JP4992008B2 - Endothelin-1 production inhibitor - Google Patents
Endothelin-1 production inhibitor Download PDFInfo
- Publication number
- JP4992008B2 JP4992008B2 JP2003307350A JP2003307350A JP4992008B2 JP 4992008 B2 JP4992008 B2 JP 4992008B2 JP 2003307350 A JP2003307350 A JP 2003307350A JP 2003307350 A JP2003307350 A JP 2003307350A JP 4992008 B2 JP4992008 B2 JP 4992008B2
- Authority
- JP
- Japan
- Prior art keywords
- endothelin
- extract
- production inhibitor
- production
- luteolin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
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- 239000000284 extract Substances 0.000 claims description 35
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Description
本発明は、エンドセリン−1産生抑制剤に関する。 The present invention relates et Ndoserin -1 production inhibitor.
エンドセリン−1は血管内皮細胞の産生する強力な血管収縮ペプチドであり、21残基のアミノ酸からなる。エンドセリン−1は血管内皮細胞に存在するエンドセリン変換酵素の働きによりビッグエンドセリンから生成される。エンドセリン−1は、標的細胞のエンドセリン受容体を介してホスホリパーゼCの活性化、カルシウムチャンネルの開口など多様な細胞内シグナル伝達系を活性化する。その結果、ホルモン・神経伝達物質分泌調節、細胞増殖・分化作用などさまざまな作用が奏される。一般的に、エンドセリン−1の濃度上昇は高血圧症や心疾患などの疾患の原因となる。従って、エンドセリン−1の産生を抑制することができれば高血圧症などの疾患を治療または予防することができる。 Endothelin-1 is a strong vasoconstrictor peptide produced by vascular endothelial cells and consists of 21 amino acids. Endothelin-1 is produced from big endothelin by the action of endothelin converting enzyme present in vascular endothelial cells. Endothelin-1 activates various intracellular signal transduction systems such as activation of phospholipase C and opening of calcium channels via the endothelin receptor of target cells. As a result, various effects such as regulation of hormone / neurotransmitter secretion and cell proliferation / differentiation are exhibited. In general, an increase in the concentration of endothelin-1 causes diseases such as hypertension and heart disease. Therefore, if endothelin-1 production can be suppressed, diseases such as hypertension can be treated or prevented.
エンドセリン−1はまた、血管以外の種々の組織細胞でも産生され、様々な生理的役割を担っている。例えば、紫外線が肌にあたるとエンドセリン変換酵素が活発に働き、ケラチノサイトにあるビッグエンドセリンが分解されてエンドセリン−1が産生されるのであるが、こうして産生されたエンドセリン−1は、メラノサイトを刺激して、シミ、ソバカスの原因となるメラニンを盛んに合成させる。従って、エンドセリン−1の産生を抑制することができればシミ、ソバカスを治療または予防することができる。 Endothelin-1 is also produced in various tissue cells other than blood vessels and plays various physiological roles. For example, when ultraviolet light hits the skin, endothelin converting enzyme works actively, big endothelin in keratinocytes is decomposed and endothelin-1 is produced, and endothelin-1 thus produced stimulates melanocytes, Melanin is actively synthesized to cause stains and buckwheat. Therefore, if the production of endothelin-1 can be suppressed, spots and buckwheat can be treated or prevented.
高血圧症、心臓病、シミ、ソバカスを治療または予防する薬剤は市場において必要とされている。なかでも、高血圧症は、長期間放置すると心血管系に強い負担がかかり、動脈硬化が進行し、脳梗塞、心臓病などの症状を引き起こす重大な疾患であり、血圧が140/90 mmHg以上の高血圧症の患者は日本全国で約3,000万人と推定され、4人に1人、50歳以上では2人に1人が高血圧症とされることから、高血圧症の治療または予防のための薬剤は切望されている。 There is a need in the market for drugs that treat or prevent hypertension, heart disease, spots, and freckles. In particular, hypertension is a serious disease that places a heavy burden on the cardiovascular system if left untreated for a long time, causes arteriosclerosis, and causes symptoms such as cerebral infarction and heart disease. Blood pressure is 140/90 mmHg or more. It is estimated that there are about 30 million patients with hypertension in Japan. One in four people and one in two over 50 years old are considered hypertensive. Is anxious.
