JP6853578B2 - Composition containing shiitake extract - Google Patents
Composition containing shiitake extract Download PDFInfo
- Publication number
- JP6853578B2 JP6853578B2 JP2018034324A JP2018034324A JP6853578B2 JP 6853578 B2 JP6853578 B2 JP 6853578B2 JP 2018034324 A JP2018034324 A JP 2018034324A JP 2018034324 A JP2018034324 A JP 2018034324A JP 6853578 B2 JP6853578 B2 JP 6853578B2
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- JP
- Japan
- Prior art keywords
- shiitake extract
- pentosidine
- concentrated
- production
- foods
- 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.)
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Description
本発明は、シイタケ抽出物含有組成物に関する。より詳細には、本発明は、シイタケ抽出物を有効成分として含有する、ペントシジン生成阻害剤、ペントシジン生成阻害作用及び／又はカルボニルストレス阻害作用を有する食品組成物、医薬組成物及び化粧用組成物に関する。 The present invention relates to a composition containing a shiitake extract. More specifically, the present invention relates to a pentosidine production inhibitor, a food composition having a pentosidine production inhibitory action and / or a carbonyl stress inhibitory action, which contains a shiitake extract as an active ingredient, a pharmaceutical composition and a cosmetic composition. ..
糖化反応は、タンパク質やアミノ酸等の遊離アミノ基と、糖のアミノ基とが反応して褐色色素を生成するものであり、発見者の名に因みメイラード反応と呼ばれる。この反応は生体内でも生じることが知られており、糖尿病等の疾病や生体の老化に強く関連していることが明らかにされている。生体内において糖化反応が生じると、生体を構成するタンパク質が糖化し、変質する。糖化によって生成する物質の代表的なものとしては終末糖化産物（ＡＧＥｓ；Advanced Glycation End-products）が挙げられる。 The saccharification reaction is a reaction between a free amino group such as a protein or an amino acid and an amino group of a sugar to produce a brown pigment, and is called a Maillard reaction in the name of the discoverer. It is known that this reaction also occurs in the living body, and it has been clarified that it is strongly related to diseases such as diabetes and aging of the living body. When a glycation reaction occurs in a living body, the proteins constituting the living body are saccharified and denatured. Typical substances produced by saccharification include advanced glycation end-products (AGEs).
ＡＧＥｓは糖化産物の総称であり、特定の物質を指すものではない。生体内で生成される公知のＡＧＥｓとしては、ペントシジン、カルボキシメチルリジン、クロスリン、ピラリン等が挙げられる。それぞれの物質は前駆物質、架橋構造や蛍光性の有無等、化学的特徴が様々に異なることが知られている。 AGEs are a general term for saccharified products and do not refer to specific substances. Known AGEs produced in vivo include pentosidine, carboxymethyl lysine, crosulin, pyrarine and the like. It is known that each substance has various chemical characteristics such as a precursor, a crosslinked structure, and the presence or absence of fluorescence.
ＡＧＥｓが生体内で生成され蓄積されると、タンパク質本来の性質や存在する生体組織の機能が衰えたり失われたりするだけでなく、様々な疾患の原因になり得る。皮膚や血管を構成するコラーゲンが糖化すると、弾力性を失い、皮膚ではシワの形成やたるみが生じる。血管組織においては動脈硬化に代表される循環器疾患の発症と進展をもたらす。本来、糖化反応に対する防御機構は生体内に備わっているが、加齢とともに減衰する。 When AGEs are produced and accumulated in a living body, not only the original properties of proteins and the functions of existing living tissues are deteriorated or lost, but also they can cause various diseases. When collagen, which constitutes the skin and blood vessels, is glycated, it loses its elasticity, and wrinkles and sagging occur on the skin. In vascular tissue, it causes the onset and progression of cardiovascular diseases such as arteriosclerosis. Originally, the defense mechanism against the glycation reaction is provided in the living body, but it declines with aging.
生体内の糖化反応は、健常な人においても日常生活で徐々に進行しており、その抑制も長期にわたって継続的に実施しないと期待する効果を得られないことから、継続使用しても安全性が高く、また継続使用により糖化反応抑制効果以外の有用な効果も得られるような手段が研究され、提案が数多くなされている。例えば、ポリフェノール類等の化合物や、食経験のある食品原料の抽出物等を含有する、ＡＧＥｓ生成阻害剤、ＡＧＥｓ結合又は分解剤、及び体内糖化反応抑制用の経口組成物等が提案されている（特許文献１から３等）。 The glycation reaction in the living body is gradually progressing in daily life even in healthy people, and it is safe to use it continuously because the expected effect cannot be obtained unless the suppression is continuously performed for a long period of time. There are many studies and proposals for means that can obtain useful effects other than the saccharification reaction inhibitory effect by continuous use. For example, AGEs production inhibitors, AGEs binding or degrading agents, and oral compositions for suppressing glycation reaction in the body, which contain compounds such as polyphenols and extracts of food raw materials having eating experience, have been proposed. (Patent Documents 1 to 3 etc.).
糖化反応は複雑かつ多経路であるため、一つの反応経路を阻害してもＡＧＥｓの生成を有効に阻止することは難しい。そのため、単一のin vitro実験系で評価された抗糖化剤が必ずしも生体内の糖化反応抑制に有効ではない（非特許文献１）。例えば、特許文献４には、多数の植物由来エキスについて、糖化反応における複数の中間生成物及び最終生成物の生成阻害能を測定したところ、エキスごとに異なる中間生成物・最終生成物の生成阻害能が確認されたことが示されている。 Since the saccharification reaction is complicated and has multiple pathways, it is difficult to effectively prevent the production of AGEs even if one reaction pathway is inhibited. Therefore, the anti-glycation agent evaluated in a single in vitro experimental system is not always effective in suppressing the glycation reaction in the living body (Non-Patent Document 1). For example, in Patent Document 4, when the ability to inhibit the production of a plurality of intermediate products and final products in a saccharification reaction was measured for a large number of plant-derived extracts, the production inhibition of intermediate products and final products different for each extract was measured. It is shown that the ability was confirmed.
抗糖化作用を有する化合物が求められており、例えば、特許文献５に開示されているアミノグアニジンは、糖尿病性腎症治療薬として開発されていた物質で優れた抗糖化作用を示すが、貧血や肝障害等の副作用を有しており、安全性の面で実用化には至っていない。 A compound having an anti-glycation effect is required. For example, aminoguanidine disclosed in Patent Document 5 is a substance developed as a therapeutic agent for diabetic nephropathy and exhibits an excellent anti-glycation effect, but anemia and anemia. It has side effects such as liver damage and has not been put into practical use in terms of safety.
一方、過酸化脂質生成やペントシジン生成とカルボニルストレスとの関係についても研究が進められている。酸化ストレス下では脂質過酸化が進行し、マロンジアルデヒドやヒドロキシノネナールの生成等、様々な糖化反応と酸化反応が同時的に進行する。生体内において、糖や脂質由来の様々なカルボニル化合物の非酵素的反応による生成が亢進し、その結果としてペントシジン等の特定のＡＧＥｓの産生が亢進し、それらが蓄積した状態をカルボニルストレスと呼ぶ。非特許文献２には、統合失調症に、カルボニルストレスが関連していることが開示されている。統合失調症患者では、ペントシジンの蓄積とカルボニルスカベンジャーとして働くビタミンＢ６の欠乏が観察されており、ペントシジンとビタミンＢ６は臨床的に有用なバイオマーカーとされている。
On the other hand, research is also underway on the relationship between lipid peroxide production and pentosidine production and carbonyl stress. Under oxidative stress, lipid peroxidation proceeds, and various saccharification reactions and oxidation reactions such as the production of malondialdehyde and hydroxynonenal proceed simultaneously. In the living body, the production of various carbonyl compounds derived from sugars and lipids by non-enzymatic reactions is enhanced, and as a result, the production of specific AGEs such as pentosidine is enhanced, and the state in which they are accumulated is called carbonyl stress.
以上のような背景のもと、本発明は、安全で経口投与可能な、食用成分由来の、ペントシジン生成阻害作用及び／又はカルボニルストレス阻害作用を有する組成物を提供することを目的とする。 Against the above background, an object of the present invention is to provide a composition which is safe and can be orally administered, is derived from an edible component, and has a pentosidine production inhibitory action and / or a carbonyl stress inhibitory action.
