JP2018158902A - Clock gene expression level regulator and elastin production promoter - Google Patents
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Abstract
Description
本発明は、スイカズラ抽出物を有効成分とする、時計遺伝子発現量調整剤及びエラスチン産生促進剤に関する。 The present invention relates to a clock gene expression level adjusting agent and an elastin production promoter comprising a honeysuckle extract as an active ingredient.
概日リズムは生物体が持つ約２４時間周期のリズムであり、生物体自信が持つ体内時計によって制御されている。体内時計は、生物学的な日周変動を引き起こし、睡眠及び覚醒をはじめ、体温、血圧、ホルモン分泌、代謝、さらには、心身の活動、接触などの様々な生体活動の日周変動を支配していると考えられている。近年、概日リズムの乱れが、睡眠障害、皮膚疾患、生活習慣病、さらにはうつ病等の精神神経疾患等、様々な心身の症状または疾患の発症要因として指摘されている。また、皮膚でも時計遺伝子は発現しており、他の臓器と同様に、脳内の中枢時計と同調して時計遺伝子がリズムを刻むことにより、生体恒常性が維持されている。 The circadian rhythm is a rhythm with a cycle of about 24 hours that a living organism has, and is controlled by a biological clock possessed by the organism's confidence. The circadian clock causes biological diurnal fluctuations and controls the diurnal fluctuations of various biological activities such as body temperature, blood pressure, hormone secretion, metabolism, as well as physical and mental activities, contact, including sleep and awakening. It is thought that In recent years, disturbance of circadian rhythm has been pointed out as a cause of various psychosomatic symptoms or diseases such as sleep disorders, skin diseases, lifestyle-related diseases, and neuropsychiatric diseases such as depression. In addition, the clock gene is expressed in the skin, and the homeostasis is maintained by rhythming the clock gene in synchronism with the central clock in the brain, as in other organs.
体内時計は、時計遺伝子（ｃｌｏｃｋ ｇｅｎｅ）と呼ばれる遺伝子群を含む体内時計系（ｃｉｒｃａｄｉａｎ ｃｌｏｃｋ ｓｙｓｔｅｍ）により制御されている。時計遺伝子の中でも特にＢＭＡＬ１遺伝子は、CLOCK遺伝子とヘテロダイマーを形成する塩基性ヘリックス―ループ―ヘリックス蛋白質であり、夜間に多く発現し、日中は発現量が少ないことが知られている。 The circadian clock is controlled by a circadian clock system that includes a group of genes called clock genes. Among clock genes, the BMAL1 gene, in particular, is a basic helix-loop-helix protein that forms a heterodimer with the CLOCK gene, and is known to be highly expressed at night and low in expression during the day.
また、時計遺伝子が皮膚の恒常性を調節することが知られている。（非特許文献１.）
It is also known that clock genes regulate skin homeostasis. (Non-patent
体内時計を正常に維持するためには、体内時計系に関与する時計遺伝子の発現を調整するものが有効である。このようなものとして、例えば、特許文献１には、ラベンダーオイル又はユーカリオイルとアルキレンオキシド誘導体とを含有する時計遺伝子発現促進剤が知られている。また、特許文献２には、特定の乳酸菌の菌体処理物を有効成分として含有する概日リズム改善剤が知られている。
In order to maintain the body clock normally, those that regulate the expression of clock genes involved in the body clock system are effective. For example,
エラスチンは、関節軟骨中や靭帯中に存在し、関節機能の円滑な作動に役立っている。変形性関節症(ＯＡ)の場合、関節周囲の血行が悪くなり酸素の供給が低下することで、軟骨細胞によるコラーゲンやプロテオグリカンなどの産生を低下させ、死滅した軟骨細胞が滑膜を刺激、炎症を起こし、関節に痛みを生じさせることとなる。さらに、炎症時のサイトカインの放出が、軟骨細胞死を誘導し、痛みの症状を激化させる。そこで、エラスチン産生促進剤が望まれていた。 Elastin is present in articular cartilage and ligaments, and helps smooth operation of joint functions. In the case of osteoarthritis (OA), the blood circulation around the joints deteriorates and the supply of oxygen decreases, thereby reducing the production of collagen and proteoglycans by chondrocytes, and dead chondrocytes stimulate the synovium and inflammation Cause pain in the joints. In addition, the release of cytokines during inflammation induces chondrocyte death and intensifies pain symptoms. Thus, an elastin production promoter has been desired.
