JP5487227B2 - Hyaluronic acid synthase gene expression promoter - Google Patents
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Description
本発明は、ヒアルロン酸合成酵素遺伝子の発現促進剤に関する。 The present invention relates to a hyaluronic acid synthase gene expression promoter.
ヒアルロン酸は、皮膚（表皮及び真皮）、軟骨、関節液などに存在する高分子多糖類であり、細胞間隙への水分の保持、組織内にジェリー状のマトリックスを形成することに基づく細胞の保持、組織の潤滑性と柔軟性の保持、機械的障害等の外力に対する抵抗、および細菌感染の防止など、多くの機能を有している。ヒアルロン酸は、皮膚に多量に存在し、水分を保持する能力が非常に高く、肌のみずみずしさ、ハリ、弾力性に深く関わっており、加齢と共にヒアルロン酸量が減少することに伴い、皮膚のハリが衰え、シワやたるみなどの皮膚老化現象が現れるといわれている。従って、うるおいや張りのある肌を保つためにヒアルロン酸を化粧品等に配合して外からヒアルロン酸を補給することが行われているが、近年、肌の表面からヒアルロン酸を与えるだけでなく、肌の中でヒアルロン酸合成を促進させる薬剤の開発が注目されている。 Hyaluronic acid is a high-molecular polysaccharide present in the skin (epidermis and dermis), cartilage, joint fluid, etc., retains moisture in the cell gap, and retains cells based on the formation of a jelly-like matrix in the tissue. It has many functions such as maintaining the lubricity and flexibility of tissues, resistance to external forces such as mechanical failure, and prevention of bacterial infection. Hyaluronic acid is present in large amounts in the skin and has a very high ability to retain moisture, and is deeply related to the freshness, firmness and elasticity of the skin. It is said that skin aging phenomena such as wrinkles and sagging appear. Therefore, hyaluronic acid is blended into cosmetics and the like to maintain moisture and tension skin, and hyaluronic acid is replenished from the outside. The development of drugs that promote hyaluronic acid synthesis in the skin is drawing attention.
また、熱傷受傷後の治癒過程で、壊死組織の下方から増生してくる肉芽組織の初期から組織全体が肉芽組織に置き換えられるまでの期間では、肉芽中にヒアルロン酸が著しく増加することが知られており（非特許文献１）、熱傷の初期の治療薬としても、ヒアルロン酸産生促進剤が期待されている。 In the healing process after burn injury, hyaluronic acid is known to increase significantly in the granulation during the period from the beginning of the granulation tissue growing from below the necrotic tissue until the entire tissue is replaced with granulation tissue. (Non-patent Document 1), hyaluronic acid production promoters are also expected as an early treatment for burns.
例えば、ウチワサボテン属（Opuntia）に属する植物の果実から得られるカクタスフルーツ果汁、アムラ（Phyllanthus emblica）の植物体またはその抽出物、ショウガ科マンゴージンジャー（Curcuma amada ROXB.）の植物体またはその抽出物等が、ヒト真皮線維芽細胞においてヒアルロン酸の産生を促進させることが報告されている（特許文献１および２）。 For example, Cactus fruit juice obtained from fruits of plants belonging to the genus Opuntia, plant of Phyllanthus emblica or its extract, plant of Ginger family mango ginger (Curcuma amada ROXB.) Or its extract Have been reported to promote hyaluronic acid production in human dermal fibroblasts (Patent Documents 1 and 2).
ヒアルロン酸は、皮膚では角層、表皮及び真皮中に含まれ、ヒトのヒアルロン酸合成に関与する酵素としては、３種類のヒアルロン酸合成酵素（HAS1、HAS2、HAS3）が存在することが報告されている。また、それらヒアルロン酸合成酵素により産生されるヒアルロン酸は、103Da程度〜107Daにおよぶ多様な分子量をとり、その分子量の違いにより多様な生物学的又は物理学的な性質を示すことが知られている。ヒアルロン酸の分子量の違いは、保水力、粘弾性等の物理的な性質に影響し、特に、保湿力の高い高分子ヒアルロン酸は、皮膚のハリの衰え、シワやたるみなどの皮膚老化現象に深く関与すると考えられている。また、真皮や表皮中の高分子ヒアルロン酸は、主にヒアルロン酸合成酵素２（HAS2）により産生されることも分っており、例えば、（−）−ムスコンがHas2遺伝子の発現を促進させることが知られている（例えば、非特許文献２、非特許文献３を参照）。 Hyaluronic acid is contained in the stratum corneum, epidermis and dermis in the skin, and three types of hyaluronic acid synthases (HAS1, HAS2, HAS3) have been reported as enzymes involved in human hyaluronic acid synthesis. ing. In addition, hyaluronic acid produced by these hyaluronic acid synthases has various molecular weights ranging from about 10 3 Da to 10 7 Da, and exhibits various biological or physical properties depending on the molecular weight. It has been known. The difference in the molecular weight of hyaluronic acid affects the physical properties such as water retention and viscoelasticity, and in particular, the high hyaluronic acid polymer hyaluronic acid can cause skin aging, wrinkles and sagging. It is thought to be deeply involved. It is also known that high molecular hyaluronic acid in the dermis and epidermis is mainly produced by hyaluronic acid synthase 2 (HAS2). For example, (-)-muscone promotes the expression of Has2 gene. Is known (see, for example, Non-Patent Document 2 and Non-Patent Document 3).