本発明者らは、上記課題を解決するため研究を重ねた結果、食経験が豊富で安全性の高いシイタケを原料としたシイタケ抽出物を投与すると生体内のペントシジン生成及び過酸化脂質生成並びにこれらに伴うカルボニルストレスを抑制することができることを見出し、本発明を完成するに至った。 As a result of repeated studies to solve the above problems, the present inventors have administered a shiitake extract made from shiitake mushrooms, which has abundant eating experience and is highly safe, to produce pentosidine and lipid peroxide in vivo, and these. We have found that the carbonyl stress associated with the above can be suppressed, and have completed the present invention.
すなわち、本発明は、以下に関する。
[１]
シイタケ抽出物を有効成分として含有する、ペントシジン生成阻害剤。
[２]
シイタケ抽出物を有効成分として含有する、ペントシジン生成阻害作用及び／又はカルボニルストレス阻害作用を有する食品組成物。
[３]
食品組成物が、サプリメント、保険機能食品、特定保健用食品、栄養機能食品、機能性表示食品、特別用途食品、病者用食品、栄養補助食品、健康補助食品、飲料、調味料、保存料及び添加物からなる群から選択される、[２]に記載の食品組成物。
[４]
シイタケ抽出物を有効成分として含有する、ペントシジン生成及び／又はカルボニルストレスに関連した疾患を治療又は予防するための医薬組成物。
[５]
前記疾患が、糖尿病、糖尿病合併症、動脈硬化、心筋梗塞、脳梗塞、癌、白内障、骨粗しょう症、アルツハイマー型認知症、慢性腎不全、リウマチ様関節炎、重症アトピー性皮膚炎及び統合失調症等からなる群から選択される、[４]に記載の医薬組成物。
[６]
シイタケ抽出物を有効成分として含有する、ペントシジン生成及び／又はカルボニルストレスに関連した状態を改善又は予防するための化粧用組成物。
[７]
前記状態が、皮膚弾力性の低下、皮膚柔軟性の低下、皮膚のきめの低下、シワの生成、ニキビ、吹き出物及び加齢臭の生成からなる群から選択される、請求項６に記載の化粧用組成物。
［８］
対象に２週間投与後、ペントシジン生成阻害作用、ペントシジン生成及び／又はカルボニルストレスに関連した疾患の治療又は予防作用、或いはペントシジン生成及び／又はカルボニルストレスに関連した状態の改善又は予防作用が得られる、［１］から［７］のいずれかに記載の剤又は組成物。
That is, the present invention relates to the following.
[1]
A pentosidine production inhibitor containing shiitake extract as an active ingredient.
[2]
A food composition containing shiitake extract as an active ingredient and having a pentosidine production inhibitory action and / or a carbonyl stress inhibitory action.
[3]
Food compositions include supplements, foods with insurance function, foods for specified health use, foods with nutritional function, foods with functional claims, special purpose foods, foods for the sick, nutritional supplements, health supplements, beverages, seasonings, preservatives and The food composition according to [2], which is selected from the group consisting of additives.
[4]
A pharmaceutical composition containing shiitake extract as an active ingredient for treating or preventing diseases related to pentosidine production and / or carbonyl stress.
[5]
The diseases include diabetes, diabetic complications, arteriosclerosis, myocardial infarction, cerebral infarction, cancer, cataract, osteoporosis, Alzheimer's dementia, chronic renal failure, rheumatoid arthritis, severe atopic dermatitis, schizophrenia, etc. The pharmaceutical composition according to [4], which is selected from the group consisting of.
[6]
A cosmetic composition containing shiitake extract as an active ingredient for improving or preventing conditions associated with pentosidine production and / or carbonyl stress.
[7]
The makeup according to claim 6, wherein the condition is selected from the group consisting of decreased skin elasticity, decreased skin flexibility, decreased skin texture, wrinkle formation, acne, pimples and aging odor formation. Composition for.
[8]
After administration to the subject for 2 weeks, a pentosidine production inhibitory effect, a pentosidine production and / or carbonyl stress-related disease treatment or preventive effect, or a pentosidine production and / or carbonyl stress-related condition improvement or preventive effect can be obtained. The agent or composition according to any one of [1] to [7].
本発明によれば、安全で経口投与可能な、食用成分由来の、ペントシジン生成阻害作用及び／又はカルボニルストレス阻害作用を有する組成物を提供することができる。 According to the present invention, it is possible to provide a composition which is safe and can be orally administered, is derived from an edible component, and has a pentosidine production inhibitory action and / or a carbonyl stress inhibitory action.
以下に、本発明の好適な実施形態について説明する。 Hereinafter, preferred embodiments of the present invention will be described.
［シイタケ抽出物］
本実施形態のシイタケ抽出物は、シイタケを原料として水系溶媒により抽出してつくられる。抽出処理は、シイタケから水溶性成分を抽出可能な方法であれば特に限定されないが、簡便には、乾燥シイタケを熱水で煮ることにより抽出処理を実施することができる。
用いるシイタケは、シイタケ属シイタケ種に属するものであれば特に限定されない。抽出には、生のシイタケを用いても乾燥シイタケを用いてもよいが、抽出効率及び保存性の観点から乾燥シイタケを用いることが好ましい。
[Shiitake extract]
The shiitake extract of the present embodiment is produced by extracting shiitake with an aqueous solvent as a raw material. The extraction treatment is not particularly limited as long as it is a method capable of extracting water-soluble components from shiitake mushrooms, but the extraction treatment can be conveniently carried out by boiling dried shiitake mushrooms in hot water.
The shiitake mushroom used is not particularly limited as long as it belongs to the genus Shiitake mushroom species. Raw shiitake mushrooms or dried shiitake mushrooms may be used for extraction, but it is preferable to use dried shiitake mushrooms from the viewpoint of extraction efficiency and storage stability.
抽出溶媒としては、水（水蒸気を含む）、塩水、メタノール、エタノール、１−プロパノール、２−プロパノール、希酢酸、希塩酸及びこれらのいずれかの混合物を用いることができ、安全性及び簡便性の観点から、水（０℃〜１００℃）を用いることが好ましい。
シイタケに対する抽出溶媒の量は、所望の抽出物が得られる限り特に限定されないが、簡便性の観点から、乾燥シイタケ１重量部に対して、例えば１０〜５０重量部、好ましくは２０〜３０重量部の抽出溶媒を用いて抽出を行うことができる。
抽出時間及び抽出温度も、所望の抽出物が得られる限り特に限定されないが、一般的には、抽出温度が高い場合、より短い抽出時間、抽出温度が低い場合、より長い抽出時間を採用することができる。例えば、８０℃〜１００℃、好ましくは９０℃〜１００℃の熱水を用いて、１０〜６０分、好ましくは２０〜４０分抽出を実施することができる。
As the extraction solvent, water (including water vapor), salt water, methanol, ethanol, 1-propanol, 2-propanol, dilute acetic acid, dilute hydrochloric acid or a mixture thereof can be used, and from the viewpoint of safety and convenience. Therefore, it is preferable to use water (0 ° C to 100 ° C).
The amount of the extraction solvent for shiitake mushrooms is not particularly limited as long as a desired extract can be obtained, but from the viewpoint of convenience, for example, 10 to 50 parts by weight, preferably 20 to 30 parts by weight, based on 1 part by weight of dried shiitake mushrooms. Extraction can be carried out using the extraction solvent of.
The extraction time and the extraction temperature are also not particularly limited as long as the desired extract can be obtained, but in general, when the extraction temperature is high, a shorter extraction time is adopted, and when the extraction temperature is low, a longer extraction time is adopted. Can be done. For example, extraction can be carried out for 10 to 60 minutes, preferably 20 to 40 minutes using hot water at 80 ° C. to 100 ° C., preferably 90 ° C. to 100 ° C.
得られた抽出物は、そのままシイタケ抽出物としてもよいし、そのまま、又は必要に応じて公知の賦形剤を添加後、乾燥・粉末化し、シイタケ抽出物としてもよい。投与量を減少させるため、得られた抽出物を、そのまま又は賦形剤を添加後更に濃縮し、これを乾燥・粉末化してシイタケ抽出物としてもよい。
賦形剤としては、医薬品、サプリメント等に一般に用いられるものであれば特に限定されず、乳糖、麦芽糖、還元麦芽糖水飴、デンプン、デキストリン、セルロース等を使用することができ、乾燥物の形状及び品質の安定性の観点から、好ましくはデキストリンを用いることができる。
シイタケ抽出物の乾燥・粉末化は、凍結乾燥、噴霧乾燥等、公知の方法を用いることができ、必要に応じてハンマーミル、回転ミル、ローラーミル、ジェットミル等公知の粉砕機を用いた粉砕を組み合わせることができる。
The obtained extract may be used as it is as a shiitake extract, or may be used as it is, or after adding a known excipient as needed, dried and powdered to obtain a shiitake extract. In order to reduce the dose, the obtained extract may be used as it is or after adding an excipient, the extract may be further concentrated, and the extract may be dried and powdered to obtain a shiitake extract.