かかる市場の要求に応えるべく、エンドセリン−1産生抑制剤が研究されてきた。従来エンドセリン−1産生抑制剤として検討されたものは化学合成品が中心であるが、安全性を考慮すれば天然物で同様の効果を有するものが望まれる。これまでに天然物として、赤ワイン抽出物に含まれるポリフェノール(ピセアタンノール、デルフィニジンなど)(非特許文献1参照)、および大豆イソフラボン(ゲニステイン)(非特許文献2参照)が血管内皮細胞エンドセリン−1の産生抑制剤として検討されてはいるものの、安全面およびコスト面において市場の要求に十分応えているとはいえない。例えばイソフラボンのなかにはエストロゲン様作用を示すものがあり過剰摂取による悪影響が懸念される。かくして、医薬品、化粧品などに使用可能な安全且つ安価なエンドセリン−1産生抑制剤は依然として必要とされている。 In order to meet such market demand, endothelin-1 production inhibitors have been studied. Conventionally studied as endothelin-1 production inhibitors are mainly chemical synthetic products, but considering safety, natural products having similar effects are desired. As natural products, polyphenols (piceatannol, delphinidin, etc.) (see Non-Patent Document 1) and soy isoflavone (Genistein) (see Non-Patent Document 2) contained in red wine extract have been used as vascular endothelial cell endothelin-1 Although it has been studied as a production inhibitor of sucrose, it cannot be said that it sufficiently meets market demands in terms of safety and cost. For example, some isoflavones exhibit an estrogen-like action, and there are concerns about the adverse effects of overdose. Thus, pharmaceutical, of a safe and inexpensive endothelin-1 production inhibitor which can be used in such cosmetics is still a need.
この出願に関連する先行技術文献情報としては次のものがある。
本発明の課題は、天然物由来のエンドセリン−1産生抑制剤を提供することである。 The subject of this invention is providing the endothelin-1 production inhibitor derived from a natural product.
本発明は以下の発明を包含する。
(1) ルテオリンおよび/またはその配糖体を含有するエンドセリン−1産生抑制剤。
(2) ルテオリンおよび/またはその配糖体を含有する植物抽出物を含有するエンドセリン−1産生抑制剤。
(3) クダモノトケイソウ(Passiflora edulis、別名パッションフルーツ)の抽出物を含有するエンドセリン−1産生抑制剤。
(4) クダモノトケイソウの抽出物が、果皮抽出物または果肉抽出物である上記(3)に記載のエンドセリン−1産生抑制剤。
The present invention includes the following inventions.
(1) An endothelin-1 production inhibitor containing luteolin and / or its glycoside.
(2) An endothelin-1 production inhibitor containing a plant extract containing luteolin and / or its glycoside.
(3) An endothelin-1 production inhibitor containing an extract of Passiflora edulis (also called passion fruit).
(4) The endothelin-1 production inhibitor according to the above (3), wherein the extract of damselfly is a peel extract or a pulp extract.
本発明により、安全性が高い天然物由来のエンドセリン−1産生抑制剤が提供される。 The present invention provides a natural product-derived endothelin-1 production inhibitor with high safety.
以下、上記本発明について詳細に説明するが、本発明の範囲はこれらの説明に拘束されることはなく、以下の例示以外についても、本発明の趣旨を損なわない範囲で適宜実施し得る。 Hereinafter, although the said this invention is demonstrated in detail, the scope of the present invention is not restrained by these explanations, and it can implement suitably in the range which does not impair the meaning of this invention except the following illustration.
本発明者らは、天然物由来のエンドセリン−1産生抑制剤を求めて鋭意探索した結果、ルテオリンおよび/またはその配糖体が血管内皮細胞に働いてエンドセリン−1産生を抑制する効果を有することを見出した。 As a result of earnest search for endothelin-1 production inhibitors derived from natural products, the present inventors have the effect that luteolin and / or its glycosides act on vascular endothelial cells to suppress endothelin-1 production. I found.