ＯＡの対症療法としては、痛み止めや抗炎症製剤の投与、高分子ヒアルロン酸(ヒアルロン酸ナトリウム)の関節腔内への注入等があげられる。近年では、対症療法以外の方法として、軟骨細胞の分化促進または軟骨細胞の肥大化の抑制、軟骨細胞によるコラーゲン、プロテオグリカンの転写、合成促進などのアプローチが取られ始めているが、エラスチンの合成促進などの研究はあまり見られない。 Symptomatic treatment of OA includes administration of pain relievers and anti-inflammatory preparations, injection of high molecular hyaluronic acid (sodium hyaluronate) into the joint cavity, and the like. In recent years, approaches other than symptomatic treatment, such as promotion of chondrocyte differentiation or suppression of chondrocyte hypertrophy, collagen and proteoglycan transcription by chondrocytes, and synthesis promotion have started to be taken. There are not many studies.
エラスチン産生促進剤としては京水菜、京壬生菜、伏見とうがらし、万願寺とうがらし及び九条ねぎ、オウバク、オタネニンジン、アルテア、ヨクイニン及びユリ等植物からの抽出物が開示されている。（特許文献３） As elastin production promoters, extracts from plants such as Kyomizuna, Kyojou Nana, Fushimi Togarashi, Manganji Togarashi and Kujo Negi, Ogaku, Ginseng, Altea, Yokuinin and Lily are disclosed. (Patent Document 3)
.
本発明は、時計遺伝子の発現量を調整する、時計遺伝子発現量調整剤を提供すること、エラスチンの産生を促進する、エラスチン産生促進剤を提供すること、を課題とする。 An object of the present invention is to provide a clock gene expression level regulator that regulates the expression level of a clock gene, and to provide an elastin production promoter that promotes the production of elastin.
本発明のスイカズラ抽出物を有効成分とする時計遺伝子発現量調整剤は、高い時計遺伝子発現量調整効果を発揮することができる。 The clock gene expression level regulator comprising the honeysuckle extract of the present invention as an active ingredient can exert a high clock gene expression level regulation effect.
本発明のスイカズラ抽出物を有効成分とするエラスチン産生促進剤は、高いエラスチン産生促進効果を発揮することができる。 The elastin production promoter comprising the honeysuckle extract of the present invention as an active ingredient can exhibit a high elastin production promotion effect.
以下本発明を実施するための形態を説明する。 Hereinafter, modes for carrying out the present invention will be described.