The excipient is not particularly limited as long as it is generally used for pharmaceuticals, supplements, etc., and lactose, maltose, reduced maltose starch syrup, starch, dextrin, cellulose, etc. can be used, and the shape and quality of the dried product can be used. From the viewpoint of stability, dextrin can be preferably used.
Known methods such as freeze-drying and spray-drying can be used for drying and pulverizing the shiitake extract, and if necessary, crushing using a known crusher such as a hammer mill, a rotary mill, a roller mill, or a jet mill. Can be combined.
シイタケ抽出物を濃縮する場合、濃縮は、公知方法を用いることができる。例えば、エバポレータ（遠心式薄膜真空蒸発装置等の真空蒸発装置、減圧濃縮装置等を含む）を用いて、又はシリカゲルカラム、ＯＤＳカラム、イオン交換樹脂等のカラムを用いて、シイタケ成分を多く含む濃縮液を調製することができる。一態様において、本実施形態のシイタケ抽出物は、イオン交換樹脂、特に陽イオン交換樹脂を用いて濃縮したものが好ましい。あるいは、公知の手法及び機器を用いて、凍結濃縮法、逆浸透膜による膜濃縮法、超音波霧化分離法等により濃縮液を調整することができる。濃縮前後でシイタケ成分が濃縮されたか否かは、例えばＢｒｉｘ値を測定することによって確認することができる。限定されるものではないが、本実施形態のシイタケ抽出物のＢｒｉｘ値は５〜６０％、好ましくは２５〜４０％である。Ｂｒｉｘ値の測定は、糖度計による測定等、当業者に公知の手法を用いて実施することができる。 When the shiitake extract is concentrated, a known method can be used for the concentration. For example, using an evaporator (including a vacuum evaporator such as a centrifugal thin film vacuum evaporator, a vacuum concentrator, etc.) or using a column such as a silica gel column, an ODS column, or an ion exchange resin, concentration containing a large amount of shiitake components The liquid can be prepared. In one aspect, the shiitake extract of the present embodiment is preferably concentrated using an ion exchange resin, particularly a cation exchange resin. Alternatively, the concentrated solution can be prepared by a freeze concentration method, a membrane concentration method using a reverse osmosis membrane, an ultrasonic atomization separation method, or the like using known methods and equipment. Whether or not the shiitake mushroom component is concentrated before and after the concentration can be confirmed, for example, by measuring the Brix value. Although not limited, the Brix value of the shiitake extract of the present embodiment is 5 to 60%, preferably 25 to 40%. The Brix value can be measured by using a method known to those skilled in the art, such as measurement with a sugar content meter.
一態様において、本実施形態のシイタケ抽出物は、エルゴチオネイン、ビタミンＢ６、ナイアシンのいずれか一以上、好ましくはこれらすべての成分を含有する。
シイタケ抽出物中のエルゴチオネイン含有量は、乾燥物１００ｇあたり２００ｍｇ以上が好ましく、５００ｍｇ以上がより好ましく、１０００ｍｇ以上が特に好ましい。上限値は特に限定されるものではないが、例えば乾燥物１００ｇあたり３０００ｍｇ以下、好ましくは２０００ｍｇ以下とすることができる。
シイタケ抽出物中のビタミンＢ６含有量は、乾燥物１００ｇあたり１ｍｇ以上が好ましく、３ｍｇ以上がより好ましく、５ｍｇが特に好ましい。上限値は特に限定されるものではないが、乾燥物１００ｇあたり例えば２０ｍｇ以下、好ましくは１０ｍｇ以下とすることができる。
シイタケ抽出物中のナイアシン含有量は、乾燥物１００ｇあたり５０ｍｇ以上が好ましく、１００ｍｇ以上がより好ましく、２００ｍｇ以上が特に好ましい。上限値は特に限定されるものではないが、乾燥物１００ｇあたり例えば５００ｍｇ以下、好ましくは４００ｍｇ以下とすることができる。
In one embodiment, the shiitake extract of the present embodiment contains any one or more of ergothioneine, vitamin B6, and niacin, preferably all of these components.
The content of ergothioneine in the shiitake extract is preferably 200 mg or more, more preferably 500 mg or more, and particularly preferably 1000 mg or more per 100 g of the dried product. The upper limit is not particularly limited, but can be, for example, 3000 mg or less, preferably 2000 mg or less per 100 g of the dried product.
The content of vitamin B6 in the shiitake extract is preferably 1 mg or more, more preferably 3 mg or more, and particularly preferably 5 mg per 100 g of the dried product. The upper limit is not particularly limited, but can be, for example, 20 mg or less, preferably 10 mg or less per 100 g of the dried product.
The niacin content in the shiitake extract is preferably 50 mg or more, more preferably 100 mg or more, and particularly preferably 200 mg or more per 100 g of the dried product. The upper limit is not particularly limited, but can be, for example, 500 mg or less, preferably 400 mg or less per 100 g of the dried product.
なお、シイタケ抽出物は、粉状もしくは液状の形態で、食品素材として販売されており、本発明ではこのような食品素材（例えば、シイタケエキスパウダーとして、池田糖化工業株式会社、井村屋シーズニング株式会社、カッセイ食品株式会社等が販売する食品素材等）も使用することができる。 The shiitake extract is sold as a food material in the form of powder or liquid, and in the present invention, such a food material (for example, as shiitake extract powder, Ikeda Saccharification Industry Co., Ltd., Imuraya Seasoning Co., Ltd.) , Food materials sold by Kassei Foods Co., Ltd., etc.) can also be used.
上記のシイタケ抽出物は、そのまま、ペントシジン生成阻害剤、食品組成物、医薬組成物又は化粧用組成物（以下、これらをまとめて「本実施形態の組成物」という。）としてもよいし、当業者に公知の手法を用いて本実施形態の組成物に添加してもよい。 The above-mentioned shiitake extract may be used as it is as a pentosidine production inhibitor, a food composition, a pharmaceutical composition or a cosmetic composition (hereinafter, these are collectively referred to as "the composition of the present embodiment"). It may be added to the composition of this embodiment by a method known to those skilled in the art.
本実施形態の組成物は、抗糖化作用として特にペントシジン生成阻害作用を有することを特徴とする。ペントシジンは皮膚や骨質等のエラスチンやコラーゲンを含有する多数の組織に認められる主要な架橋性ＡＧＥｓであり、リジン残基とアルギニン残基が五炭糖により架橋された構造を有する。糖尿病、慢性腎不全、リウマチ様関節炎、重症アトピー性皮膚炎等、様々な疾患において、血中ペントシジンが高値であることが報告されているため、本実施形態の組成物は、ペントシジン生成が関連するこれらの疾患や状態の治療又は予防にも有用である。さらに、ヒト硬膜や皮膚コラーゲンでは加齢に伴うペントシジン蓄積の進行が確認されており、架橋性のペントシジンの増加は、皮膚弾力性にも影響するため、本実施形態の組成物は、これらの状態の改善又は予防にも有用である。 The composition of the present embodiment is characterized by having a pentosidine production inhibitory action as an anti-glycation action. Pentosidine is a major cross-linking AGEs found in many tissues containing elastin and collagen such as skin and bone, and has a structure in which lysine residues and arginine residues are cross-linked by pentacarbon sugar. Since it has been reported that blood pentosidine is high in various diseases such as diabetes, chronic renal failure, rheumatoid arthritis, and severe atopic dermatitis, the composition of the present embodiment is associated with pentosidine production. It is also useful for the treatment or prevention of these diseases and conditions. Furthermore, it has been confirmed that pentosidine accumulation progresses with age in human dura mater and skin collagen, and an increase in crosslinkable pentosidine also affects skin elasticity. It is also useful for improving or preventing the condition.
本明細書において、ペントシジン生成阻害作用とはペントシジン生成を予防又は抑制する作用を指し、より具体的には、ペントシジンの量又は濃度が低下することを指す。生体内におけるペントシジン生成阻害作用の評価は、例えば後述の実施例に示す通り、血中のペントシジン濃度の推移をＥＬＩＳＡ法等公知の手法で測定することによって行うことができる。 As used herein, the action of inhibiting pentosidine production refers to an action of preventing or suppressing pentosidine production, and more specifically, it means that the amount or concentration of pentosidine is reduced. The evaluation of the pentosidine production inhibitory action in the living body can be performed by measuring the transition of the pentosidine concentration in blood by a known method such as the ELISA method, as shown in Examples described later.