すなわち本発明は、ルテオリンおよび/またはその配糖体を含有するエンドセリン−1産生抑制剤に関する。ルテオリン(3', 4', 5, 7-テトラヒドロキシフラボン)はフラボノイドの一種であり、セロリ、ピーマン、春菊、カモミール、紫蘇などに含まれている天然物である。また、種々の配糖体が天然に存在し、例えばクダモノトケイソウから6-C-フコシルルテオリン、6-C-キノボシルルテオリンが単離されている(Phytochemistry, 30, 3486, 1991)。従来、ルテオリンまたはその配糖体がエンドセリン−1の産生を抑制する効果を有することは知られていない。 That is, the present invention relates to an endothelin-1 production inhibitor containing luteolin and / or a glycoside thereof. Luteolin (3 ', 4', 5, 7-tetrahydroxyflavone) is a kind of flavonoid and is a natural product contained in celery, peppers, spring chrysanthemum, chamomile, shiso and the like. Moreover, various glycosides exist in nature, for example, 6-C-fucosyl luteolin and 6-C-quinovosyl luteolin have been isolated from Kuda monodiatom (Phytochemistry, 30, 3486, 1991). Conventionally, it is not known that luteolin or its glycoside has an effect of suppressing the production of endothelin-1.
本発明において、ルテオリンは市販品を用いることもできるが、種々の植物から単離して用いてもよい。本発明に使用できるルテオリン配糖体はルテオリンと任意の糖(例えばグルコース、フコース、ガラクトース、6-デオキシグルコース)との配糖体であってよく、また、糖の結合位置は例えばルテオリン分子の6-C、8-C、7-O、または4'-Oであり、好ましいルテオリンの配糖体はルテオリン-6-C-グルコシドである。 In the present invention, luteolin may be a commercially available product, but may be isolated from various plants and used. The luteolin glycoside that can be used in the present invention may be a glycoside of luteolin and any sugar (eg, glucose, fucose, galactose, 6-deoxyglucose), and the binding position of the sugar is, for example, 6 of the luteolin molecule. -C, 8-C, 7-O, or 4'-O, and a preferred luteolin glycoside is luteolin-6-C-glucoside.
本発明の、ルテオリンおよび/またはその配糖体を含有するエンドセリン−1産生抑制剤は、ルテオリンおよび/もしくはその配糖体それ自体であっても、または通常用いられる固体または液体の担体、乳化分散剤等により錠剤、粉剤、乳剤、カプセル剤等の剤形に製剤化されたものであってもよい。上記担体としては、水、ゼラチン、澱粉、ステアリン酸マグネシウム、ラクトース、植物油等が挙げられる。該エンドセリン−1産生抑制剤は更なる成分を含んでいてもよい。 The endothelin-1 production inhibitor containing luteolin and / or its glycoside according to the present invention may be luteolin and / or its glycoside itself, or a commonly used solid or liquid carrier, emulsified dispersion It may be formulated into a dosage form such as a tablet, powder, emulsion, capsule, etc. Examples of the carrier include water, gelatin, starch, magnesium stearate, lactose, and vegetable oil. The endothelin-1 production inhibitor may contain further components.
本発明のエンドセリン−1産生抑制剤中でのルテオリンおよび/またはその配糖体の含有量は、投与目的、投与経路、剤形等によって適宜変更しうるが、例えば、製剤全重量に対して1.0〜20重量%である。 The content of luteolin and / or its glycoside in the endothelin-1 production inhibitor of the present invention can be appropriately changed depending on the administration purpose, administration route, dosage form, etc. ~ 20% by weight.