本発明で使用するスイカズラ抽出物は、スイカズラ科（Ｃａｐｒｉｆｏｌｉａｃｅａｅ）スイカズラ属（Ｌｏｎｉｃｅｒａ Ｌ．）の植物から得られるエキスであればよい。スイカズラ属植物としては、スイカズラ（Ｌｏｎｉｃｅｒａ ｊａｐｏｎｉｃａ Ｔｈｕｎｂ．）、ウグイスカグラ；ウグイスノキ（Ｌｏｎｉｃｅｒａ ｇｒａｃｉｌｉｐｅｓ Ｍｉｑ． ｖａｒ． ｇｌａｂｒａ Ｍｉｑ．）、ハナヒョウタンボク（Ｌｏｎｉｃｅｒａ ｍａａｃｋｉｉ （Ｒｕｐｒ．） Ｍａｘｉｍ．）、ヒョウタンボク；キンギンボク（Ｌｏｎｉｃｅｒａ ｍｏｒｒｏｗｉｉ Ａ． Ｇｒａｙ）、ニオイニンドウ（Ｌｏｎｉｃｅｒａ ｐｅｒｉｃｌｙｍｅｎｕｍ Ｌ．）、ツキヌキニンドウ（Ｌｏｎｉｃｅｒａ ｓｅｍｐｅｒｖｉｒｅｎｓ Ｌ．）、クロミノウグイスカグラ；クロミノウグイス、クロウグイス（Ｌｏｎｉｃｅｒａ ｃａｅｒｕｌｅａ ｓｕｂｓｐ． ｅｄｕｌｉｓ （Ｔｕｒｃｚ．） Ｈｕｌｔｅｎ ｖａｒ． ｅｍｐｈｙｌｌｏｃａｌｙｘ （Ｍａｘｉｍ．） Ｎａｋａｉ）、アラゲヒョウタンボク；オオバヒョウタンボク（Ｌｏｎｉｃｅｒａ ｓｔｒｏｐｈｉｏｐｈｏｒａ Ｆｒａｎｃｈ．）、ヤマウグイスカグラ（Ｌｏｎｉｃｅｒａ ｇｒａｃｉｌｉｐｅｓ Ｍｉｑ． ｖａｒ． ｇｒａｃｉｌｉｐｅｓ）、ミヤマウグイスカグラ（Ｌｏｎｉｃｅｒａ ｇｒａｃｉｌｉｐｅｓ Ｍｉｑ． ｖａｒ． ｇｌａｎｄｕｌｏｓａ Ｍａｘｉｍ．）、コウグイスカグラ（Ｌｏｎｉｃｅｒａ ｒａｍｏｓｉｓｓｉｍａ Ｆｒａｎｃｈ． ｅｔ Ｓａｖ． ｅｘ Ｍａｘｉｍ．）、コゴメヒョウタンボク（Ｌｏｎｉｃｅｒａ ｌｉｎｄｅｒｉｆｏｌｉａ Ｍａｘｉｍ． ｖａｒ． ｋｏｎｏｉ （Ｍａｋｉｎｏ） Ｏｋｕｙａｍａ）、イボタヒョウタンボク（Ｌｏｎｉｃｅｒａ ｄｅｍｉｓｓａ Ｒｅｈｄｅｒ）、チシマヒョウタンボク（Ｌｏｎｉｃｅｒａ ｃｈａｍｉｓｓｏｉ Ｂｕｎｇｅ）、ウスバヒョウタンボク（Ｌｏｎｉｃｅｒａ ｃｅｒａｓｉｎａ Ｍａｘｉｍ．）、オニヒョウタンボク（Ｌｏｎｉｃｅｒａ ｖｉｄａｌｉｉ Ｆｒａｎｃｈ． ｅｔ Ｓａｖ．）、オオヒョウタンボク（Ｌｏｎｉｃｅｒａ ｔｓｃｈｏｎｏｓｋｉｉ Ｍａｘｉｍ．）、ニッコウヒョウタンボク（Ｌｏｎｉｃｅｒａ ｍｏｃｈｉｄｚｕｋｉａｎａ Ｍａｋｉｎｏ）、エゾヒョウタンボク（Ｌｏｎｉｃｅｒａ ａｌｐｉｇｅｎａ Ｌ． ｓｕｂｓｐ． ｇｌｅｈｎｉ （Ｆ． Ｓｃｈｍｉｄｔ）Ｈ． Ｈａｒａ）、キダチニンドウ；トウニンドウ、チョウセンニンドウ（Ｌｏｎｉｃｅｒａ ｈｙｐｏｇｌａｕｃａ Ｍｉｑ．）、ハマニンドウ（Ｌｏｎｉｃｅｒａ ａｆｆｉｎｉｓ Ｈｏｏｋ． ｅｔ Ａｒｎ．）、ニオイニンドウ（Ｌｏｎｉｃｅｒａ ｐｅｒｉｃｌｙｍｅｎｕｍ）、ロニケラ・エトルスカ（Ｌｏｎｉｃｅｒａ ｅｔｒｕｓｃａ）、ネムロブシダマ（Ｌｏｎｉｃｅｒａ ｃｈｒｙｓａｎｔｈａ ｖａｒ． ｃｒａｓｓｉｐｅｓ）、ハヤザキヒョウタンボク（Ｌｏｎｉｃｅｒａ ｐｒａｅｆｌｏｒｅｎｓ ｖａｒ． ｊａｐｏｎｉｃａ）、ベニバナヒョウタンボク（Ｌｏｎｉｃｅｒａ ｍａｘｉｍｏｗｉｃｚｉｉ ｖａｒ． ｓａｃｈａｌｉｎｅｎｓｉｓ）、スルガヒョウタンボク（Ｌｏｎｉｃｅｒａ ａｌｐｉｇｅｎａ ｓｓｐ． ｇｌｅｈｎｉｉ ｖａｒ． ｖｉｒｉｄｉｓｓｉｍａ）、ロニケラ・アルピゲナ（Ｌｏｎｉｃｅｒａ ａｌｐｉｇｅｎａ ｓｓｐ． ａｌｐｉｇｅｎａ）、ケヨノミ（Ｌｏｎｉｃｅｒａ ｃａｅｒｕｌｅａ ｓｓｐ． ｅｄｕｌｉｓ）、マルバヨノミ（Ｌｏｎｉｃｅｒａ ｃａｅｒｕｌｅａ ｓｓｐ． ｅｄｕｌｉｓ ｖａｒ． ｖｅｎｕｌｏｓａ）、クロミノウグイスカグラ（Ｌｏｎｉｃｅｒａ ｃａｅｒｕｌｅａ ｓｓｐ． ｅｄｕｌｉｓ ｖａｒ． ｅｍｐｈｙｌｌｏｃａｌｙｘ）、ヨーロッパヨノミ（Ｌｏｎｉｃｅｒａ ｃａｅｒｕｌｅａ ｓｓｐ． ｃａｅｒｕｌｅａ）等が知られている。本発明に用いられる原料となる植物は、スイカズラ属植物であれば特に限定されないが、入手が比較的容易なことや有効性などの理由から、スイカズラ（Ｌｏｎｉｃｅｒａ ｊａｐｏｎｉｃａ Ｔｈｕｎｂ．）を用いることが好ましい。抽出には、これら植物の花、葉、茎、枝、果実等の各部位を用いることができるが、本発明においては有効性の点から、花を用いるとよい。 The honeysuckle extract used in the present invention may be an extract obtained from a plant of the genus Caprifoliaaceae ( Lonicera L.). The honeysuckle plant, honeysuckle, warbler Kagura (Lonicera japonica Thunb.); Uguisunoki, Hana gourd I (Lonicera maackii (Rupr) Maxim. .), Gourd I (Lonicera gracilipes Miq var glabra Miq. ..); Lonicera Morrowii (Lonicera morrowii A. Gray), smell caulis lonicerae. (Lonicera periclymenum L.), luck Nuqui caulis lonicerae (Lonicera