本実施形態の組成物は、様々なＡＧＥｓ及びその中間生成物のうち、ペントシジン生成を阻害する物であれば特に限定されない。ＡＧＥｓには様々な生成経路が存在するため、ある一種のＡＧＥｓの生成が阻害されても、他のＡＧＥｓの生成は阻害されない場合もある。一態様において、本実施形態の組成物は、ＡＧＥｓ及びその中間生成物のうち、カルボキシメチルリジン（ＣＭＬ）及び／又は３−デオキシグルコソン（３−ＤＧ）の生成を阻害しない。 The composition of the present embodiment is not particularly limited as long as it inhibits pentosidine production among various AGEs and intermediate products thereof. Since there are various production pathways for AGEs, even if the production of one kind of AGEs is inhibited, the production of other AGEs may not be inhibited. In one aspect, the composition of this embodiment does not inhibit the production of carboxymethyl lysine (CML) and / or 3-deoxyglucosone (3-DG) among AGEs and their intermediate products.
一態様において、本実施形態の組成物は、また、カルボニルストレス阻害作用を有する。カルボニルストレスには様々な要因が関与しているが、ペントシジンの蓄積と、カルボニルストレスに関連した統合失調症や糖尿病合併症等の疾患の関連が強く示唆されている。また、過酸化脂質の生成も、カルボニルストレスに関与すると考えられている。 In one aspect, the composition of this embodiment also has a carbonyl stress inhibitory effect. Although various factors are involved in carbonyl stress, it is strongly suggested that the accumulation of pentosidine is associated with diseases such as schizophrenia and diabetic complications related to carbonyl stress. The production of lipid peroxides is also thought to be involved in carbonyl stress.
本明細書において、カルボニルストレス阻害作用とはカルボニルストレスを予防又は抑制する作用を指す。生体内において、糖や脂質由来の様々なカルボニル化合物の非酵素的反応による生成が亢進し、その結果としてペントシジン等の特定のＡＧＥｓの産生が亢進し、それらが蓄積した状態がカルボニルストレスと呼ばれる。よって、より具体的には、カルボニルストレス阻害作用は、ペントシジン及び／又は過酸化脂質の量又は濃度の低下によって確認することができる。ペントシジンは生体内におけるカルボニルストレスによる組織変性の指標となるものであり、血中のペントシジン濃度が減少している場合に、カルボニルストレスが除去、低減又は抑制され、カルボニルストレスが阻害されていると評価することができる。なお、ペントシジンは臨床検査項目として保険収載されている。生体内におけるペントシジンの量又は濃度の評価については上述したとおりであり、同様に、血中の過酸化脂質濃度が減少している場合に、カルボニルストレスが除去、低減又は抑制され、カルボニルストレスが阻害されていると評価することができる。生体内における過酸化脂質の量又は濃度の評価は、例えば後述の実施例に示すとおり、血中の過酸化脂質の濃度の推移をＴＢＡ法（チオバルビツール酸法）等公知の手法で測定することによって行うことができる。 As used herein, the carbonyl stress inhibitory action refers to an action of preventing or suppressing carbonyl stress. In the living body, the production of various carbonyl compounds derived from sugars and lipids by non-enzymatic reactions is enhanced, and as a result, the production of specific AGEs such as pentosidine is enhanced, and the state in which they are accumulated is called carbonyl stress. Therefore, more specifically, the carbonyl stress inhibitory effect can be confirmed by a decrease in the amount or concentration of pentosidine and / or lipid peroxide. Pentosidine is an index of tissue degeneration caused by carbonyl stress in the living body, and it is evaluated that carbonyl stress is removed, reduced or suppressed, and carbonyl stress is inhibited when the concentration of pentosidine in blood is decreased. can do. Pentosidine is covered by insurance as a clinical test item. The evaluation of the amount or concentration of pentosidine in the living body is as described above. Similarly, when the blood lipid peroxide concentration is decreased, the carbonyl stress is removed, reduced or suppressed, and the carbonyl stress is inhibited. It can be evaluated as being done. To evaluate the amount or concentration of lipid peroxide in a living body, for example, as shown in Examples described later, the transition of the concentration of lipid peroxide in blood is measured by a known method such as the TBA method (thiobarbituric acid method). Can be done by
上記のペントシジン生成／カルボニルストレス阻害作用の確認に先立って、抗糖化作用を確認してもよい。抗糖化作用を有するか否かの判断は、例えば後述の実施例に示すとおり、ＡＧＥｓ量をＡＧＥリーダー等の測定器を用いて測定することによって行うことができる。一態様において、本実施形態の組成物の投与前と投与後（例えば、継続投与４週間後、より好ましくは、継続投与２週間後）において、投与前のＡＧＥｓ量を１００％とした場合に２％以上、好ましくは３％以上、より好ましくは５％以上、投与後のＡＧＥｓ量が減少している場合に、本実施形態の組成物が、抗糖化作用を有すると判断することができる。
一態様において、本実施形態の組成物は、短期間の投与で上記抗糖化作用を発揮することが可能であり、例えば、後述の実施例に示すとおり、比較的ＡＧＥｓ量の減少に時間がかかると考えられる皮膚ＡＧＥｓ量を、投与開始から２週間後（例えば、１回／日の投与２週間後）に減少し得る。
Prior to confirming the above-mentioned pentosidine production / carbonyl stress inhibitory action, the anti-glycation action may be confirmed. Whether or not it has an anti-glycation effect can be determined, for example, by measuring the amount of AGEs using a measuring device such as an AGE reader, as shown in Examples described later. In one embodiment, when the amount of AGEs before administration is 100% before and after administration of the composition of the present embodiment (for example, 4 weeks after continuous administration, more preferably 2 weeks after continuous administration), 2 When the amount of AGEs after administration is reduced by% or more, preferably 3% or more, more preferably 5% or more, it can be determined that the composition of the present embodiment has an anti-glycation effect.
In one embodiment, the composition of the present embodiment can exert the above-mentioned anti-glycation effect by administration for a short period of time, and for example, as shown in Examples described later, it takes a relatively long time to reduce the amount of AGEs. The amount of skin AGEs considered to be considered can be reduced 2 weeks after the start of administration (for example, 2 weeks after administration once a day).
本実施形態の組成物の投与量は、用途（医薬、食品、化粧品等）や投与対象（年齢、体重、疾患・状態の重篤度等）に応じて適宜調整することができるが、例えば、後述の実施例を参照して、同程度の濃度の本実施形態の組成物を、固形分（乾燥物）換算で０．１〜１０ｇ／日を投与する量とすることができる。一態様において、本実施形態の組成物の投与量は、組成物中のエルゴチオネイン、ビタミンＢ６及びナイアシンから選択される成分の含有量を目安に調整することができ、エルゴチオネイン約１〜１００ｍｇ／日、好ましくは、５〜５０ｍｇ／日、例えば、約１０ｍｇ／日程度；ビタミンＢ６約５〜５００μｇ／日、好ましくは１０〜３００μｇ／日、例えば約４０μｇ／日程度、ナイアシン約０．２〜２０ｍｇ／日、好ましくは０．５〜１０ｍｇ／日、例えば、約２ｍｇ／日程度、のいずれか一以上を満たす量を投与することができる。
投与回数は特に制限されないが、好ましくは１日１〜３回であり、必要に応じて投与回数を増減してもよい。上記の投与量を実現するよう、投与回数及び単回投与量を適宜調整することができる。
例えば食品組成物に本実施形態の組成物を配合して製品加工する場合、食品組成物製品の全量中、本実施形態の組成物を固形分換算で０．０１〜９９．９重量％含有するように製品を製造することもできる。
The dose of the composition of the present embodiment can be appropriately adjusted according to the intended use (medicine, food, cosmetics, etc.) and the administration target (age, body weight, severity of disease / condition, etc.). With reference to the examples described later, the composition of the present embodiment having the same concentration can be administered in an amount of 0.1 to 10 g / day in terms of solid content (dried product). In one embodiment, the dose of the composition of the present embodiment can be adjusted based on the content of a component selected from ergothioneine, vitamin B6 and niacin in the composition, and the dose of ergothioneine is about 1 to 100 mg / day. Preferably, 5 to 50 mg / day, for example, about 10 mg / day; vitamin B6, about 5 to 500 μg / day, preferably 10 to 300 μg / day, for example, about 40 μg / day, niacin, about 0.2 to 20 mg / day. , Preferably 0.5 to 10 mg / day, for example, about 2 mg / day, an amount satisfying any one or more can be administered.
The number of administrations is not particularly limited, but is preferably 1 to 3 times a day, and the number of administrations may be increased or decreased as needed. The number of doses and the single dose can be appropriately adjusted so as to achieve the above dose.