また、トクサ科トクサ属に属する植物の抽出物が、正常ヒト表皮ケラチノサイトにおいてHAS2mRNA発現量を高め、表皮細胞における高分子ヒアルロン酸の産生を促進させることが報告されている（特許文献３）。 Further, it has been reported that an extract of a plant belonging to the genus Toxaaceae increases the expression level of HAS2 mRNA in normal human epidermal keratinocytes and promotes the production of high molecular hyaluronic acid in epidermal cells (Patent Document 3).
さらに、正常ヒト皮膚線維芽細胞においてヒアルロン酸合成酵素遺伝子の発現の概日リズムを誘導し、さらにその評価系において、ジュニパーオイル、ユーカリオイル、サイプレスオイル等の精油がHas2遺伝子の発現を促進したことが報告されている（特許文献４）。 Furthermore, induced circadian rhythms of hyaluronan synthase gene expression in normal human skin fibroblasts, and in the evaluation system, essential oils such as juniper oil, eucalyptus oil, and cypress oil promoted the expression of Has2 gene. Has been reported (Patent Document 4).
上述したように、ヒアルロン酸合成酵素遺伝子、特に高分子ヒアルロン酸の産生に寄与するヒアルロン酸合成酵素２遺伝子（Has2）の発現を促進させることにより、皮膚の老化防止（皮膚のハリや弾力性保持）、保湿、関節炎の予防、改善等、熱傷の初期の治療等、ヒアルロン酸産生の促進により恩恵を受ける様々な症状、疾病等を効果的に防止または改善等することが可能である。従って、幅広い用途に活用できかつ効果的にヒアルロン酸合成酵素遺伝子の発現を促進できる新規薬剤の開発が尚強く望まれている。 As mentioned above, it promotes the expression of hyaluronic acid synthase gene, especially hyaluronic acid synthase 2 gene (Has2), which contributes to the production of high molecular hyaluronic acid, thereby preventing skin aging (retaining skin elasticity and elasticity) ), Prevention and improvement of moisturization, arthritis, etc., early treatment of burns, etc. It is possible to effectively prevent or ameliorate various symptoms, illnesses, etc. that benefit from the promotion of hyaluronic acid production. Accordingly, there is still a strong demand for the development of new drugs that can be used for a wide range of applications and can effectively promote the expression of hyaluronic acid synthase gene.
本発明は、上記のような事情に鑑み、ヒアルロン酸合成酵素遺伝子の発現を促進できる新規薬剤を提供することを目的とするものである。 In view of the circumstances as described above, an object of the present invention is to provide a novel drug capable of promoting the expression of a hyaluronic acid synthase gene.
本発明者は、培養ヒト皮膚線維芽細胞において、ヒアルロン酸合成酵素遺伝子の発現の概日リズムを誘導することに成功し、さらにその系において、遺伝子発現量が高い時点で評価することにより、試験物質のヒアルロン酸合成酵素遺伝子発現促進効果を高感度で評価することを可能にした。本発明者は、その評価系において、β−カリオフィレン、カリオフィレンオキサイド、ならびに安息香酸メチル（メチルベンゾエート）誘導体が、ヒアルロン酸合成酵素遺伝子の発現を促進し得ることを見出し、本発明を完成するに至った。 The present inventor succeeded in inducing a circadian rhythm of expression of a hyaluronic acid synthase gene in cultured human skin fibroblasts, and further evaluated in the system at a time when the gene expression level is high. The hyaluronic acid synthase gene expression promoting effect of substances can be evaluated with high sensitivity. The present inventor has found that β-caryophyllene, caryophyllene oxide, and methyl benzoate (methylbenzoate) derivative can promote the expression of hyaluronic acid synthase gene in the evaluation system, and have completed the present invention. It was.
本発明のヒアルロン酸合成酵素遺伝子発現促進剤は、β−カリオフィレン、カリオフィレンオキサイド、および下記構造式を有する化合物より成る群から選択される１以上を有効成分とする。
これら特定の化合物がヒアルロン酸合成酵素遺伝子の発現を促進できることは今まで全く知られていなかった。
The hyaluronic acid synthase gene expression promoter of the present invention contains at least one selected from the group consisting of β-caryophyllene, caryophyllene oxide, and a compound having the following structural formula as an active ingredient.
Until now, it has not been known at all that these specific compounds can promote the expression of the hyaluronic acid synthase gene.
ヒトのヒアルロン酸合成酵素としてHAS1、HAS2、HAS3が存在するが、保湿力の高い高分子ヒアルロン酸は主にHAS2により産生されるため、本発明のヒアルロン酸合成酵素遺伝子発現促進剤は、HAS2の遺伝子（has2）の発現を促進するものであることが好ましい。 HAS1, HAS2, and HAS3 exist as human hyaluronic acid synthase, but high molecular hyaluronic acid with high moisturizing power is mainly produced by HAS2. Therefore, the hyaluronic acid synthase gene expression promoter of the present invention is HAS2. It is preferable to promote the expression of the gene (has2).