本発明はさらに、ルテオリンおよび/またはその配糖体を含有する植物抽出物を含有するエンドセリン−1産生抑制剤に関する。植物抽出物は安全性が高く且つ安価であるため、医薬品、化粧品などへの使用に特に適している。ここで植物抽出物とは、植物の全部または根、茎、葉、花、果実などの部分に含まれる成分を、水、エタノールなどの溶媒に溶解させて抽出し適宜乾燥させた、通常は液体または固体のものを指す。本発明には、ルテオリンおよび/またはその配糖体を含有する限り任意の植物の抽出物を用いることができ、例えば、クダモノトケイソウのほかに、青ジソ、赤ジソ、エゴマなどのシソ科植物、セリ、アシタバなどのセリ科の植物、セロリ、レタス、春菊、ピーマンなどの野菜、大豆の葉、ピーナッツ種皮、イチョウ、スイカズラ、西洋サクラソウ、カモミール、ペパーミントなどの抽出物を用いることができる。なかでもクダモノトケイソウの抽出物が好ましい。 The present invention further relates to an endothelin-1 production inhibitor containing a plant extract containing luteolin and / or its glycoside. Since the plant extract is high and inexpensive safety, medicines, are particularly suitable for use in such cosmetics. Here, the plant extract is a liquid usually extracted by dissolving components contained in the whole plant or parts such as roots, stems, leaves, flowers, fruits, etc. in a solvent such as water or ethanol, and drying appropriately. Or a solid thing. In the present invention, an extract of any plant can be used as long as it contains luteolin and / or its glycoside. For example, in addition to damselfly, Lamiaceae plants such as blue dissociation, red dissociation, egoma, Extracts such as celery family plants such as celery and ashitaba, vegetables such as celery, lettuce, spring chrysanthemum and bell pepper, soybean leaves, peanut seed coat, ginkgo biloba, honeysuckle, western primrose, chamomile and peppermint can be used. Of these, an extract of damselfly is preferred.
本発明はさらにまた、クダモノトケイソウの抽出物を含有するエンドセリン−1産生抑制剤に関する。クダモノトケイソウの抽出物としては、果皮、果肉、果実、葉、茎または根の抽出物が好ましく、果皮抽出物または果肉抽出物が特に好ましい。 Furthermore, this invention relates to the endothelin-1 production inhibitor containing the extract of a damselfly. As the extract of cereals, fruit skin, fruit, fruit, leaf, stem or root extract is preferable, and fruit skin extract or pulp extract is particularly preferable.
クダモノトケイソウは南米原産のつる性多年生熱帯果樹であり、現在では世界中の熱帯、亜熱帯地域に広まっており、オーストラリアや東南アジア、台湾などで産業的に栽培されている。日本では沖縄での生産が一番多いが、奄美諸島、小笠原諸島でも栽培されておいる。本発明に使用するクダモノトケイソウの品種と産地は、特に限定されるものではない。 Kudamono Passiflora is a vine perennial tropical fruit tree native to South America and is now widely distributed in tropical and subtropical regions around the world and is cultivated industrially in Australia, Southeast Asia, Taiwan and other countries. In Japan, it is the most produced in Okinawa, but it is also cultivated in the Amami and Ogasawara Islands. There are no particular limitations on the variety and production area of the damselfly used in the present invention.
本発明に使用できるクダモノトケイソウ果皮抽出物は、例えば、クダモノトケイソウの果皮をミキサー等で細かく破砕した後、抽出溶媒中で攪拌し、遠心分離または濾過により不溶物を除去し、上清または濾液を減圧下で乾燥することにより粉末として得ることができる。本発明において「果皮」とは、果実の外側の皮の部分を意味するが、一般に言う果肉の部分が付着していてもよい。抽出溶媒は任意の溶媒であってよく、例えばメチルアルコール、エチルアルコール、酢酸エチル、その他の有機溶剤、および水のうち1種または2種以上を用いることができる。 For example, the citrus peel extract that can be used in the present invention is crushed with a mixer or the like after finely crushing the peel of the pearl fly diatom, and then insoluble solvent is removed by centrifugation or filtration. It can be obtained as a powder by drying under reduced pressure. In the present invention, the “fruit skin” means a skin portion outside the fruit, but generally said pulp portion may be attached. The extraction solvent may be any solvent, and for example, one or more of methyl alcohol, ethyl alcohol, ethyl acetate, other organic solvents, and water can be used.
本発明に使用できるクダモノトケイソウ果肉抽出物は、例えば、クダモノトケイソウの果肉を水と共に攪拌し、遠心分離または濾過により不溶物を除去し、上清または濾液を分画分子量10,000の限外濾過膜を通過させ、回収した溶液を減圧下で乾燥することにより粉末として得ることができる。本発明において「果肉」とは、果実の半透明のゼリー状の部分を意味するが、一般に言う果皮、種子の部分が付着していてもよい。抽出溶媒は任意の溶媒であってよく、例えばメチルアルコール、エチルアルコール、酢酸エチル、その他の有機溶剤、および水のうち1種または2種以上を用いることができる。 For example, the fruit extract of Kudamono Passiflora that can be used in the present invention is stirred with water, and the insoluble matter is removed by centrifugation or filtration, and the supernatant or filtrate is separated from an ultrafiltration membrane having a molecular weight cut off of 10,000. The solution that has been passed through and recovered can be obtained as a powder by drying under reduced pressure. In the present invention, “fruit pulp” means a semi-transparent jelly-like portion of a fruit, but generally referred to skin and seed portions may be attached. The extraction solvent may be any solvent, and for example, one or more of methyl alcohol, ethyl alcohol, ethyl acetate, other organic solvents, and water can be used.
