extraction temperature is not particularly limited and may be appropriately set depending on the particle size of the pulverized material, the type of solvent, etc. Usually, it is set within the range from room temperature to the boiling point of the solvent. Further, the extraction time is not particularly limited, and may be appropriately set depending on the particle size of the pulverized material, the type of solvent, the extraction temperature, etc. Furthermore, during extraction, stirring may be performed, the mixture may be left standing without stirring, or ultrasonic waves may be applied.
抽出溶媒としては、通常抽出に用いられる溶媒であれば任意に用いることができ、例えば、例えば水、生理食塩水、リン酸緩衝液、ホウ酸緩衝液などの水性溶媒、エタノール、プロピレングリコール、1、3-ブチレングリコール、グリセリン等のアルコール類、クロロホルム、ジクロルエタン、四塩化炭素、アセトン、酢酸エチル、ヘキサン等の有機溶媒、含水エタノール、含水プロピレングリコール、含水1、3-ブチレングリコール、含水グリセリン等の含水アルコール類といった含水有機溶媒を、それぞれ単独あるいは組み合わせて用いることができる。 As the extraction solvent, any solvent commonly used for extraction can be used, such as water, physiological saline, aqueous solvents such as phosphate buffer, borate buffer, ethanol, propylene glycol, etc. , 3-butylene glycol, alcohols such as glycerin, organic solvents such as chloroform, dichloroethane, carbon tetrachloride, acetone, ethyl acetate, hexane, etc., hydrous ethanol, hydrous propylene glycol, hydrous 1,3-butylene glycol, hydrous glycerin, etc. Hydrous organic solvents such as hydrous alcohols can be used alone or in combination.
含水有機溶媒の例として、含水１，３－ブチレングリコール等の含水低級アルコール（例えば、Ｃ１～Ｃ４）を用いてもよく、その場合の含水率は、例えば0～10v/v％、10～40v/v％、20～30v/v％、30～40v/v％、30～50v/v％、60～70v/v％、50～80v/v％、80～99.5v/v％等であってもよい。 As an example of the water-containing organic solvent, a water-containing lower alcohol (for example, C1 to C4) such as water-containing 1,3-butylene glycol may be used, and the water content in this case is, for example, 0 to 10 v/v%, 10 to 40 v /v%, 20-30v/v%, 30-40v/v%, 30-50v/v%, 60-70v/v%, 50-80v/v%, 80-99.5v/v%, etc. Good too.
このような抽出操作により、有効成分が抽出され、溶媒に溶け込む。抽出物を含む溶媒は、そのまま使用してもよいが、滅菌、洗浄、濾過、脱色、脱臭等の慣用の精製処理を加えてから使用してもよい。また、必要により凍結乾燥といった乾燥処理などにより濃縮あるいは任意の溶媒で希釈してから使用してもよい。さらに、溶媒を全て揮発させて固体状（乾燥物）としてから使用してもよいし、該乾燥物を任意の溶媒に再溶解してから使用してもよい。 Through such an extraction operation, the active ingredient is extracted and dissolved in the solvent. The solvent containing the extract may be used as is, or may be used after being subjected to conventional purification treatments such as sterilization, washing, filtration, decolorization, and deodorization. Further, if necessary, it may be used after being concentrated by a drying process such as freeze-drying or diluted with an arbitrary solvent. Furthermore, it may be used after all the solvent has been volatilized to form a solid (dried product), or the dried product may be used after being redissolved in an arbitrary solvent.
また、原料の植物を圧搾することにより得られる圧搾液にも抽出物と同様の有効成分が含まれているので、抽出物の代わりに圧搾液を使用することもできる。 Moreover, since the pressed liquid obtained by pressing the raw material plant also contains the same active ingredients as the extract, the pressed liquid can be used instead of the extract.