本発明のヒアルロン酸合成酵素遺伝子発現促進剤は、医薬、医薬部外品、化粧料、食品、雑貨、衣料等様々な態様で使用でき、安全かつ効果的にヒアルロン酸合成酵素遺伝子の発現を高めて、皮膚の老化防止（皮膚のハリや弾力性保持）、保湿、潤い付与、関節炎等の予防、改善等、さらには熱傷の初期の治療等、ヒアルロン酸の産生促進により恩恵を受ける様々な症状または疾患を治療または改善等することが可能である。 The hyaluronic acid synthase gene expression promoter of the present invention can be used in various forms such as pharmaceuticals, quasi-drugs, cosmetics, foods, miscellaneous goods, clothing, etc., and enhances hyaluronic acid synthase gene expression safely and effectively. Various symptoms that benefit from the promotion of hyaluronic acid production, such as prevention of skin aging (retention of skin elasticity and elasticity), moisturizing, moisturizing, prevention and improvement of arthritis, etc., as well as early treatment of burns Alternatively, the disease can be treated or improved.
本発明のヒアルロン酸合成酵素遺伝子発現促進剤は、β−カリオフィレン、カリオフィレンオキサイド、または上記の安息香酸メチル（メチルベンゾエート）誘導体を有効成分とする。それら化合物はいずれも既知化合物であるが、以下に簡単に説明する。 The hyaluronic acid synthase gene expression promoter of the present invention contains β-caryophyllene, caryophyllene oxide, or the above methyl benzoate (methylbenzoate) derivative as an active ingredient. These compounds are all known compounds, but will be briefly described below.
β−カリオフィレン（4, 11, 11-トリメチル−8−メチレンバイサイクロ[7.2.0]ウンデセン）は、下記構造式で示される分子量２０４．３６のセスキテルペン類で、市販品の多くはクローブ油から分離されたものである。天然には、クローブ油、コパイバ油、ラベンダー油などに存在することが知られている。
カリオフィレンオキサイド（(1R,4R,6R,10S)-4,12,12-トリメチル-9-メチレン-5-オキサトリシクロ[8.2.0.04,6]ドデカン）は、下記構造式で示される分子量２２０．３５のセスキテルペン類で、β-カリオフィレンを過酸でモノエポキシ化することにより合成することができる。天然にはクローブ油、ラベンダー油等に存在することが知られている。
また、本発明で用いられる安息香酸メチル誘導体である2-メチル安息香酸メチルは分子量150.18の無色液体である。2-アミノ安息香酸メチルは分子量１５１．１７の液体で、メタノール120部にアントラニル酸８０部を加え、４０度以下で濃硫酸１００部を徐々に加え、７５〜８３度で反応を完結し、メタノール回収後、炭酸ナトリウム１１０部、水２４０部の溶液中に加えて中和し水洗後蒸留により精製することにより得られる。O-ニトロトルエンからの合成法もある。天然には、ネロリ、イランイラン花精油等に存在することが知られている。2-メチルアミノ安息香酸メチルは分子量１６５．２の無色液体で、天然にはオレンジの果皮、マンダリン油等に存在することが知られている。 Further, methyl 2-methylbenzoate, which is a methyl benzoate derivative used in the present invention, is a colorless liquid having a molecular weight of 150.18. Methyl 2-aminobenzoate is a liquid having a molecular weight of 151.17. Add 80 parts of anthranilic acid to 120 parts of methanol, gradually add 100 parts of concentrated sulfuric acid at 40 degrees or less, and complete the reaction at 75 to 83 degrees. After recovery, it is obtained by adding to a solution of 110 parts of sodium carbonate and 240 parts of water, neutralizing, washing with water and then purifying by distillation. There is also a synthesis method from O-nitrotoluene. Naturally, it is known to exist in neroli, ylang ylang flower essential oil, and the like. Methyl 2-methylaminobenzoate is a colorless liquid having a molecular weight of 165.2 and is known to exist naturally in orange peel, mandarin oil, and the like.
本発明のヒアルロン酸合成酵素遺伝子発現促進剤は、上記化合物の１種または２種以上を含む。本発明において、上記化合物は天然由来のものであっても、あるいは合成されたものであってもよい。 The hyaluronic acid synthase gene expression promoter of the present invention contains one or more of the above compounds. In the present invention, the compound may be naturally derived or synthesized.
本発明のヒアルロン酸合成酵素遺伝子発現促進剤は、単独で用いてもよいが、他のヒアルロン酸合成酵素遺伝子発現促進作用を有する薬剤と組み合せて使用してもよい。 The hyaluronic acid synthase gene expression promoter of the present invention may be used alone, or may be used in combination with other agents having hyaluronic acid synthase gene expression promoting action.
さらに、本発明のヒアルロン酸合成酵素遺伝子発現促進剤は、それらを単独で用いてもよいが、様々な対象物に含めることができる。その対象物の種類に応じて、上記の必須成分の他に、任意の構成要素をさらに含めることができる。 Furthermore, although the hyaluronic acid synthase gene expression promoter of the present invention may be used alone, it can be included in various objects. Depending on the type of the object, optional components can be further included in addition to the essential components.