本発明の、ルテオリンおよび/もしくはその配糖体を含有する植物抽出物を含有するエンドセリン−1産生抑制剤、またはクダモノトケイソウの抽出物を含有するエンドセリン−1産生抑制剤は、抽出物それ自体であっても、または通常用いられる固体または液体の担体、乳化分散剤等により錠剤、粉剤、乳剤、カプセル剤等の剤形に製剤化されたものであってもよい。上記担体としては、水、ゼラチン、澱粉、ステアリン酸マグネシウム、ラクトース、植物油等が挙げられる。該エンドセリン−1産生抑制剤は更なる成分を含んでいてもよい。 The endothelin-1 production inhibitor containing a plant extract containing luteolin and / or its glycoside of the present invention, or the endothelin-1 production inhibitor containing an extract of damselfly is an extract itself. Alternatively, it may be formulated into a dosage form such as a tablet, powder, emulsion, capsule or the like by a commonly used solid or liquid carrier, emulsifying dispersant and the like. Examples of the carrier include water, gelatin, starch, magnesium stearate, lactose, and vegetable oil. The endothelin-1 production inhibitor may contain further components.
本発明のエンドセリン−1産生抑制剤中での植物抽出物の含有量は、投与目的、投与経路、剤形等によって適宜変更し得るが、例えば、クダモノトケイソウ果皮抽出物を含有する場合その含有量は製剤全重量に対して1.0〜80重量%であり、クダモノトケイソウ果肉抽出物を含有する場合その含有量は製剤全重量に対して1.0〜90重量%である。 The content of the plant extract in the endothelin-1 production inhibitor of the present invention can be appropriately changed depending on the purpose of administration, the administration route, the dosage form, and the like. Is 1.0 to 80% by weight with respect to the total weight of the preparation, and when it contains the extract of citrus fruit juice, the content is 1.0 to 90% by weight with respect to the total weight of the preparation.
本発明のエンドセリン−1産生抑制剤は医薬品として用いることができる。 The endothelin-1 production inhibitor of this invention can be used as a pharmaceutical.
本発明のエンドセリン−1産生抑制剤の使用形態は使用目的に応じた任意の形態であってよく、例えば経口的投与が可能である。また、エンドセリン−1産生抑制剤を含有する化粧品は、典型的には、皮膚に直接塗布して用いられる。 The usage form of the endothelin-1 production inhibitor of the present invention may be any form depending on the purpose of use, for example, oral administration is possible. In addition, cosmetics containing an endothelin-1 production inhibitor are typically applied directly to the skin.
本発明のエンドセリン−1産生抑制剤の投与量は、特に限定されるものではなく、例えば、病気の種類、患者の年齢、性別、体重、症状の程度、または投与方法などに応じて適宜決定することができる。 The dose of the endothelin-1 production inhibitor of the present invention is not particularly limited, and is appropriately determined according to, for example, the type of illness, the patient's age, sex, weight, symptom level, or administration method. be able to.
以下、実施例によって本発明を具体的に説明するが、これらは本発明の範囲を限定するものではない。 EXAMPLES Hereinafter, the present invention will be specifically described by way of examples, but these do not limit the scope of the present invention.