sempervirens L.), chromium Roh warbler Kagura;.. chromium Roh warbler, black warbler (Lonicera caerulea subsp edulis (Turcz) Hulten var emphylloc (. Maxim) alyx Nakai), Arage gourd me;... Oba gourd I (Lonicera strophiophora Franch), mountain warbler Kagura (Lonicera gracilipes Miq var gracilipes), Miyama warbler Kagura (Lonicera gracilipes Miq var glandulosa Maxim) ,... co-warbler Kagura (Lonicera ramosissima Franch. et Sav. ex Maxim.), small basket gourd I (Lonicera linderifolia Maxim. var. konoi (Makino) Okuyama), privet gourd I (Lonicera demissa Rehder), Chishimahyoutanboku (Lonicera chamissoi Bunge), thin blade gourd I (Lonicera cerasina Maxim.), Demon gourd I (Lonicera vidalii Franch. Et Sav. ), Giant gourd I (Lonicera tschonoskii Maxim.), Nikko gourd I (Lonicera mochidzukiana Makino), Ezo gourd I (Lonicera alpigena L. subsp glehni (F. Schmidt) H Hara..), Kidachinindou; Tounindou, Korean caulis lonicerae (Lonicera hypoglauca Miq. ), Hamanindou (Lonicera affinis Hook. Et Arn. ), Smell caulis lonicerae (Lonicera periclymenum), Ronikera-Etorusuka (Lonicera etrusca), Nemurobushidama (Lonicera chrysantha var. Crassipes), Ha Yazaki gourd I (Lonicera praeflorens var. Japonica), safflower gourd I (Lonicera maximowiczii var. sachalinensis), Suruga gourd I (Lonicera alpigena ssp. glehnii var. viridissima), Ronikera-Arupigena (Lonicera alpigena ssp. alp igena), Keyonomi (Lonicera caerulea ssp. edulis), Marubayonomi (Lonicera caerulea ssp. edulis var. venulosa), chromium Roh warbler Kagura (Lonicera caerulea ssp. edulis var. emphyllocalyx), Europe Yo flea (Lonicera caerulea ssp. caerulea), etc. It has been known. The plant used as a raw material used in the present invention is not particularly limited as long as it is a honeysuckle genus plant, but honeysuckle ( Lonicera japonica Thunb.) Is preferably used because of its relatively easy availability and effectiveness. For extraction, each part of the plant such as flowers, leaves, stems, branches and fruits can be used. In the present invention, flowers are preferably used from the viewpoint of effectiveness.