For example, when the composition of the present embodiment is blended with the food composition and processed into a product, the composition of the present embodiment is contained in an amount of 0.01 to 99.9% by weight in terms of solid content in the total amount of the food composition product. The product can also be manufactured as such.
［食品組成物］
一態様において、本発明は、上記のシイタケ抽出物を有効成分として含有する、上記ペントシジン生成阻害作用及び／又はカルボニルストレス阻害作用を有する食品組成物に関する。
[Food composition]
In one aspect, the present invention relates to a food composition containing the above-mentioned shiitake extract as an active ingredient and having the above-mentioned pentosidine production inhibitory action and / or carbonyl stress inhibitory action.
食品組成物としては、通常の飲食品のほか、サプリメント、保険機能食品（特定保健用食品、栄養機能食品、機能性表示食品）、特別用途食品（病者用食品等）、栄養補助食品、健康補助食品等が挙げられる。
食品組成物の形状としては、ジュース、清涼飲料、ドリンク剤、調味料、茶等の液状、ビスケット、タブレット、顆粒粉末、粉末、カプセル等の固形状、ペースト、ゼリー、スープ、調味料、ドレッシング等の半流動状等が挙げられる。シイタケ抽出物は可溶性であり、容易に飲料形態とすることができる。また、旨味成分であるグルタミン酸やグアニル酸を含有するため、調味料としても用いることができる。さらに、食品の褐変や変色防止を期待して、食品保存料、食品添加物等としても用いることができる。
これらの食品組成物は、いずれも当業者に公知の手法を用いて、本実施形態のシイタケ抽出物を添加して製造することができる。例えば、本実施形態のシイタケ抽出物のほかに、所望の作用を損なわない範囲で、その他の成分をさらに含有してもよい。例えば、乳化剤、甘味料、酸化防止剤、着色料、調味料、ビタミン類、ミネラル類、香料、着色料、増粘多糖類等の従来公知の食品添加物等、従来食品に添加される他の成分を含んでもよい。
In addition to ordinary foods and drinks, food compositions include supplements, foods with insurance function (foods for specified health use, foods with nutritional function, foods with functional claims), special-purpose foods (foods for the sick, etc.), nutritional supplements, and health. Supplements and the like can be mentioned.
The shape of the food composition includes juices, soft drinks, drinks, seasonings, liquids such as tea, solids such as biscuits, tablets, granule powders, powders, capsules, pastes, jellies, soups, seasonings, dressings, etc. Semi-fluid state and the like. The shiitake extract is soluble and can be easily made into a beverage form. Further, since it contains glutamic acid and guanylic acid, which are umami components, it can also be used as a seasoning. Further, it can be used as a food preservative, a food additive, etc. in anticipation of preventing browning or discoloration of food.
All of these food compositions can be produced by adding the shiitake extract of the present embodiment using a method known to those skilled in the art. For example, in addition to the shiitake extract of the present embodiment, other components may be further contained as long as the desired action is not impaired. Others added to conventional foods, such as conventionally known food additives such as emulsifiers, sweeteners, antioxidants, colorants, seasonings, vitamins, minerals, flavors, colorants, thickening polysaccharides, etc. Ingredients may be included.
本実施形態の食品組成物は、ペントシジン生成及び／又はカルボニルストレスに関連した状態の予防又は改善作用（例えば、糖尿病、糖尿病合併症、動脈硬化、慢性腎不全、リウマチ様関節炎、重症アトピー性皮膚炎、統合失調症、骨粗しょう症等の予防作用、加齢に伴う血管組織老化の予防又は改善作用、皮膚弾力性の低下、皮膚柔軟性の低下、シワの生成等、加齢に伴う皮膚組織老化の予防又は改善作用、加齢臭の予防又は改善作用、口臭の予防又は改善作用、便臭の改善作用等）、生鮮食品又は鮮魚等の色落ち・味の変化の防止作用を有する旨の表示を付した食品組成物であってもよい。 The food composition of the present embodiment has a preventive or ameliorating effect on conditions associated with pentosidine production and / or carbonyl stress (eg, diabetes, diabetic complications, arteriosclerosis, chronic renal failure, rheumatoid arthritis, severe atopic dermatitis). , Preventive action such as schizophrenia and osteoporosis, preventive or ameliorating action of vascular tissue aging associated with aging, decreased skin elasticity, decreased skin flexibility, generation of wrinkles, etc. (Prevention or improvement of aging, prevention or improvement of aging odor, prevention or improvement of mouth odor, improvement of stool odor, etc.) It may be a food composition with.
［医薬組成物］
一態様において、本発明は、上記のシイタケ抽出物を有効成分として含有する、ペントシジン生成及び／又はカルボニルストレスに関連した疾患を治療又は予防するための医薬組成物に関する。当該疾患の治療又は予防には、疾患に伴う症状の改善又は予防も含まれる。
[Pharmaceutical composition]
In one aspect, the present invention relates to a pharmaceutical composition containing the above-mentioned shiitake extract as an active ingredient for treating or preventing a disease related to pentosidine production and / or carbonyl stress. Treatment or prevention of the disease also includes improvement or prevention of symptoms associated with the disease.
医薬組成物は、特に限定されないが、錠剤、カプセル剤、顆粒剤、細粒剤、散剤、液剤、シロップ剤、チュアブル、トローチ等の経口剤、軟膏剤、ゲル剤、クリーム剤、貼付剤等の外用剤、注射剤、舌下剤、吸入剤、点眼剤、坐剤等の剤型であることができる。一態様において、好ましい剤型は、経口剤である。
医薬組成物は、当業者に公知の薬学的に許容可能な賦形剤、緩衝剤、充填剤、湿潤剤、乳化剤、滑沢剤、着色剤、放出剤、コーティング剤、甘味剤、香料、保存剤及び抗酸化剤等の一以上を含むものであってもよい。
The pharmaceutical composition is not particularly limited, but includes tablets, capsules, granules, fine granules, powders, liquids, syrups, chewables, oral preparations such as troches, ointments, gels, creams, patches and the like. It can be a dosage form such as an external preparation, an injection, a sublingual preparation, an inhalant, an eye drop, or a suppository. In one aspect, the preferred dosage form is an oral preparation.
Pharmaceutical compositions are pharmaceutically acceptable excipients, buffers, fillers, wetting agents, emulsifiers, lubricants, colorants, release agents, coating agents, sweeteners, fragrances, storage, known to those skilled in the art. It may contain one or more agents, antioxidants and the like.
ペントシジン生成及び／又はカルボニルストレスに関連した疾患としては、例えば、糖尿病、糖尿病合併症、動脈硬化、心筋梗塞、脳梗塞、癌、白内障、骨粗しょう症、アルツハイマー型認知症、慢性腎不全、リウマチ様関節炎、重症アトピー性皮膚炎、統合失調症等が挙げられる。糖尿病合併症としては、例えば、糖尿病網膜症、糖尿病腎症、糖尿病神経障害等が挙げられる。一態様において、ペントシジン生成及び／又はカルボニルストレスに関連した疾患は、糖尿病、糖尿病合併症、動脈硬化、心筋梗塞、骨粗しょう症、アルツハイマー型認知症及び統合失調症から選択される疾患である。 Diseases associated with pentosidine production and / or carbonyl stress include, for example, diabetes, diabetic complications, arteriosclerosis, myocardial infarction, cerebral infarction, cancer, cataracts, osteoporosis, Alzheimer's dementia, chronic renal failure, rheumatism-like. Examples include arthritis, severe atopic dermatitis, and schizophrenia. Examples of diabetic complications include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. In one aspect, the disease associated with pentosidine production and / or carbonyl stress is a disease selected from diabetes, diabetic complications, arteriosclerosis, myocardial infarction, osteoporosis, Alzheimer's dementia and schizophrenia.
［化粧用組成物］
一態様において、本発明は、上記のシイタケ抽出物を有効成分として含有する、ペントシジン生成及び／又はカルボニルストレスに関連した状態を改善又は予防するための化粧用組成物に関する。さらに、上記のシイタケ抽出物を含有する組成物を適用する工程を含む、ペントシジン生成及び／又はカルボニルストレスに関連した状態を改善又は予防するための美容方法にも関する。
[Cosmetic composition]
In one aspect, the present invention relates to a cosmetic composition containing the above-mentioned shiitake extract as an active ingredient for improving or preventing a condition associated with pentosidine production and / or carbonyl stress. It also relates to cosmetological methods for improving or preventing conditions associated with pentosidine production and / or carbonyl stress, including the step of applying the composition containing the shiitake extract described above.