試験例1 ルテオリン及びルテオリン配糖体のエンドセリン−1産生抑制活性
ブタ大動脈内皮細胞(継代数1、25 cm2培養フラスコ入り、大日本製薬(Cell Systems Corporation)より購入)をCS-C培地(D-MEM培地とハムF12培地を1:1に等比混合した培地に、10%ウシ胎児血清、15mM HEPES、酸性FGF、およびヘパリンを添加した培地、Cell Systems Corporationより購入)に分散させ、コラーゲンをコーティングした24穴(1穴2cm2)のプレート1枚に添加して、5% CO2存在下、37℃で4日間の培養を行った。次にプレートの各穴の培地を廃棄し、1mlのクレブス-リンガー重炭酸(KRB)緩衝液(NaCl 129 mM、NaHCO3 5 mM、KCl 4.8 mM、KH2PO4 1.2 mM、CaCl2 1.0 mM、MgSO4 1.2 mM、グルコース 2.8 mM、 ウシ血清アルブミン 0.1%、HEPES 10 mM、PH 7.4)にて各穴を2回洗浄した。その後、360μl のKRB緩衝液に40μlの試料(10%DMSO (ジメチルスルホキシド)水溶液中の63〜500μMルテオリン、10%DMSO水溶液中の250〜1000μMルテオリン配糖体、または対照としての10%DMSO水溶液)を加えた溶液(反応液)400μlを各穴に添加し、5%CO2存在下、37℃で0〜8時間静置し、溶液中のエンドセリン−1濃度を測定した。その結果を表1及び図1に示す。表1は3時間の間に溶液中へ放出されたエンドセリン−1量を、10%DMSO水溶液添加時(反応液中でのDMSOの終濃度1%)のエンドセリン−1量(対照)を100%として比較した値(n = 4の平均値)で示す。図1は試料添加後の各時点における溶液中のエンドセリン−1濃度(n = 3の平均値)を示す。ルテオリン及びルテオリン配糖体(ルテオリン-6-C-グルコシド)にエンドセリン−1産生抑制効果が認められた。
Test Example 1 Endothelin-1 Production Inhibitory Activity of Luteolin and Luteolin Glycoside Porcine Aortic Endothelial Cells (
次に、MTT (臭化 3-[4,5-ジメチルチアゾール-2-イル]-2,5-ジフェニルテトラゾリウム)キット(Roche) により細胞増殖に対するクダモノトケイソウ果皮抽出物及び果肉抽出物の影響を検討したところ、表1の濃度範囲では細胞増殖に対して全く影響のないことが確認できた。 Next, we examined the effects of citrus peel and flesh extract on cell growth using MTT (3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide) kit (Roche) As a result, it was confirmed that the concentration range in Table 1 had no effect on cell proliferation.
試験例2 クダモノトケイソウ果皮抽出物からなるエンドセリン−1産生抑制剤の製造法
クダモノトケイソウの果実3個(那覇市内で購入)から剥いた果皮(150g)をミキサーで細かく破砕した後、メタノール200mlを加え、十分に攪拌した(電磁スターラー、400rpm、60分間)。次いで、濾紙(アドバンテック東洋製濾紙、No.2、直径30cm)による濾過を行って不溶物を除去し濾液を回収した。濾液をロータリエバポレーターで濃縮し、さらに真空ポンプによる減圧下で乾燥することにより、紫色の粉末3.6gを得た。
Test Example 2 Production Method of Endothelin-1 Production Inhibitor Consisting of Extract of Kudamono Passiflora Skin Extract Peeled peel (150 g) from 3 Kudamono passiflora fruits (purchased in Naha city) with a mixer, and then 200 ml of methanol In addition, the mixture was sufficiently stirred (electromagnetic stirrer, 400 rpm, 60 minutes). Subsequently, filtration with a filter paper (Advantech Toyo filter paper, No. 2, diameter 30 cm) was performed to remove insoluble matters, and the filtrate was recovered. The filtrate was concentrated with a rotary evaporator and further dried under reduced pressure using a vacuum pump to obtain 3.6 g of a purple powder.