本発明のAPJ発現促進剤は、ゲンノショウコエキスからなってもよく、又は有効成分として含有してもよい。また、本発明の皮膚弾力改善剤は、本発明のAPJ発現促進剤を含有する。本発明の皮膚弾力改善剤は、APJ発現を促進し、発現が促進されたAPJが血管に作用し安定化することにより、血管周囲でコラーゲン合成が促進され、皮膚弾力を改善することができる。 The APJ expression promoter of the present invention may consist of Gennoshoko extract, or may contain it as an active ingredient. Furthermore, the skin elasticity improving agent of the present invention contains the APJ expression promoter of the present invention. The skin elasticity improving agent of the present invention promotes APJ expression, and the APJ whose expression is promoted acts on and stabilizes blood vessels, thereby promoting collagen synthesis around blood vessels and improving skin elasticity.
APJは、血管系、神経系、脂肪細胞などで広く発現が報告されている7回膜貫通型のGタンパク質共役型の受容体である。APJの発現は、心臓では心筋収縮作用、神経系ではバソプレシンの発現の制御、血管やリンパ管の安定、血管形成、体液の調節機構等に関与することが示されている。 APJ is a seven-transmembrane G protein-coupled receptor that is widely reported to be expressed in the vascular system, nervous system, adipocytes, etc. Expression of APJ has been shown to be involved in myocardial contraction in the heart, regulation of vasopressin expression in the nervous system, stability of blood vessels and lymphatic vessels, angiogenesis, body fluid regulation, etc.
更に、本発明者らにより、APJの発現を促進することにより血管の安定化が起こり血管周囲でコラーゲンが合成され、皮膚弾力が改善することが発見された（特許文献１）。本発明の皮膚弾力改善剤は、APJの発現を増強させることにより皮膚弾力を改善させる。一実施形態では、皮膚弾力の改善は、APJ発現促進による血管の安定化を介する。本発明において、血管の安定化とは、特許文献1に記載のように、皮膚の血管におけるAPJ発現とコラーゲン合成による皮膚弾力との密接な相互作用により、生体内でAPJが周囲のマトリックス環境の物性に応じて発現増強する結果起こる血管構造の安定化を指す。 Furthermore, the present inventors have discovered that by promoting the expression of APJ, blood vessels are stabilized, collagen is synthesized around blood vessels, and skin elasticity is improved (Patent Document 1). The skin elasticity improving agent of the present invention improves skin elasticity by enhancing the expression of APJ. In one embodiment, the improvement in skin elasticity is through stabilization of blood vessels by promoting APJ expression. In the present invention, stabilization of blood vessels means that, as described in Patent Document 1, APJ expression in skin blood vessels and skin elasticity due to collagen synthesis closely interact, so that APJ is stabilized in the surrounding matrix environment in vivo. It refers to the stabilization of vascular structure that occurs as a result of enhanced expression depending on physical properties.
APJ発現の促進は、例えば、生体試料におけるAPJのmRNA量又はタンパク質量が、本発明のAPJ発現促進剤を添加すると、添加しない場合と比べて増加することを指す。増加は、例えば、有意水準を5％とした統計学的有意差（例えばスチューデントのt検定）を有する増加であってもよく、及び／又は、例えば10％以上、20％以上、30％以上、40％以上、50％以上、60％以上、70％以上、80％以上、90％以上、100％以上の増加であってもよい。 Promotion of APJ expression refers to, for example, an increase in the amount of APJ mRNA or protein in a biological sample when the APJ expression promoter of the present invention is added, compared to when it is not added. The increase may be, for example, an increase with a statistically significant difference (e.g., Student's t-test) with a significance level of 5%, and/or, for example, 10% or more, 20% or more, 30% or more, The increase may be 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 100% or more.
APJ発現の測定は、生体試料におけるAPJのmRNA量又はタンパク質量を測定することにより決定されうる。mRNA量の測定としては、定量的PCRやノーザンブロティングなど本技術分野に既知の手法を用いて行うことができる。例えば、実施例に記載のように、APJ mRNAに対するプローブを用いてもよい。タンパク質量についは、ウエスタンブロッティング、免疫染色、FACSなどの本技術分野に既知の任意の手法を用いて行うことができる。例えば、APJに特異的に結合する抗体を使用してもよい。あるいは、例えば特許文献5、特許文献6に記載のようなAPJ発現細胞を用いたスクリーニング系を確立して使用してもよい。 Measurement of APJ expression can be determined by measuring the amount of APJ mRNA or protein in a biological sample. The amount of mRNA can be measured using methods known in the art, such as quantitative PCR and Northern blotting. For example, a probe for APJ mRNA may be used, as described in the Examples. The amount of protein can be determined using any technique known in the art, such as Western blotting, immunostaining, and FACS. For example, antibodies that specifically bind APJ may be used. Alternatively, a screening system using APJ-expressing cells as described in Patent Document 5 and Patent Document 6 may be established and used.