例えば、対象物が皮膚外用剤である場合には、その剤形（例えば、液剤、粉末剤、顆粒剤、エアゾール剤、固形剤、ジェル剤、パッチ剤、坐剤等）や、製品形態（例えば化粧料、医薬品、医薬部外品等）に応じて、通常そのような皮膚外用剤に含まれる任意の成分を、上記のヒアルロン酸合成酵素遺伝子発現促進剤と共に含んでいてよい。皮膚外用剤は、皮膚（頭皮、頭髪、爪も含む）に対して適用する組成物全般を包括する概念であり、例えば、基礎化粧料、メーキャップ化粧料、毛髪化粧料、皮膚もしくは毛髪洗浄料等の化粧料や、軟膏剤、パッチ剤、坐剤、歯磨等の種々の医薬品ないし医薬部外品等を含む。その剤形も特に限定されず、例えば、水溶液系、可溶化系、乳化系、油液系、ゲル系、ペースト系、軟膏系、エアゾール系、水−油２層系、水−油−粉末３層など、任意の剤型を含む。皮膚外用剤が化粧料である場合、例えば、香水、オードトワレ、オーデコロン、クリーム、乳液類、化粧水、ファンデーション類、粉白粉、口紅、石鹸、シャンプー・リンス類、ボディーシャンプー、ボディーリンス、ボディーパウダー類、浴剤類等が挙げられる。 For example, when the object is an external preparation for skin, its dosage form (for example, liquid, powder, granule, aerosol, solid, gel, patch, suppository, etc.) or product form (for example, Depending on cosmetics, pharmaceuticals, quasi drugs, etc., any component usually contained in such an external preparation for skin may be included together with the hyaluronic acid synthase gene expression promoter. The topical skin preparation is a concept that encompasses all compositions applied to the skin (including the scalp, hair, and nails). For example, basic cosmetics, makeup cosmetics, hair cosmetics, skin or hair cleansing agents, etc. Cosmetics, ointments, patches, suppositories, various drugs such as dentifrices and quasi drugs. The dosage form is also not particularly limited. For example, an aqueous solution system, a solubilization system, an emulsification system, an oil liquid system, a gel system, a paste system, an ointment system, an aerosol system, a water-oil two-layer system, a water-oil-powder 3 Includes any dosage form, such as a layer. When the external preparation for skin is a cosmetic, for example, perfume, eau de toilette, eau de cologne, cream, milky lotion, lotion, foundations, powdered white powder, lipstick, soap, shampoo / rinse, body shampoo, body rinse, body powder And bath agents.
また、例えば、芳香剤、消臭剤、アロマキャンドル、インセンス、文房具、財布、バッグ、靴等の任意の雑貨類や、例えば下着、洋服、帽子、ストッキング、靴下等の任意の衣類、あるいは例えば散剤、顆粒、錠剤、カプセル剤等様々な形態のサプリメント（栄養補助食品）、菓子、飲料等の任意の食品等に、本発明のヒアルロン酸合成酵素遺伝子発現促進剤を含めることができ、また吸入医薬品や空間散布剤のような吸入製品において用いてもよい。 Also, for example, any miscellaneous goods such as fragrance, deodorant, aroma candle, incense, stationery, wallet, bag, shoes, etc., and any clothing such as underwear, clothes, hats, stockings, socks, etc. The hyaluronic acid synthase gene expression promoter of the present invention can be included in any form of supplements (nutritional supplements) such as powders, granules, tablets, capsules, confectionery, beverages, etc., and inhalation It may be used in inhalation products such as pharmaceuticals and space sprays.
尚、本発明のヒアルロン酸合成酵素遺伝子発現促進剤の使用態様を例示したが、これらに限定されるものではなく、本発明の効果を達成できる限り、任意の態様で用いることができる。また、本発明のヒアルロン酸合成酵素遺伝子発現促進剤の他に、具体的な態様に応じて、他のヒアルロン酸産生促進作用を有する薬剤を、本発明の効果を損なわない限り配合することができる。 In addition, although the usage aspect of the hyaluronic acid synthase gene expression promoter of this invention was illustrated, it is not limited to these, As long as the effect of this invention can be achieved, it can be used in arbitrary aspects. In addition to the hyaluronic acid synthase gene expression promoter of the present invention, other drugs having a hyaluronic acid production promoting action can be added according to specific embodiments as long as the effects of the present invention are not impaired. .
対象物中における本発明のヒアルロン酸合成酵素遺伝子発現促進剤の配合量は、用いる化合物の種類や形態、対象物等によって適宜選択することができ、特に限定されないが、例えば、対象物の全質量に対して、０．００００１〜１００質量％であり、より好適には、０．０００１〜５０質量％であり、さらに好適には、０．０００１〜２０質量％である。 The amount of the hyaluronic acid synthase gene expression promoter of the present invention in the object can be appropriately selected depending on the type and form of the compound used, the object, etc., and is not particularly limited. For example, the total mass of the object On the other hand, it is 0.00001-100 mass%, More preferably, it is 0.0001-50 mass%, More preferably, it is 0.0001-20 mass%.