試験例3 クダモノトケイソウ果肉抽出物からなるエンドセリン−1産生抑制剤の製造法
クダモノトケイソウの果実3個からゼリー状の果肉(種子を含む)110mlを採取し、これに同量の蒸留水を加え、十分に攪拌した(電磁スターラー、400rpm、60分間)。次いで、15,000rpmで20分間の遠心分離を行い不溶物を沈殿させ、上清を回収した。この溶液は限外濾過膜YM-10(分画分子量1万、Millipore)を通過させ、濾液を遠心式エバポレーターで濃縮し、さらに真空ポンプによる減圧下で乾燥することにより、薄いオレンジ色の粉末16gを得た。
Test Example 3 Production Method of Endothelin-1 Production Inhibitor Composed of Kudamono Passiflora Fruit Extract 110 ml of jelly-like flesh (including seeds) was collected from 3 Kudamono passiflora fruits, and the same amount of distilled water was added thereto. Stir well (electromagnetic stirrer, 400 rpm, 60 minutes). Subsequently, centrifugation was performed at 15,000 rpm for 20 minutes to precipitate insoluble matter, and the supernatant was collected. This solution was passed through an ultrafiltration membrane YM-10 (molecular weight cut off 10,000, Millipore), and the filtrate was concentrated with a centrifugal evaporator and dried under reduced pressure with a vacuum pump to obtain a light orange powder of 16 g. Got.
試験例4 クダモノトケイソウ果皮抽出物及び果肉抽出物のエンドセリン−1産生抑制活性
試験例1と同様に24穴プレートで培養したブタ大動脈内皮細胞をKRB緩衝液で2回洗浄した後、360μl のKRB緩衝液に40μlの試料(2.5〜40 mg/mlのクダモノトケイソウ果皮抽出物水溶液、0.75〜7.5 mg/mlのクダモノトケイソウ果肉抽出物水溶液、または対照としての蒸留水)を加えた溶液(反応液)400μlを各穴に添加し、5%CO2存在下、37℃で0〜8時間静置した。なお、試料添加時における細胞数は1穴あたり4.0 x 105個である。その後、上清200μlを回収して、遠心により混入した細胞を除去した。上清中のエンドセリン−1量は、エンドセリン−1 ELISAシステム(Amersham Biosciences)を用いた酵素免疫測定法により測定した。その結果を表2及び図2に示す。表2は3時間の間に溶液中へ放出されたエンドセリン−1量を、蒸留水添加時のエンドセリン−1量(対照)を100%として比較した値(n = 4の平均値)で示した。図2は試料添加後の各時点における溶液中のエンドセリン−1濃度(n = 3の平均値)を示した。クダモノトケイソウ果皮抽出物及びクダモノトケイソウ果肉抽出物にエンドセリン−1産生抑制効果が認められた。
Test Example 4 Endothelin-1 Production Inhibitory Activity of Kudamonodiaceutum Skin Extract and Flesh Extract As in Test Example 1, porcine aortic endothelial cells cultured in 24-well plates were washed twice with KRB buffer, and then 360 μl of KRB buffer. 400 μl of solution (reaction solution) with 40 μl of sample (2.5-40 mg / ml aqueous solution of citrus peel extract, 0.75-7.5 mg / ml aqueous solution of citrus fruit extract, or distilled water as a control) Was added to each hole and allowed to stand at 37 ° C. for 0-8 hours in the presence of 5% CO 2 . The number of cells at the time of sample addition is 4.0 × 10 5 per well. Thereafter, 200 μl of the supernatant was collected, and the contaminated cells were removed by centrifugation. The amount of endothelin-1 in the supernatant was measured by enzyme immunoassay using an endothelin-1 ELISA system (Amersham Biosciences). The results are shown in Table 2 and FIG. Table 2 shows the amount of endothelin-1 released into the solution during 3 hours as a value (average value of n = 4) compared with the amount of endothelin-1 at the time of adding distilled water (control) as 100%. . FIG. 2 shows the endothelin-1 concentration (average value of n = 3) in the solution at each time point after sample addition. An inhibitory effect on endothelin-1 production was observed in the citrus peel extract and the citrus peel extract.
次に、試験例1と同様に、MTT (臭化 3-[4,5-ジメチルチアゾール-2-イル]-2,5-ジフェニルテトラゾリウム)キット(Roche) により細胞増殖に対するクダモノトケイソウ果皮抽出物及び果肉抽出物の影響を検討したところ、表2の濃度範囲では細胞増殖に対して全く影響のないことが確認できた。 Next, as in Test Example 1, MTT (3- [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium bromide) kit (Roche) was used to extract citrus peel extract against cell proliferation and When the influence of the pulp extract was examined, it was confirmed that there was no influence on cell proliferation in the concentration range shown in Table 2.
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