本発明において用いるスイカズラ抽出物を抽出する場合、生のまま用いてもよいが、抽出効率を考えると、細切、乾燥、粉砕等の処理を行った後抽出を行うことが好ましい。抽出は、抽出溶媒に浸漬するか、超臨界流体や亜臨界流体を用いた抽出方法でも行うことができる。抽出効率を上げるため、攪拌や抽出溶媒中でホモジナイズしてもよい。抽出温度としては、５℃程度から抽出溶媒の沸点以下の温度とするのが適切である。抽出時間は抽出溶媒の種類や抽出温度によっても異なるが、１時間〜１４日間程度とするのが適切である。 When extracting the honeysuckle extract used in the present invention, the honeysuckle extract may be used as it is, but considering the extraction efficiency, it is preferable to perform the extraction after performing processing such as shredding, drying, and pulverization. The extraction can be performed by immersing in an extraction solvent or by an extraction method using a supercritical fluid or a subcritical fluid. In order to increase the extraction efficiency, homogenization may be performed in stirring or an extraction solvent. The extraction temperature is suitably about 5 ° C. to the boiling point of the extraction solvent. The extraction time varies depending on the type of extraction solvent and the extraction temperature, but it is appropriate to set it to about 1 hour to 14 days.
抽出溶媒としては、水の他、メタノール、エタノール、プロパノール、イソプロパノール等の低級アルコール、１，３−ブチレングリコール、プロピレングリコール、ジプロピレングリコール、グリセリン等の多価アルコール、エチルエーテル、プロピルエーテル等のエーテル類、酢酸ブチル、酢酸エチル等のエステル類、アセトン、エチルメチルケトン等のケトン類などの極性有機溶媒を用いることができ、これらより１種又は２種以上を選択して用いる。また、生理食塩水、リン酸緩衝液、リン酸緩衝生理食塩水等を用いてもよい。さらに、水や二酸化炭素、エチレン、プロピレン、エタノール、メタノール、アンモニアなどの１種又は２種以上の超臨界流体や亜臨界流体を用いてもよい。これらの抽出溶媒の中でも本発明の効果の点から、水及びエタノールから選択される１種又は２種を用いることが好ましい。 Extraction solvents include water, lower alcohols such as methanol, ethanol, propanol, and isopropanol, polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, dipropylene glycol, and glycerin, and ethers such as ethyl ether and propyl ether. , Polar organic solvents such as esters such as butyl acetate and ethyl acetate, and ketones such as acetone and ethyl methyl ketone can be used, and one or more of these are selected and used. Further, physiological saline, phosphate buffer, phosphate buffered saline, or the like may be used. Furthermore, you may use 1 type, or 2 or more types of supercritical fluids and subcritical fluids, such as water, a carbon dioxide, ethylene, propylene, ethanol, methanol, ammonia. Among these extraction solvents, it is preferable to use one or two selected from water and ethanol from the viewpoint of the effect of the present invention.
上記溶媒によるスイカズラ抽出物は、そのままでも使用することができるが、濃縮，乾固したものを水や極性溶媒に再度溶解したり、或いはそれらの皮膚生理機能向上作用を損なわない範囲で脱色，脱臭，脱塩等の精製処理を行ったり、カラムクロマトグラフィーによる分画処理を行った後に用いてもよい。また保存のため、精製処理の後凍結乾燥し、用時に溶媒に溶解して用いることもできる。また、リポソーム等のベシクルやマイクロカプセル等に内包させて用いることもできる。 Honeysuckle extract with the above-mentioned solvent can be used as it is, but it is decolorized and deodorized as long as the concentrated and dried solids are dissolved again in water or a polar solvent or their skin physiology is not impaired. , And may be used after a purification treatment such as desalting or a fractionation treatment by column chromatography. For storage, it can be freeze-dried after purification and dissolved in a solvent before use. It can also be used by encapsulating in vesicles such as liposomes or microcapsules.