化粧用組成物は、化粧品であっても医薬部外品であってもよく、特に限定されないが、ローション剤、乳剤、ゲル剤、クリーム剤、マスク剤、パック剤、エアゾール剤等の剤型とすることができる。例えば、化粧用組成物１００ｍｌあたり０．１〜１０ｇ程度の上記のシイタケ抽出物を配合し、これを身体に塗布、貼付、噴霧等により適用することができる。
化粧用組成物には、所望の効果を損なわない範囲内において、化粧品、医薬部外品等に一般に用いられる各種成分、たとえば水、油脂類、炭化水素類、高級脂肪酸、高級アルコール、シリコーン、各種界面活性剤、防腐剤、糖類、金属イオン封鎖剤、増粘剤、粉体成分、紫外線吸収剤、紫外線遮蔽剤、保湿剤、香料、ｐＨ調整剤等を配合することができる。また、所望の効果を損なわない範囲内において、ビタミン類、皮膚賦活剤、血行促進剤、活性酸素消去剤、抗炎症剤、美白剤、殺菌剤等の他の薬効成分、生理活性成分、他のペントシジン生成阻害剤、カルボニルストレス阻害剤を配合することができる。
The cosmetic composition may be a cosmetic product or a quasi-drug, and is not particularly limited, but may be a dosage form such as a lotion agent, an emulsion, a gel agent, a cream agent, a mask agent, a pack agent, or an aerosol agent. can do. For example, about 0.1 to 10 g of the above-mentioned shiitake extract can be blended per 100 ml of a cosmetic composition, and this can be applied to the body by application, sticking, spraying or the like.
Cosmetic compositions include various components generally used in cosmetics, non-pharmaceutical products, etc., such as water, oils and fats, hydrocarbons, higher fatty acids, higher alcohols, silicones, etc., as long as the desired effects are not impaired. Surfactants, preservatives, sugars, sequestrants, thickeners, powder components, UV absorbers, UV shields, moisturizers, fragrances, pH adjusters and the like can be blended. In addition, other medicinal ingredients such as vitamins, skin activators, blood circulation promoters, active oxygen scavengers, anti-inflammatory agents, whitening agents, bactericides, physiologically active ingredients, and others, as long as the desired effects are not impaired. A pentosidine production inhibitor and a carbonyl stress inhibitor can be blended.
ペントシジン生成及び／又はカルボニルストレスに関連した状態としては、特に、これらの生成に関連した皮膚状態が挙げられ、より具体的には、皮膚弾力性の低下、皮膚柔軟性の低下、皮膚のきめの低下、シワの生成、加齢臭等、加齢に伴う皮膚組織老化、乾燥、ニキビ、吹き出物等の皮膚表面状態の悪化が挙げられる。一態様において、ペントシジン生成及び／又はカルボニルストレスに関連した状態は、皮膚弾力性の低下、皮膚のきめの低下、加齢臭、乾燥、ニキビ及び吹き出物から選択される。 Conditions associated with pentocidin production and / or carbonyl stress include, in particular, skin conditions associated with these productions, and more specifically, reduced skin elasticity, decreased skin flexibility, and skin texture. Examples include deterioration of skin surface conditions such as deterioration, wrinkle formation, aging odor, aging of skin tissue with aging, dryness, acne, and pimples. In one embodiment, the conditions associated with pentosidine production and / or carbonyl stress are selected from reduced skin elasticity, reduced skin texture, body odor, dryness, acne and pimples.
［ペントシジン生成阻害剤］
一態様において、本発明は、上記のシイタケ抽出物を有効成分として含有する、ペントシジン生成阻害剤に関する。ペントシジン生成阻害剤は、上記の本実施形態の各組成物について記載したいずれの作用を有するものであってもよい。ペントシジン生成阻害剤の例としては、上記の本実施形態の各組成物のほか、ペントシジン生成阻害を引き起こす試薬等が挙げられる。
[Pentosidine production inhibitor]
In one aspect, the present invention relates to a pentosidine production inhibitor containing the above-mentioned shiitake extract as an active ingredient. The pentosidine production inhibitor may have any of the actions described for each composition of the present embodiment described above. Examples of the pentosidine production inhibitor include the above-mentioned compositions of the present embodiment, as well as reagents and the like that cause inhibition of pentosidine production.
以上説明した実施形態及び以下に記載する実施例が、本発明の理解を容易にするためのものであり、本発明を限定して解釈するためのものではない。 The embodiments described above and the examples described below are for facilitating the understanding of the present invention, and are not for limiting the interpretation of the present invention.
製造例１：シイタケ抽出物含有組成物の製造
乾燥したシイタケ（Lentinus edodes）１００ｋｇに水２５００ｋｇを加えて、約９０〜９５℃で３０分水煮し、抽出液約２０００ｋｇを得た。得られた抽出液を固形分濃度１２％まで遠心式薄膜真空蒸発装置（エバポール、株式会社大川原製作所製）で濃縮し、濃縮液約２００ｋｇを得た。
濃縮液に賦形剤（デキストリン）を２４ｋｇ（固形分重量比１：１）添加し、オートクレーブ滅菌した。これを一晩冷凍後、凍結乾燥させ、凍結乾燥物約４８ｋｇを得た。凍結乾燥物をハンマーミルで粉砕し、粉末約４７ｋｇを得た。この粉末を、シイタケエキス原末とする。
Production Example 1: Production of composition containing shiitake extract 2500 kg of water was added to 100 kg of dried shiitake mushrooms (Lentinus edodes) and boiled in water at about 90 to 95 ° C. for 30 minutes to obtain about 2000 kg of an extract. The obtained extract was concentrated to a solid content concentration of 12% with a centrifugal thin film vacuum evaporator (Evapol, manufactured by Okawara Seisakusho Co., Ltd.) to obtain about 200 kg of the concentrated solution.
Excipient (dextrin) was added to the concentrate in an amount of 24 kg (solid content weight ratio 1: 1) and sterilized by autoclave. This was frozen overnight and then lyophilized to obtain about 48 kg of lyophilized product. The lyophilized product was pulverized with a hammer mill to obtain about 47 kg of powder. This powder is used as the raw powder of shiitake extract.
シイタケエキス原末１ｋｇに対し、陽イオン交換水１０ｋｇを加えて溶かし、さらに塩酸を用いてｐＨ２に調整した。この溶液を、陽イオン交換樹脂（ＤＯＷＥＸ ５０Ｗｘ８）１ｋｇを充填したカラムに負荷し、シイタケ成分を吸着させた。カラムを陽イオン交換水で十分に洗浄した後、１ｍｏｌ／Ｌ水酸化ナトリウム５Ｌを通液し、市販の糖度計で測定したＢｒｉｘ値を参照して最初の２Ｌをシイタケ成分が含まれる溶出液として回収した。溶出液を中和後、ロータリーエバポレーターで濃縮し、２００ｍＬの濃縮液を得た。これらのバッチ操作を５回繰り返し、合計１Ｌの濃縮液を作製した。 To 1 kg of raw powder of shiitake extract, 10 kg of cation-exchanged water was added to dissolve the powder, and the pH was adjusted to 2 with hydrochloric acid. This solution was loaded on a column packed with 1 kg of a cation exchange resin (DOWNEX 50Wx8) to adsorb the shiitake mushroom component. After thoroughly washing the column with cation-exchanged water, pass 5 L of 1 mol / L sodium hydroxide and refer to the Brix value measured with a commercially available sugar content meter, and use the first 2 L as the eluate containing the shiitake mushroom component. Recovered. The eluate was neutralized and then concentrated on a rotary evaporator to give a 200 mL concentrate. These batch operations were repeated 5 times to prepare a total of 1 L of concentrated solution.
シイタケエキス原末０．２５ｋｇを、濃縮液１Ｌに溶かし（Ｂｒｉｘ値約３５％）、０．２μｍメンブレンフィルターで減圧ろ過したものを乾燥し、乾燥物約０．３ｋｇを得て、シイタケ抽出物含有組成物とした。 0.25 kg of shiitake extract raw powder was dissolved in 1 L of concentrated solution (Brix value: about 35%), filtered under reduced pressure with a 0.2 μm membrane filter, and dried to obtain about 0.3 kg of dried product, which contained shiitake extract. It was made into a composition.