生体試料としては、血管内皮細胞、脂肪細胞など任意であり、APJ発現が測定できれば限定されない。例えば、特許文献１に記載のようにヒト等の動物の皮下脂肪組織から血管形成を誘導して作成した血管モデルにおける血管内皮細胞、ペリサイトといった血管構成細胞でもよく、生体から取得された血管内皮細胞、ペリサイト、又はそれらの継代された細胞であってもよく、株化された細胞であってもよく、実施例に記載のようにヒト臍帯血静脈内皮細胞（HUVEC）、ヒト大動脈内皮細胞（HAEC）、ヒト肺微小血管内皮細胞（HMVEC）等を用いてもよい。あるいは、特許文献５、特許文献６に記載のように、APJ発現細胞を用いてもよい。 The biological sample may be any vascular endothelial cell, adipocyte, etc., and is not limited as long as APJ expression can be measured. For example, as described in Patent Document 1, blood vessel constituent cells such as vascular endothelial cells and pericytes in a blood vessel model created by inducing blood vessel formation from subcutaneous adipose tissue of animals such as humans may be used, or vascular endothelial cells obtained from a living body may be used. cells, pericytes, or their passaged cells, or established cell lines, such as human umbilical cord blood vein endothelial cells (HUVECs) and human aortic endothelial cells, as described in Examples. Cells (HAEC), human pulmonary microvascular endothelial cells (HMVEC), etc. may also be used. Alternatively, APJ-expressing cells may be used as described in Patent Documents 5 and 6.
本発明のAPJ発現促進剤及び皮膚弾力改善剤（以降これらを総称して「本発明の剤」という場合がある。）は、ゲンノショウコエキスを有効成分として含有するが、さらに1種又は2種以上の他の成分、例えば賦形剤、担体及び/又は希釈剤等と組み合わせた組成物とすることもできる。組成物の組成や形態は任意であり、有効成分や用途等の条件に応じて適切に選択すればよい。当該組成物は、その剤形に応じ、賦形剤、担体及び/又は希釈剤等及び他の成分と適宜組み合わせた処方で、常法を用いて製造することができる。 The APJ expression promoter and skin elasticity improving agent of the present invention (hereinafter, these may be collectively referred to as "the agent of the present invention") contain Gennoshoko extract as an active ingredient, and further contain one or more kinds. The composition can also be made in combination with other ingredients such as excipients, carriers and/or diluents. The composition and form of the composition are arbitrary and may be appropriately selected depending on the conditions such as the active ingredient and the intended use. The composition can be manufactured by a conventional method in a formulation in which the composition is appropriately combined with excipients, carriers and/or diluents, and other components depending on the dosage form.
本発明の剤は、化粧品、医薬品、医薬部外品等に配合してヒト及び動物に使用してもよく、各種の飲食品、例えばサプリメントなどの栄養補助食品に配合してヒト及び動物に摂取させてもよいし、或いは医薬製剤としてヒト及び動物に投与してもよい。本発明の剤は経口的にあるいは非経口的（経皮投与、静脈投与、腹腔内投与、等）に適宜に使用され、任意の経路で投与されてもよい。しかしながら、皮膚の血管に作用するよう経皮投与が好ましい。 The agent of the present invention may be incorporated into cosmetics, pharmaceuticals, quasi-drugs, etc. and used for humans and animals, and may be incorporated into various food and drink products, such as nutritional supplements such as supplements, and ingested by humans and animals. Alternatively, it may be administered to humans and animals as a pharmaceutical formulation. The agent of the present invention is appropriately used orally or parenterally (transdermal administration, intravenous administration, intraperitoneal administration, etc.), and may be administered by any route. However, transdermal administration is preferred so as to affect blood vessels in the skin.