尚、本発明のヒアルロン酸合成酵素遺伝子発現促進剤やそれを配合した対象物の具体的な適用は、特に限定されないが、例えば、皮膚の老化防止（皮膚のハリや弾力性保持）、保湿、関節炎の予防、改善等、熱傷の初期の治療等、ヒアルロン酸産生の促進により恩恵を受ける様々な症状、疾病等の予防、改善等に使用できる。 In addition, the specific application of the hyaluronic acid synthase gene expression promoter of the present invention and the object containing the hyaluronic acid synthase gene expression promoter is not particularly limited. For example, skin aging prevention (skin elasticity and elasticity retention), moisturizing, It can be used for prevention and improvement of various symptoms and diseases that can benefit from promotion of hyaluronic acid production, such as prevention and improvement of arthritis, early treatment of burns, etc.
以下、実施例を挙げて本発明を具体的に説明するが、本発明は下記の実施例に限定されるものではない。尚、ヒトにおけるヒアルロン酸合成酵素遺伝子としてHas1, Has2, Has3が知られているが、本実施例では代表として、ヒトヒアルロン酸合成酵素２遺伝子（hHas2）の発現を測定した。下記で用いる試験物質は市販されている化合物を購入したものを使用した。 EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated concretely, this invention is not limited to the following Example. In addition, Has1, Has2, Has3 are known as human hyaluronic acid synthase genes. In this example, the expression of human hyaluronic acid synthase 2 gene (hHas2) was measured as a representative. The test substances used below were purchased from commercially available compounds.
培養ヒト皮膚線維芽細胞におけるヒアルロン酸合成酵素遺伝子発現の概日リズムの誘導
培養ヒト皮膚線維芽細胞を用いた系でヒアルロン酸合成酵素遺伝子（hHas2）の発現の概日リズムを誘導できることを確認した。
Induction of circadian rhythm of hyaluronic acid synthase gene expression in cultured human skin fibroblasts We confirmed that circadian rhythm of hyaluronic acid synthase gene (hHas2) expression can be induced in cultured human skin fibroblasts .
培養ヒト皮膚線維芽細胞は、正常成人皮膚由来線維芽細胞を購入し（Cell Application, Inc）、実験に用いた。10%FBS、20mM HEPES、Glutamax、抗菌剤を添加したDMEM培地に播種し、37℃、5%CO2にて培養した。培養６日目に、コルチゾール50ng/mlを添加して２時間処理した後、経時的に細胞をサンプリングした。市販のRNA抽出キットを使用して細胞からRNAを抽出し、市販のPCRプライマー（Perfect Real Time Primer、タカラバイオ社）を用い、RT-PCR法によりhHas2遺伝子の発現量を測定した。また同様に、ハウスキーピング遺伝子であるRPLP0の発現量を定量して内部標準として用い、RPLP0の発現量に対する目的遺伝子の相対的発現量を算出した。 As cultured human skin fibroblasts, normal adult skin-derived fibroblasts were purchased (Cell Application, Inc) and used for experiments. The cells were seeded on a DMEM medium supplemented with 10% FBS, 20 mM HEPES, Glutamax, and an antibacterial agent, and cultured at 37 ° C. and 5% CO 2 . On the sixth day of culture, 50 ng / ml of cortisol was added and treated for 2 hours, and then the cells were sampled over time. RNA was extracted from the cells using a commercially available RNA extraction kit, and the expression level of the hHas2 gene was measured by RT-PCR using a commercially available PCR primer (Perfect Real Time Primer, Takara Bio Inc.). Similarly, the expression level of the housekeeping gene RPLP0 was quantified and used as an internal standard, and the relative expression level of the target gene relative to the expression level of RPLP0 was calculated.
生体内で、コルチゾール等のグルココルチコイドは末梢組織等の生体時計の調節に関与し、朝起床時にコルチゾールの血中濃度が上昇して生体時計をリセットすると考えられている。培養細胞では通常、個々の細胞がばらばらのタイミングでリズムを刻んでいるが、コルチゾールのようなシグナル刺激因子で刺激することにより、培養細胞においても概日リズムを誘導することができる。 In vivo, glucocorticoids such as cortisol are involved in the regulation of biological clocks such as peripheral tissues, and are considered to increase the blood concentration of cortisol when waking up in the morning and reset the biological clock. In cultured cells, individual cells usually have rhythms at different timings, but circadian rhythm can also be induced in cultured cells by stimulation with a signal stimulating factor such as cortisol.
hHas2の発現を測定した結果を図１に示す。コルチゾールで刺激することにより、約２４時間周期の概日リズムを刻んでhHas2が発現されることを確認できた。 The result of measuring the expression of hHas2 is shown in FIG. By stimulating with cortisol, it was confirmed that hHas2 was expressed with a circadian rhythm of about 24 hours.