スイカズラ抽出物は、優れた時計遺伝子発現量調整効果を発揮し、時計遺伝子発現量調整剤として利用することができる。 The honeysuckle extract exhibits an excellent clock gene expression level adjusting effect and can be used as a clock gene expression level adjusting agent.
スイカズラ抽出物は、エラスチン産生遺伝子の発現を増加させることにより、エラスチン産生促進効果を発揮し、エラスチン産生促進剤として利用することができる。 The honeysuckle extract exhibits an elastin production promoting effect by increasing the expression of the elastin production gene, and can be used as an elastin production promoter.
以下、実施例により本発明を具体的に説明するが、これにより本発明の範囲が限定されるものではない。 EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereby.
［スイカズラ抽出物］
スイカズラ（Lonicera japonica）の花を乾燥後細切し、２０質量倍量のエタノール／精製水混液（１：３）に浸漬し、ろ過後ろ液を採取し、スイカズラ抽出物とした。
[Honeysuckle extract]
Honeysuckle (Lonicera japonica) flowers were dried and then chopped and immersed in a 20-mass volume ethanol / purified water mixture (1: 3), and the filtrate after filtration was collected to obtain a honeysuckle extract.
［ＢＭＡＬ１遺伝子発現調整作用、ELASTIN遺伝子発現促進作用］
ヒト線維芽細胞を５×105個/ウェルとなるように6ウェルプレートに播種し、1%FBSを含むDMEM培地にて一晩培養した。スイカズラ抽出物を溶解した培地に交換し、37℃、５％ CO2インキュベーター内で24時間培養した。細胞からのTotal RNA抽出はTrizol reagentを用い、ライフテクノロジーズ社のプロトコールに従って調製した。cDNA合成後に下記のプライマーを使用してサイバーグリーン法によるリアルタイムPCRにより遺伝子発現を確認した。内部標準としてGAPDHを使用した。結果を表２に示す。
[BMAL1 gene expression regulating action, ELASTIN gene expression promoting action]
Human fibroblasts were seeded in a 6-well plate at 5 × 10 5 cells / well and cultured overnight in DMEM medium containing 1% FBS. The honeysuckle extract was replaced with a dissolved medium, and cultured in a 37 ° C., 5% CO 2 incubator for 24 hours. Total RNA extraction from cells was prepared using Trizol reagent according to the protocol of Life Technologies. After cDNA synthesis, gene expression was confirmed by real-time PCR by the cyber green method using the following primers. GAPDH was used as an internal standard. The results are shown in Table 2.
図１に示した通り、スイカズラ抽出物を添加することにより、時計遺伝子の一種であるＢＭＡL１遺伝子の発現量に変化が認められた。特に夜間に相当する８と１２においてはＢＭＡL１遺伝子の発現量が顕著に増加した。これに対し、日中に相当する０、２、４、２４においてはＢＭＡL１遺伝子の発現量に大きな変化は認められなかった。従って、スイカズラ抽出物を添加することにより、時計遺伝子の発現量が調整されることが明らかとなった。 As shown in FIG. 1, the expression level of the BMAL1 gene, which is a type of clock gene, was changed by adding the honeysuckle extract. In particular, the expression level of the BMAL1 gene markedly increased in 8 and 12 corresponding to nighttime. In contrast, no significant change was observed in the expression level of the BMAL1 gene at 0, 2, 4, and 24 corresponding to daytime. Therefore, it was revealed that the expression level of the clock gene is adjusted by adding the honeysuckle extract.
図２に示した通りスイカズラ抽出物を添加することにより、エラスチン遺伝子の発現が増加傾向にあり、特に夜間に相当する４、８において顕著な増加が認められた。従って、スイカズラ抽出物を添加することにより、エラスチン産生遺伝子の発現量が増加することが明らかとなった。 As shown in FIG. 2, the addition of the honeysuckle extract tended to increase the expression of the elastin gene, and a remarkable increase was observed particularly at 4 and 8 corresponding to nighttime. Therefore, it became clear that the expression level of an elastin production gene increases by adding a honeysuckle extract.
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