本発明を化粧品、医薬品、医薬部外品等の皮膚外用剤に適用する場合、ゲンノショウコエキスの配合量（乾燥質量）は、それらの種類、目的、形態、利用方法などに応じて、適宜決めることができる。例えば、化粧料全量中に、ゲンノショウコエキスをそれぞれ約0.000001重量％～50.0重量％（乾燥量）を配合でき、約0.0001重量％～10.0重量％（乾燥量）、約0.001重量％～1.0重量％（乾燥量）、約0.005重量％～1.0重量％（乾燥量）、約0.01重量％～1.0重量％（乾燥量）、約0.05重量％～0.5重量％（乾燥量）、約0.1重量％～0.5重量％（乾燥量）となるように添加してもよい。 When applying the present invention to external skin preparations such as cosmetics, pharmaceuticals, and quasi-drugs, the amount (dry mass) of Gennoshoko extract to be blended should be determined as appropriate depending on the type, purpose, form, usage method, etc. Can be done. For example, in the total amount of cosmetics, Gennoshoko extract can be blended in amounts of approximately 0.000001% to 50.0% by weight (dry amount), approximately 0.0001% to 10.0% by weight (dry amount), and approximately 0.001% to 1.0% by weight (dry amount). (dry amount), approximately 0.005% to 1.0% by weight (dry amount), approximately 0.01% to 1.0% (dry amount), approximately 0.05% to 0.5% (dry amount), approximately 0.1% to 0.5% by weight % (dry amount).
上記成分に加えて、さらに必要により、本発明の効果を損なわない範囲内で、通常化粧品、医薬品、医薬部外品等等の皮膚外用剤に用いられる成分、例えば酸化防止剤、油分、紫外線防御剤、界面活性剤、増粘剤、アルコール類、粉末成分、色材、水性成分、水、各種皮膚栄養剤等を必要に応じて適宜配合することができる。 In addition to the above ingredients, if necessary, ingredients normally used in external skin preparations such as cosmetics, pharmaceuticals, quasi-drugs, etc., such as antioxidants, oils, and ultraviolet protection, may be added to the extent that does not impair the effects of the present invention. Agents, surfactants, thickeners, alcohols, powder components, colorants, aqueous components, water, various skin nutrients, and the like can be appropriately blended as needed.
さらに、エデト酸二ナトリウム、エデト酸三ナトリウム、クエン酸ナトリウム、ポリリン酸ナトリウム、メタリン酸ナトリウム、グルコン酸等の金属イオン封鎖剤、メチルパラベン、エチルパラベン、ブチルパラベン等の防腐剤、カフェイン、タンニン、ベラパミル、トラネキサム酸及びその誘導体、甘草抽出物、グラブリジン、カリンの果実の熱水抽出物、各種生薬、酢酸トコフェロール、グリチルリチン酸及びその誘導体又はその塩等の薬剤、ビタミンC、アスコルビン酸リン酸マグネシウム、アスコルビン酸グルコシド、アルブチン、コウジ酸等の美白剤、グルコース、フルクトース、マンノース、ショ糖、トレハロース等の糖類なども適宜配合することができる。 Furthermore, metal ion sequestering agents such as disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, preservatives such as methylparaben, ethylparaben, butylparaben, caffeine, tannins, Verapamil, tranexamic acid and its derivatives, licorice extract, glabridin, hot water extract of quince fruit, various herbal medicines, drugs such as tocopherol acetate, glycyrrhizic acid and its derivatives or its salts, vitamin C, magnesium ascorbate phosphate, Whitening agents such as ascorbic acid glucoside, arbutin, and kojic acid, and saccharides such as glucose, fructose, mannose, sucrose, and trehalose may also be appropriately incorporated.
本発明の皮膚外用剤は、外皮に適用される化粧料、医薬部外品等、特に好適には化粧料として適用可能であり、その剤型も皮膚に適用できるものであれば限定されず、溶液系、可溶化系、乳化系、粉末分散系、水-油二層系、水-油-粉末三層系、軟膏、化粧水、ゲル、エアゾール等、任意の剤型が適用される。 The skin external preparation of the present invention can be applied particularly preferably as a cosmetic, such as a cosmetic applied to the outer skin, a quasi-drug, etc., and its dosage form is not limited as long as it can be applied to the skin. Any dosage form can be applied, such as a solution system, solubilized system, emulsion system, powder dispersion system, water-oil two-layer system, water-oil-powder three-layer system, ointment, lotion, gel, aerosol, etc.