ヒアルロン酸合成酵素遺伝子発現促進効果の評価
上記の結果から、培養ヒト皮膚線維芽細胞評価系において、hHas2はコルチゾールによる刺激により概日リズムを刻むことが認められた。発現量が高い時間帯での評価が望ましいため、刺激の１６時間後における遺伝子発現量を指標として、試験物質のヒアルロン酸合成酵素遺伝子発現促進効果を評価した。
Evaluation of hyaluronic acid synthase gene expression promoting effect From the above results, it was confirmed that hHas2 inclines circadian rhythm by stimulation with cortisol in the cultured human skin fibroblast evaluation system. Since evaluation in a time zone with a high expression level is desirable, the hyaluronic acid synthase gene expression promoting effect of the test substance was evaluated using the gene expression level 16 hours after stimulation as an index.
上記と同様の方法により、正常成人皮膚由来線維芽細胞（Cell Application, Inc）を播種し、培養６日目に、各薬剤を50ppmとなるように添加して、１６時間後に細胞をサンプリングした。尚、コントロールとして、試験物質の代わりに同量のエタノールを添加した。市販のRNA抽出キットを使用して細胞からRNAを抽出し、市販のPCRプライマー（Perfect Real Time Primer、タカラバイオ社）を用い、RT-PCR法によりhHas2遺伝子の発現量を測定した。また同様に、ハウスキーピング遺伝子であるRPLP0の発現量を定量して内部標準として用い、RPLP0の発現量に対する目的遺伝子の相対的発現量を算出した。得られた値について、Dunnettの多重比較検定を行い、コントロールと比較して片側５％の危険率で有意差があるものを効果有りと判定した。 Normal adult skin-derived fibroblasts (Cell Application, Inc) were seeded by the same method as described above, and each drug was added to 50 ppm on the sixth day of culture, and the cells were sampled after 16 hours. As a control, the same amount of ethanol was added instead of the test substance. RNA was extracted from the cells using a commercially available RNA extraction kit, and the expression level of the hHas2 gene was measured by RT-PCR using a commercially available PCR primer (Perfect Real Time Primer, Takara Bio Inc.). Similarly, the expression level of the housekeeping gene RPLP0 was quantified and used as an internal standard, and the relative expression level of the target gene relative to the expression level of RPLP0 was calculated. Dunnett's multiple comparison test was performed on the obtained values, and those having a significant difference in the risk rate of 5% on one side compared with the control were judged to be effective.
図２に、試験物質の添加１６時間後のhHas2遺伝子の相対発現量を示す。 FIG. 2 shows the relative expression level of the hHas2 gene 16 hours after the addition of the test substance.
また、下記の表１に、１６時間後のhHas2遺伝子の相対発現量を示す。
β−カリオフィレン、カリオフィレンオキサイド、２−メチル安息香酸メチル、２−メチルアミノ安息香酸メチル、およびアミノ安息香酸メチル（メチルアンスラニレート）は、コントロールと比較してhHas2遺伝子の発現量を共に有意に高め、それら化合物がヒアルロン酸合成酵素遺伝子の発現を促進し得ることが示された。 β-caryophyllene, caryophyllene oxide, methyl 2-methylbenzoate, methyl 2-methylaminobenzoate, and methyl aminobenzoate (methylanthranilate) both significantly increased the expression level of the hHas2 gene compared to the control. It was shown that these compounds can promote the expression of the hyaluronic acid synthase gene.
(配合例)
以下、本発明のヒアルロン酸合成酵素遺伝子発現促進剤の配合例を示すが、本発明の実施は以下に限定されるものではない。尚、下記において配合量は全て製品全量に対する質量％で表す。
(Formulation example)
Hereinafter, although the combination example of the hyaluronic acid synthase gene expression promoter of this invention is shown, implementation of this invention is not limited to the following. In addition, in the following, all compounding quantities are represented by the mass% with respect to the total product.