陽イオン交換樹脂を用いて濃縮したシイタケ抽出物と濃縮前のシイタケ抽出物について、成分分析を行った結果を表１に示す。成分分析項目は、エルゴチオネイン、ビタミンＢ６、ビタミンＤ、ビタミンＫ１、ビタミンＫ２（メナキノン−４、メナキノン−７）、ナイアシン（ナイアシン当量）、遊離アミノ酸（アスパラギン酸、アラニン、アルギニン、イソロイシン、グリシン、グルタミン酸、シスチン、スレオニン、セリン、チロシン、トリプトファン、バリン、ヒスチジン、フェニルアラニン、プロリン、メチオニン、リジン、ロイシン）であった（いずれも、一般財団法人日本食品分析センターにおいて測定）。なお表１における機能性成分とは、単純な栄養素ではなく生体機能の調節等に関与することが知られている成分のことを指し、必ずしも本実施形態の組成物の作用に直接的に関与する成分を指すものではない。
実施例１：シイタケ抽出物含有組成物の経口投与試験１
製造例１で得た組成物をカプセルに詰めたものを用いてヒト試験を実施した。健常な男女６人からなる試験組成物投与群に、１日１回、製造例１で得た組成物１ｇを、２週間継続して経口投与した。また、健常な男女５人からなる非投与群を対照区とした。
観察項目は皮膚ＡＧＥｓ値とした。皮膚ＡＧＥｓ値の測定は、ＡＧＥリーダー（Diagnoptics社製）を使用した。本測定器によれば、蛍光分光方式で皮膚及び皮下の血管壁に累積されるＡＧＥｓをＡＦ（Skin Autoflourescence）値として検出し、非侵襲的にＡＧＥｓ値を算出することができる。測定部位は、右前腕内側部の肘から手首方向に１０ｃｍの部位とし、１日１回、５営業日／週測定した。それぞれの群について、前観察期間（投与開始前１週間）における各被験者の皮膚ＡＧＥｓ値の平均値を１００とした値（皮膚ＡＧＥｓ指数）を用いて、１週間ごとにその変化を比較することにより評価を行った。投与終了後１週間後にも、後観察期間として同様に１週間、皮膚ＡＧＥｓ値の測定を行った。５回／週の測定値の平均値を図１に示す。例えば、図１中「試験組成物投与期間１Ｗ」の値は、投与開始から１週間の各被験者の５回の測定値を平均し、投与開始前の１週間の各被験者の５回の測定値の平均値を１００とした場合の相対値とした後、５人の相対値を平均した値を示す。
なお、本試験及び以降の実施例２から３に示す試験は、ヘルシンキ宣言の精神に則り、研究倫理委員会の承認を得た上で、自発的に試験参加を表明し、文書による同意が得られた者を対象に実施された。
Example 1: Oral administration test of a composition containing shiitake extract 1
A human test was carried out using the composition obtained in Production Example 1 encapsulated. To the test composition administration group consisting of 6 healthy men and women, 1 g of the composition obtained in Production Example 1 was orally administered once a day for 2 consecutive weeks. In addition, a non-administration group consisting of 5 healthy men and women was used as a control group.
The observation item was the skin AGEs value. An AGE reader (manufactured by Diagnoptics) was used to measure the skin AGEs value. According to this measuring instrument, AGEs accumulated on the skin and the blood vessel wall under the skin can be detected as AF (Skin Autoflourescence) values by fluorescence spectroscopy, and AGEs values can be calculated non-invasively. The measurement site was 10 cm from the elbow to the wrist on the medial side of the right forearm, and the measurement was performed once a day for 5 business days / week. For each group, the changes were compared weekly using a value (skin AGEs index) in which the average value of the skin AGEs of each subject during the pre-observation period (1 week before the start of administration) was set to 100. Evaluation was performed. One week after the end of administration, the skin AGEs value was measured for one week as a follow-up period. The average value of the measured values 5 times / week is shown in FIG. For example, in FIG. 1, the value of "test composition administration period 1 W" is the average of 5 measured values of each subject in 1 week from the start of administration, and 5 measured values of each subject in 1 week before the start of administration. After setting the relative value when the average value of is 100, the value obtained by averaging the relative values of 5 persons is shown.
In addition, in this test and the tests shown in Examples 2 to 3 thereafter, in accordance with the spirit of the Declaration of Helsinki, after obtaining the approval of the Research Ethics Committee, voluntarily announce participation in the test and obtain written consent. It was carried out for those who were affected.
図１に示したとおり、試験組成物投与群では、投与開始後２週後に、非投与群と比較して、皮膚ＡＧＥｓ指数は有意に低下した。製造例１で得たシイタケ抽出物含有組成物の投与により、体内における糖化反応が抑制されていることがわかった。特に、製造例１で得たシイタケ抽出物含有組成物を、１日１回、１ｇ経口投与し、二週間という比較的短期間で、顕著な抗糖化作用が得られることがわかった。 As shown in FIG. 1, in the test composition-administered group, the skin AGEs index was significantly decreased 2 weeks after the start of administration as compared with the non-administered group. It was found that the saccharification reaction in the body was suppressed by the administration of the shiitake extract-containing composition obtained in Production Example 1. In particular, it was found that the shiitake extract-containing composition obtained in Production Example 1 was orally administered in an amount of 1 g once a day, and a remarkable anti-glycation effect was obtained in a relatively short period of two weeks.
実施例２：シイタケ抽出物含有組成物の経口投与試験２
製造例１で得た組成物を腸溶性カプセルに詰めたものを用いてヒト試験を実施した。健常な男女１１人に、１日１回、製造例１で得た組成物１ｇを、４週間継続して経口投与した。検査項目は血清中のペントシジン（ＥＬＩＳＡ法）、３−デオキシグルコソン（３−ＤＧ）（ＨＰＬＣ法）、カルボキシメチルリジン（ＣＭＬ）（ＥＬＩＳＡ法）の各濃度とし、前観察期間（投与開始１週間前）、投与１週間後及び４週間投与後に採血して測定した（いずれも、日研ザイル株式会社日本老化制御研究所において測定）。ペントシジン及びＣＭＬは、ＡＧＥｓの一種として、３−ＤＧは、ＡＧＥｓ生成時のメイラード反応における中間生成物として知られる成分である。
Example 2:
A human test was carried out using the composition obtained in Production Example 1 packed in enteric-coated capsules. Eleven healthy men and women were orally administered once a day to 1 g of the composition obtained in Production Example 1 for 4 consecutive weeks. The test items were the concentrations of pentosidine (ELISA method), 3-deoxyglucosone (3-DG) (HPLC method), and carboxymethyl lysine (CML) (ELISA method) in serum, and the pre-observation period (1 week after the start of administration). (Before), 1 week after administration and 4 weeks after administration, blood was collected and measured (both measured at Nikken Zile Co., Ltd. Japan Aging Control Laboratory). Pentosidine and CML are a type of AGEs, and 3-DG is a component known as an intermediate product in the Maillard reaction during the formation of AGEs.
図２に示したとおり、試験組成物の投与により、投与開始後４週後に、３−ＤＧ及びＣＭＬは低下しなかったが、ペントシジンが有意に低下した。製造例１で得たシイタケ抽出物含有組成物の投与により、体内におけるペントシジン生成阻害作用が認められた。 As shown in FIG. 2, administration of the test composition did not decrease 3-DG and CML, but significantly decreased pentosidine 4 weeks after the start of administration. Administration of the shiitake extract-containing composition obtained in Production Example 1 was found to have an inhibitory effect on pentosidine production in the body.
また、投与終了日の翌週に、女性８人に対して肌状態改善の自覚症状を調査した。調査は、１０ｃｍの直線の左端を「非常に悪化した：−１００点」、中点を「変化無し；０点」、右端を「非常に改善した：１００点」とするＶＡＳ（Ｖｉｓｕａｌ ａｎａｌｏｇ ｓｃａｌｅ）による方法で、表２に示す各評価項目について行った。各評価項目について、各被験者に、現在の状態が、試験前の状態と比べて、直線上のどの位置に当てはまるかを直線状に×印を記入させ、中点から×印までの距離を１ｍｍ単位（１ｍｍ未満の値は切り捨てる）で測定し、点数に換算（１ｍｍ＝２点）した。記入されなかった項目は解析対象から除外した。結果を表２に示す。ＶＡＳスコアの数値は、大きいほど自覚症状が良く改善されたことを示す。また、ＶＡＳスコアについて、試験前を０点として、対応のあるｔ検定による比較を行って得られたｐ値も、表２に併せて示す。
表２に示したとおり、「化粧のノリ」、「乾燥」に有意な改善が認められ、「身体の疲労」、「うるおいの持続」、「ニキビ・吹き出物」に改善の傾向がみられた。
As shown in Table 2, significant improvement was observed in "makeup glue" and "dryness", and there was a tendency for improvement in "body fatigue", "sustaining moisture", and "acne / pimples".