本発明の剤を化粧品として用いる場合は、例えば、フェイスクリーム、マッサージクリーム、ボディクリーム、乳液、ローション、美容液、ジェル、パック、クレンジングクリーム、ハンドクリーム、化粧水、ファンデーション、口紅、リップクリーム、ハンドパウダー、ボディシャンプー、浴用化粧品等の形態として用いてもよい。外用製剤であれば、ローション剤、懸濁剤・乳剤、液剤、軟膏剤、貼付剤等の各種形態として使用できる When the agent of the present invention is used as a cosmetic, for example, face cream, massage cream, body cream, emulsion, lotion, serum, gel, pack, cleansing cream, hand cream, lotion, foundation, lipstick, lip balm, hand cream, etc. It may be used in the form of powder, body shampoo, bath cosmetics, etc. External preparations can be used in various forms such as lotions, suspensions/emulsions, solutions, ointments, and patches.
しかしながら、本発明の剤の採り得る形態は、上述のものに限定されるものではなく、例えば錠剤、顆粒剤、散剤、カプセル剤等の経口用固形製剤や、内服液剤、シロップ剤等の経口用液体製剤、又は、注射剤などの非経口用液体製剤など、いずれの形態にも公知の方法により適宜調製することができる。 However, the forms that the agent of the present invention can take are not limited to those mentioned above, and include oral solid preparations such as tablets, granules, powders, and capsules, and oral liquid preparations and syrups. It can be appropriately prepared in any form such as a liquid preparation or a parenteral liquid preparation such as an injection by a known method.
本発明は、それを必要とする対象に本発明のAPJ発現促進剤又は皮膚弾力改善剤を投与することによりAPJ発現促進を介して皮膚弾力を改善する方法にも関する。一実施形態では、それを必要とする対象は、例えば、皮膚における血管の減少、血管構造の不安定化、皮膚弾力の低下、又はAPJ発現の低下が起こっている対象である。皮膚弾力が改善されれば、しわ、たるみの改善が期待される。本明細書の皮膚弾力を改善する方法は、美容を目的とする美容方法に関しており、医師や医療関係者により行われる治療とは区別できる。このような美容方法は、個人的に行われてもよいし、美容室や、化粧品の販売店、エステサロンなどで行われてもよい。 The present invention also relates to a method for improving skin elasticity through promotion of APJ expression by administering the APJ expression promoter or skin elasticity improving agent of the present invention to a subject in need thereof. In one embodiment, a subject in need thereof is, for example, a subject experiencing reduced blood vessels in the skin, destabilization of vasculature, decreased skin elasticity, or decreased APJ expression. If skin elasticity is improved, wrinkles and sagging can be expected to be improved. The method of improving skin elasticity herein relates to a cosmetic method for cosmetic purposes and can be distinguished from treatments performed by doctors and medical personnel. Such beauty methods may be performed personally, or may be performed at a beauty salon, a cosmetics store, a beauty salon, or the like.
さらに、本発明は、皮膚弾力の改善のための薬剤の製造におけるゲンノショウコの使用も提供する。本発明は、APJ発現を促進することにより、皮膚弾力の改善に使用するためのゲンノショウコも提供する。 Furthermore, the present invention also provides the use of Gennoshoko in the manufacture of a medicament for improving skin elasticity. The present invention also provides Gennoshoko for use in improving skin elasticity by promoting APJ expression.
本明細書において言及される全ての文献はその全体が引用により本明細書に取り込まれる。 All documents mentioned herein are incorporated by reference in their entirety.