フレグランス
（１）アルコール ７５．０
（２）精製水 残余
（３）ジプロピレングリコール ５．０
（４）本発明のHas遺伝子発現促進剤：β−カリオフィレン １０．０
（５）酸化防止剤 ８．０
（６）色素 適量
（７）紫外線吸収剤 適量
Fragrance (1) Alcohol 75.0
(2) Purified water Residual (3) Dipropylene glycol 5.0
(4) Has gene expression promoter of the present invention: β-caryophyllene 10.0
(5) Antioxidant 8.0
(6) Appropriate amount of dye (7) Appropriate amount of UV absorber
ルームフレグランス
（１）アルコール ８０．０
（２）精製水 残余
（３）酸化防止剤 ５．０
（４）本発明のHas遺伝子発現促進剤：カリオフィレンオキサイド ３．０
（５）３−メチル−３メトキシブタノール ５．０
（６）ジベンジリデンソルビトール ５．０
Room Fragrance (1) Alcohol 80.0
(2) Purified water Residue (3) Antioxidant 5.0
(4) Has gene expression promoter of the present invention: Caryophyllene oxide 3.0
(5) 3-Methyl-3methoxybutanol 5.0
(6) Dibenzylidenesorbitol 5.0
インセンス
（１）タブ粉 ７５．５
（２）安息香酸ナトリウム １５．５
（３）本発明のHas遺伝子発現促進剤：２−メチル安息香酸メチル ５．０
（４）ユーカリオイル １．０
（５）精製水 残余
Incense (1) Tab powder 75.5
(2) Sodium benzoate 15.5
(3) Has gene expression promoter of the present invention: methyl 2-methylbenzoate 5.0
(4) Eucalyptus oil 1.0
(5) Purified water residue
入浴剤
（１）硫酸ナトリウム ４５．０
（２）炭酸水素ナトリウム ４５．０
（３）ラベンダーオイル ９．０
（４）本発明のHas遺伝子発現促進剤：２−メチルアミノ安息香酸メチル １．０
Bath salt (1) Sodium sulfate 45.0
(2) Sodium bicarbonate 45.0
(3) Lavender oil 9.0
(4) Has gene expression promoter of the present invention: methyl 2-methylaminobenzoate 1.0
マッサージ用ジェル
（１）エリスリトール ２．０
（２）カフェイン ５．０
（３）オウバク抽出物 ３．０
（４）グリセリン ５０．０
（５）カルボキシビニルポリマー ０．４
（６）ポリエチレングリコール４００ ３０．０
（７）エデト３ナトリウム ０．１
（８）ポリオキシレン（１０）メチルポリシロキサン共重合体 ２．０
（９）スクワラン １．０
（１０）水酸化カリウム ０．１５
（１１）本発明のHas遺伝子発現促進剤：２−アミノ安息香酸メチル １．０
Massage Gel (1) Erythritol 2.0
(2) Caffeine 5.0
(3) Oat extract 3.0
(4) Glycerin 50.0
(5) Carboxyvinyl polymer 0.4
(6) Polyethylene glycol 400 30.0
(7) edet trisodium 0.1
(8) Polyoxylene (10) Methyl polysiloxane copolymer 2.0
(9) Squalane 1.0
(10) Potassium hydroxide 0.15
(11) Has gene expression promoter of the present invention: methyl 2-aminobenzoate 1.0
マッサージクリーム
（１）固形パラフィン ５．０
（２）ミツロウ １０．０
（３）ワセリン １５．０
（４）流動パラフィン ４１．０
（５）１．３−ブチレングリコール ４．０
（６）モノステアリン酸グリセリン ２．０
（７）ＰＯＥ（２０）ソルビタンモノラウリン酸エステル ２．０
（８）ホウ砂 ０．２
（９）カフェイン ２．０
（１０）防腐剤 適量
（１１）酸化防止剤 適量
（１２）本発明のHas遺伝子発現促進剤：カリオフィレンオキサイド ０．５
（１３）本発明のHas遺伝子発現促進剤：２−メチルアミノ安息香酸メチル ０．５
（１４）精製水 残余
Massage cream (1) Solid paraffin 5.0
(2) Beeswax 10.0
(3) Vaseline 15.0
(4) Liquid paraffin 41.0
(5) 1.3-butylene glycol 4.0
(6) Glycerol monostearate 2.0
(7) POE (20) sorbitan monolaurate 2.0
(8) Borax 0.2
(9) Caffeine 2.0
(10) Preservative appropriate amount (11) Antioxidant appropriate amount (12) Has gene expression promoter of the present invention: Caryophyllene oxide 0.5
(13) Has gene expression promoter of the present invention: methyl 2-methylaminobenzoate 0.5
(14) Purified water residue
芳香性繊維
キュプロアンモニウムセルロース溶液（セルロース濃度１０重量％、アンモニウム濃度７重量％、銅濃度３．６重量％）に、本発明のHas遺伝子発現促進剤を内包したマイクロカプセル（粒子径５０μｍ以下、マイクロカプセルに占める化合物の割合は５０重量％）をセルロース重量に対して０．１〜２０重量％の範囲内で添加、混和した後、通常の湿式紡糸方法に従って紡糸し、精錬工程、乾燥工程を経て、芳香性繊維を得た。
Aromatic fiber A microcapsule (particle diameter of 50 μm or less, microcapsule containing a Has gene expression promoter of the present invention in a cupro ammonium cellulose solution (cellulose concentration 10% by weight, ammonium concentration 7% by weight, copper concentration 3.6% by weight). (The ratio of the compound in the capsule is 50% by weight) within a range of 0.1 to 20% by weight of the cellulose weight, and after mixing, spinning according to a normal wet spinning method, through a refining process and a drying process Obtained aromatic fiber.