「化粧のノリ」とは化粧仕上がりのことを指し、化粧仕上がりは、ニキビ、微細な凹凸等の皮膚表面状態の変化、水分や弾力性等の皮膚物性の変化により影響を受けることが報告されている（Okiyama N., et al., J. Soc. Cosmet. Chem. Jpn., 47(4):292-300, 2013）。製造例１で得たシイタケ抽出物含有組成物の経口投与により、「乾燥」や「ニキビ・吹き出物」等の肌表面状態が改善し、「化粧のノリ」が改善されたことが示された。 "Makeup paste" refers to the makeup finish, and it has been reported that the makeup finish is affected by changes in the skin surface condition such as acne and fine irregularities, and changes in skin physical properties such as moisture and elasticity. (Okiyama N., et al., J. Soc. Cosmet. Chem. Jpn., 47 (4): 292-300, 2013). It was shown that oral administration of the shiitake extract-containing composition obtained in Production Example 1 improved the skin surface conditions such as "dryness" and "acne / pimples" and improved "makeup glue".
実施例３：シイタケ抽出物含有組成物の経口投与試験３
製造例１で得た組成物を腸溶性カプセルに詰めたものを用いてヒト試験を実施した。健常な男女６人に、１日１回、製造例１で得た組成物１ｇを、６週間継続して経口投与した。検査項目は血清中のペントシジン及び過酸化脂質（ＬＰＯ）の濃度、そして顔の水分及び弾力性とした。ペントシジン（ＥＬＩＳＡ法）及びＬＰＯ（ＴＢＡ法）は、前観察期間（投与開始１週間前）、２週間投与後及び６週間投与後に採血して測定した（いずれも、日研ザイル株式会社日本老化制御研究所において測定）。
腕及び顔の弾力性の測定には、肌診断測定器ＡＯＴ−ＳＴ（佐藤商事社製）を使用し、前観察期間（投与開始１週間前）及び投与開始から２週間毎に測定した。本測定器によれば、計測センサー部を測定部位に押し当てることにより、非侵襲的に皮膚の水分値及び弾力性値を計測することができる。測定部位は、左目の目じりから下方向ヘ約１０ｃｍの部位とし、２営業日／週に５回ずつ測定した。５回の測定値のうち、最大値と最小値を除いた３点の平均値を測定平均値とし、さらに２営業日の測定平均値の平均を検査値とした。前観察期間における各被験者の皮膚弾力性値の検査値を１００とした値（皮膚弾力性指数）を用いて、その変化を比較することにより評価を行った。
Example 3:
A human test was carried out using the composition obtained in Production Example 1 packed in enteric-coated capsules. Six healthy men and women were orally administered once a day with 1 g of the composition obtained in Production Example 1 for 6 consecutive weeks. The test items were the concentration of pentosidine and lipid peroxide (LPO) in serum, and the water content and elasticity of the face. Pentosidine (ELISA method) and LPO (TBA method) were measured by collecting blood during the pre-observation period (1 week before the start of administration), 2 weeks after administration, and 6 weeks after administration (both are Nikken Zile Co., Ltd. Japan Aging Control). Measured in the laboratory).
The elasticity of the arms and face was measured using a skin diagnostic measuring instrument AOT-ST (manufactured by Sato Shoji Co., Ltd.) during the pre-observation period (1 week before the start of administration) and every 2 weeks after the start of administration. According to this measuring instrument, the moisture value and elasticity value of the skin can be measured non-invasively by pressing the measurement sensor unit against the measurement site. The measurement site was a site about 10 cm downward from the corner of the left eye, and measurement was performed 5 times a week for 2 business days. Of the five measured values, the average value of three points excluding the maximum value and the minimum value was used as the measured average value, and the average of the measured average values for two business days was used as the inspection value. The evaluation was performed by comparing the changes in the skin elasticity index of each subject during the pre-observation period, using a value (skin elasticity index) set to 100.
図３に示したとおり、試験組成物の投与開始後２週後に、ペントシジンの低下、同６週後には有意な低下が認められた。また、試験組成物の投与開始後２週後に過酸化脂質の有意な低下が認められた。以上のことから、製造例１で得たシイタケ抽出物含有組成物の投与により、体内におけるペントシジン生成阻害作用、過酸化脂質生成阻害作用が認められた。 As shown in FIG. 3, a decrease in pentosidine was observed 2 weeks after the start of administration of the test composition, and a significant decrease was observed 6 weeks after the start of administration. In addition, a significant decrease in lipid peroxide was observed 2 weeks after the start of administration of the test composition. From the above, administration of the shiitake extract-containing composition obtained in Production Example 1 was found to have an inhibitory effect on pentosidine production and an inhibitory effect on lipid peroxide production in the body.
一方、図４に示したとおり、試験組成物の投与開始後２週後に皮膚弾力性は増加し、同４週後には有意に増加した。
また、被験者女性のうち１名について、試験組成物投与３週間後及び６週間後に、皮膚の拡大写真によるキメの確認及び水分量の測定を行ったところ、図５に示すとおりキメの状態の改善がみられ（図５Ａ：投与３週間後。図５Ｂ：投与６週間後。投与３週間後と比較して、投与６週間後の方がキメが整っている）、水分量も大幅に増加していた（３５％→７４％）。
On the other hand, as shown in FIG. 4, the skin elasticity increased 2 weeks after the start of administration of the test composition, and significantly increased 4 weeks after the start of administration.
In addition, for one of the female subjects, the texture was confirmed and the water content was measured by an enlarged photograph of the
以上、ペントシジン及び過酸化脂質が低下したことから試験組成物の投与により、生体内のカルボニルストレスが改善されていると考えられた。また、試験組成物の投与により過酸化脂質が低下することで、実施例２において「ニキビ・吹き出物」の自覚症状が改善したと考えられた。加えて、架橋性ＡＧＥｓであるペントシジンが低下することにより皮膚弾力組織の物性が改善され、皮膚表面状態が整うことにより、「化粧のノリ」の自覚症状が改善したと推察された。 As described above, since pentosidine and lipid peroxide decreased, it was considered that the administration of the test composition improved the carbonyl stress in the living body. In addition, it was considered that the subjective symptom of "acne / pimple" was improved in Example 2 by reducing the lipid peroxide by the administration of the test composition. In addition, it was speculated that the decrease in pentosidine, which is a crosslinkable AGEs, improved the physical properties of the skin elastic tissue, and the condition of the skin surface was improved, so that the subjective symptom of "makeup paste" was improved.
なお、図１から４の図中において、＊は前値（試験組成物投与前の検査値）と比較してｐ＜０．０５（対応のあるｔ検定によって求められた）であり、統計学的に有意差があることを示す。 In the figures of FIGS. 1 to 4, * is p <0.05 (determined by a paired t-test) as compared with the previous value (test value before administration of the test composition), and is statistical. It shows that there is a significant difference.
本発明によれば、安全で経口投与可能な、食用原料由来の、ペントシジン生成阻害作用及び／又はカルボニルストレス阻害作用を有する組成物を提供することができる。本発明は、医薬、健康食品、化粧品、試薬、添加剤等の分野において産業上の利用可能性を有する。 According to the present invention, it is possible to provide a composition derived from an edible raw material, which is safe and can be orally administered, and has an inhibitory effect on pentosidine production and / or an inhibitory effect on carbonyl stress. The present invention has industrial applicability in the fields of pharmaceuticals, health foods, cosmetics, reagents, additives and the like.
Claims (12)
エルゴチオネイン ２００ｍｇ以上３０００ｍｇ以下、 Ergothioneine 200 mg or more and 3000 mg or less,
ビタミンＢ６ １ｍｇ以上２０ｍｇ以下、及び Vitamin B6 1 mg or more and 20 mg or less, and
ナイアシン（ナイアシン当量） ５０ｍｇ以上５００ｍｇ以下 Niacin (niacin equivalent) 50 mg or more and 500 mg or less
を含む、請求項１又は２に記載のペントシジン生成阻害剤。The pentosidine production inhibitor according to claim 1 or 2.
前記濃縮工程後のシイタケ抽出物のＢｒｉｘ値が５〜６０％であり、 The Brix value of the shiitake extract after the concentration step is 5 to 60%.
前記濃縮工程後のシイタケ抽出物が、乾燥物１００ｇあたり、 The shiitake extract after the concentration step is per 100 g of dried product.
エルゴチオネイン ２００ｍｇ以上３０００ｍｇ以下、 Ergothioneine 200 mg or more and 3000 mg or less,
ビタミンＢ６ １ｍｇ以上２０ｍｇ以下、及び Vitamin B6 1 mg or more and 20 mg or less, and
ナイアシン（ナイアシン当量） ５０ｍｇ以上５００ｍｇ以下 Niacin (niacin equivalent) 50 mg or more and 500 mg or less
を含む、方法。Including methods.
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