以下に説明する本発明の実施例は例示のみを目的とし、本発明の技術的範囲を限定するものではない。本発明の技術的範囲は特許請求の範囲の記載によってのみ限定される。本発明の趣旨を逸脱しないことを条件として、本発明の変更、例えば、本発明の構成要件の追加、削除及び置換を行うことができる。 The embodiments of the invention described below are for illustrative purposes only and are not intended to limit the scope of the invention. The technical scope of the present invention is limited only by the claims. Changes in the present invention, such as additions, deletions, and substitutions of constituent elements of the present invention, may be made without departing from the spirit of the present invention.
実験1：試料の調製
ゲンノショウコエキスは、含水１，３ブチレングリコールを抽出溶媒としてゲンノショウコの地上部を抽出し、溶媒を留去後、抽出物を乾燥して得た。このゲンノショウコエキスをジメチルスルホキシド（DMSO）で溶解して調製し、下記培地に最終濃度が0.1％（w/w）となるように添加した。対照として、ゲンノショウコエキスを含まない同量のDMSO溶液を使用した。
Experiment 1: Preparation of sample Gennoshoko extract was obtained by extracting the aerial parts of Gennoshoko using water-containing 1,3-butylene glycol as an extraction solvent, distilling off the solvent, and drying the extract. This Gennoshoko extract was prepared by dissolving it in dimethyl sulfoxide (DMSO), and added to the following medium at a final concentration of 0.1% (w/w). As a control, the same amount of DMSO solution without Gennoshoko extract was used.
実験2：APJ発現の解析
12wellプレートにヒト臍帯血静脈内皮細胞（HUVEC）を105cells/wellで播種し、EGMTM-2(Endothelial cell Growth Medium-2)BulletKit (Lonza, Switzerland)を用いて、コンフルエントまで培養した。その後、実験1で作成したゲンノショウコエキスを含む試料は最終濃度が0.1％（w/w）となるように、又は対照としてのDMSO溶液を添加し、更に培養を行った。培養4時間後、RNeasy（登録商標） Mini Kit(Qiagen,Germany) を用いて、細胞回収、及びトータルRNAを得た。得られたトータルRNAをnano dropにより濃度測定し、RNase free waterで100ng/μlに調整した。その後、TaqManTM RNA-to-CT
TM 1-Step Kit（Applied Biosystems、CA）とヒトAPJ mRNAに対するTaqmanプローブ（Hs00270873、Applied Biosystems、CA）を用いて、APJのmRNA発現量を検出し、内部標準であるβアクチンのmRNA発現量で割った値を比較した。
Experiment 2: Analysis of APJ expression
Human umbilical cord blood vein endothelial cells (HUVEC) were seeded at 10 5 cells/well in a 12-well plate and cultured to confluence using EGM TM -2 (Endothelial cell Growth Medium-2) Bullet Kit (Lonza, Switzerland). Thereafter, the sample containing the Gennoshoko extract prepared in Experiment 1 was further cultured so that the final concentration was 0.1% (w/w), or a DMSO solution was added as a control. After 4 hours of culture, cells were collected and total RNA was obtained using RNeasy (registered trademark) Mini Kit (Qiagen, Germany). The concentration of the obtained total RNA was measured using a nano drop, and the concentration was adjusted to 100 ng/μl with RNase free water. Then, the expression level of APJ mRNA was detected using TaqMan TM RNA-to-C T TM 1-Step Kit (Applied Biosystems, CA) and Taqman probe for human APJ mRNA (Hs00270873, Applied Biosystems, CA), and the internal The value divided by the standard β-actin mRNA expression level was compared.
結果を図１に示す。図１よりゲンノショウコエキスを用いた場合に、対照と比較してAPJの発現が有意に増加した。よって、ゲンノショウコエキスを、APJの発現促進作用を有する物質として特定した。 The results are shown in Figure 1. From FIG. 1, when Gennoshoko extract was used, the expression of APJ was significantly increased compared to the control. Therefore, Gennoshoko extract was identified as a substance that has the effect of promoting APJ expression.
本発明は、ゲンノショウコエキスを有効成分として含有するAPJ発現促進剤の投与により、APJの発現を促進することができ、APJ発現促進により皮膚弾力の改善に有効である。 The present invention can promote the expression of APJ by administering an APJ expression promoter containing Gennoshoko extract as an active ingredient, and is effective in improving skin elasticity by promoting APJ expression.
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