顆粒
（１）スクラロース ０．１
（２）本発明のHas遺伝子発現促進剤：β−カリオフィレン ０．１
（３）本発明のHas遺伝子発現促進剤：２−メチル安息香酸メチル ０．１
（３）香味料 ５．０
（４）賦形剤（セオラス） １０．０
（５）マルチトール 残余
Granule (1) Sucralose 0.1
(2) Has gene expression promoter of the present invention: β-caryophyllene 0.1
(3) Has gene expression promoter of the present invention: methyl 2-methylbenzoate 0.1
(3) Flavoring 5.0
(4) Excipient (Theolus) 10.0
(5) Maltitol residual
錠剤（チュアブルタイプ）
（１）イノシトール １１．０
（２）マルチトール ２１．０
（３）スクロース ０．５
（４）鮭白子抽出物（ＤＮＡ Ｎａ） ０．１
（５）酵母抽出物 ０．１
（６）本発明のHas遺伝子発現促進剤：２−アミノ安息香酸メチル ０．１
（７）本発明のHas遺伝子発現促進剤：２−メチルアミノ安息香酸メチル ０．１
（７）香味料 ５．０
（８）賦形剤 残余
Tablet (chewable type)
(1) Inositol 11.0
(2) Maltitol 21.0
(3) Sucrose 0.5
(4) White coconut extract (DNA Na) 0.1
(5) Yeast extract 0.1
(6) Has gene expression promoter of the present invention: methyl 2-aminobenzoate 0.1
(7) Has gene expression promoter of the present invention: methyl 2-methylaminobenzoate 0.1
(7) Flavoring 5.0
(8) Excipient residue
タブレット
（１）潤沢剤（ショ糖脂肪酸エステル等） １．０
（２）アラビアガム水溶液（５％） ２．０
（３）酸味料 １．０
（４）着色料 適量
（５）本発明のHas遺伝子発現促進剤：２−メチル安息香酸メチル ０．１
（５）本発明のHas遺伝子発現促進剤：２−メチルアミノ安息香酸メチル ０．１
（６）糖質（粉糖またはソルビトール等） 残余
Tablet (1) Lubricant (sucrose fatty acid ester, etc.) 1.0
(2) Gum arabic aqueous solution (5%) 2.0
(3) Acidulant 1.0
(4) Coloring agent appropriate amount (5) Has gene expression promoter of the present invention: methyl 2-methylbenzoate 0.1
(5) Has gene expression promoter of the present invention: methyl 2-methylaminobenzoate 0.1
(6) Carbohydrate (such as powdered sugar or sorbitol)
キャンディー
（１）砂糖 ５０．０
（２）水飴 ４７．９５
（３）有機酸 ２．０
（４）本発明のHas遺伝子発現促進剤：２−アミノ安息香酸メチル ０．０５
Candy (1) Sugar 50.0
(2) Minamata 47.95
(3) Organic acid 2.0
(4) Has gene expression promoter of the present invention: methyl 2-aminobenzoate 0.05
ガム
（１）砂糖 ４３．０
（２）ガムベース ３０．９５
（３）グルコース １０．０
（４）水飴 １６．０
（５）本発明のHas遺伝子発現促進剤：２−メチル安息香酸メチル ０．０５
Gum (1) Sugar 43.0
(2) Gum base 30.95
(3) Glucose 10.0
(4) Minamata 16.0
(5) Has gene expression promoter of the present invention: methyl 2-methylbenzoate 0.05
これら配合例の製品は、それぞれの製品形態の典型的な使用態様における使用テストにより、ヒアルロン酸合成酵素遺伝子の発現を促進して、ヒアルロン酸の産生を高めることができる。 The products of these formulation examples can promote the expression of the hyaluronic acid synthase gene and increase the production of hyaluronic acid by a usage test in a typical usage mode of each product form.
Claims (2)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2012053460A JP5487227B2 (en) | 2012-03-09 | 2012-03-09 | Hyaluronic acid synthase gene expression promoter |
| TW102108386A TW201340987A (en) | 2012-03-09 | 2013-03-08 | Promoter for expression of hyaluronic acid synthase gene |
| PCT/JP2013/001531 WO2013132873A1 (en) | 2012-03-09 | 2013-03-08 | Promoter for expression of hyaluronic acid synthase gene |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2012053460A JP5487227B2 (en) | 2012-03-09 | 2012-03-09 | Hyaluronic acid synthase gene expression promoter |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2013271051A Division JP2014074063A (en) | 2013-12-27 | 2013-12-27 | Expression promoter of hyaluronic acid synthase gene |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2013184953A JP2013184953A (en) | 2013-09-19 |
| JP5487227B2 true JP5487227B2 (en) | 2014-05-07 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2012053460A Active JP5487227B2 (en) | 2012-03-09 | 2012-03-09 | Hyaluronic acid synthase gene expression promoter |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JP5487227B2 (en) |
| TW (1) | TW201340987A (en) |
| WO (1) | WO2013132873A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112107563B (en) * | 2020-10-19 | 2021-07-23 | 中国科学院动物研究所 | Compound for influencing cold feeling of human and animal and application thereof |
| MX2023004854A (en) * | 2020-11-06 | 2023-06-28 | Univ Kinki | Composition for treating vascular disease, composition for preventing vascular disease, composition for treating hypertension, and composition for preventing hypertension. |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130022692A1 (en) * | 2010-03-31 | 2013-01-24 | Shiseido Company, Ltd. | Expression Modulator For Clock Gene Period |
-
2012
- 2012-03-09 JP JP2012053460A patent/JP5487227B2/en active Active
-
2013
- 2013-03-08 WO PCT/JP2013/001531 patent/WO2013132873A1/en active Application Filing
- 2013-03-08 TW TW102108386A patent/TW201340987A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| TW201340987A (en) | 2013-10-16 |
| WO2013132873A1 (en) | 2013-09-12 |
| JP2013184953A (en) | 2013-09-19 |
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