JP2006342077A - Stress inhibitor of endoplasmic reticulum - Google Patents
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Abstract
Description
本発明は、老人性痴呆症（アルツハイマー病）やパーキンソン病、ハンチントン病に代表される神経変性疾患の予防および／または治療に有効な小胞体ストレス抑制剤に関する。 The present invention relates to an endoplasmic reticulum stress inhibitor effective for the prevention and / or treatment of neurodegenerative diseases represented by senile dementia (Alzheimer's disease), Parkinson's disease, and Huntington's disease.
老人性痴呆症（アルツハイマー病）やパーキンソン病、ハンチントン病に代表される神経変性疾患は、今だもって明確な治療法が存在しない難病であり、現在、多くの研究および探索がその治療法の確立のために行われている。神経変性疾患に対する現時点において最も有効とされている治療法は、アルツハイマー病患者の脳内で観察されるアセチルコリンの低下という現象を阻害する薬剤（ドネペジルなど）を用いたものである。しかしながら、このような薬剤での治療は対症療法に過ぎない。従って、真に疾病の発症を予防したり進行を阻止したりできる薬剤の出現が待ち望まれている。
神経変性疾患は、脳内に異常タンパク質が蓄積することにより発症すると考えられている。即ち、この異常タンパク質の蓄積が、細胞内の核の周辺に存在する小胞体に物理的あるいは化学的なストレスをかけ、細胞のアポトーシスを誘導する。その結果、脳内において神経細胞が死滅し、神経疾患を引き起こす。
このような疾患発症メカニズムに鑑み、小胞体にストレスがかかることを抑制する活性を持つ天然物由来の物質や成分を探索する試みが行われている。
ところで、キノコの中には、人体に有効な薬理活性を持つ物質や成分を含むものが数多く存在し、既に、キノコ由来の種々の物質や成分が薬剤などとして利用されている。例えば、カワラタケからはクレスチン、シイタケからはレンチナン、スエヒロタケからはシゾフィランという多糖体が単離され、抗ガン剤として利用されている。また、ヤマブシタケからは、神経成長因子を誘導産生するヘリセノンやエリナシンが単離されている。従って、キノコの中に、小胞体ストレス抑制活性を持つ物質や成分を含むものが存在することも大いに期待され、現に、特許文献１には、ヤマブシタケ由来の脂溶性抽出成分にこの活性があることが報告されている。しかしながら、キノコ由来の小胞体ストレス抑制剤についての報告はこれ以外には存在しない。
Neurodegenerative diseases are thought to develop as abnormal proteins accumulate in the brain. That is, the accumulation of this abnormal protein applies physical or chemical stress to the endoplasmic reticulum existing around the nucleus in the cell, and induces apoptosis of the cell. As a result, nerve cells die in the brain and cause neurological diseases.
In view of such a disease onset mechanism, attempts have been made to search for substances and components derived from natural products having an activity to suppress stress on the endoplasmic reticulum.
By the way, there are many mushrooms containing substances and components having pharmacological activity effective for the human body, and various substances and components derived from mushrooms are already used as drugs. For example, a polysaccharide called krestin from Kawaratake, lentinan from Shiitake, and schizophyllan from Suehirotake has been isolated and used as an anticancer agent. Further, from Yamabushitake, helicenone and erinasin that induce and produce nerve growth factor have been isolated. Therefore, it is highly expected that some mushrooms contain substances and components having endoplasmic reticulum stress-inhibiting activity. In fact, Patent Document 1 shows that this fat-soluble extract component derived from Yamabushitake has this activity. Has been reported. However, there are no other reports on mushroom-derived endoplasmic reticulum stress inhibitors.
そこで本発明は、老人性痴呆症（アルツハイマー病）やパーキンソン病、ハンチントン病に代表される神経変性疾患の予防および／または治療に有効なキノコ由来の新規な小胞体ストレス抑制剤を提供することを目的とする。 Accordingly, the present invention provides a novel endoplasmic reticulum stress inhibitor derived from mushrooms that is effective in the prevention and / or treatment of neurodegenerative diseases represented by senile dementia (Alzheimer's disease), Parkinson's disease, and Huntington's disease. Objective.
本発明者らは、上記の技術背景をもとに鋭意研究を重ねた結果、桑黄に由来する脂溶性抽出成分が、小胞体ストレス抑制活性に基づいて神経細胞のアポトーシス（プログラム細胞死）を抑制することを見出した。 As a result of intensive research based on the above technical background, the present inventors have found that a fat-soluble extract component derived from mulberry yellow induces apoptosis of neuronal cells (programmed cell death) based on endoplasmic reticulum stress inhibitory activity. I found it to suppress.
上記の知見に基づいてなされた本発明の小胞体ストレス抑制剤は、請求項１記載の通り、桑黄由来の脂溶性抽出成分を有効成分とすることを特徴とする。
また、請求項２記載の小胞体ストレス抑制剤は、請求項１記載の小胞体ストレス抑制剤において、桑黄が、メシマコブ、キコブタケ、エゾキコブタケ、マツノカタワタケから選ばれる少なくとも１つであることを特徴とする。
また、本発明の神経変性疾患予防治療剤は、請求項３記載の通り、桑黄由来の脂溶性抽出成分を有効成分とすることを特徴とする。
また、請求項４記載の神経変性疾患予防治療剤は、請求項３記載の神経変性疾患予防治療剤において、桑黄が、メシマコブ、キコブタケ、エゾキコブタケ、マツノカタワタケから選ばれる少なくとも１つであることを特徴とする。
また、本発明の小胞体ストレス抑制組成物は、請求項５記載の通り、桑黄由来の脂溶性抽出成分を有効成分として含有することを特徴とする。
また、本発明の小胞体ストレス抑制食品は、請求項６記載の通り、桑黄由来の脂溶性抽出成分を有効成分として含有することを特徴とする。
The endoplasmic reticulum stress inhibitor of the present invention made based on the above findings is characterized in that, as described in claim 1, a fat-soluble extract component derived from mulberry yellow is used as an active ingredient.
The endoplasmic reticulum stress suppressor according to claim 2 is characterized in that, in the endoplasmic reticulum stress suppressor according to claim 1, mulberry yellow is at least one selected from Meshimakobu, Mushroom, Ezo-kitake, and Matsunokatatake. To do.
Moreover, the neurodegenerative disease preventive and therapeutic agent of the present invention is characterized in that, as described in claim 3, a fat-soluble extract component derived from mulberry yellow is used as an active ingredient.
The preventive or therapeutic agent for neurodegenerative disease according to claim 4 is characterized in that in the preventive and therapeutic agent for neurodegenerative disease according to claim 3, mulberry yellow is at least one selected from Meshimakobu, Mushroom, Ezo-kitake, and Matsunokatatake. Features.
Moreover, the endoplasmic reticulum stress suppression composition of this invention contains the fat-soluble extract component derived from mulberry yellow as an active ingredient as described in Claim 5.
Moreover, the endoplasmic reticulum stress suppression foodstuff of this invention contains the fat-soluble extraction component derived from mulberry yellow as an active ingredient as described in Claim 6.
本発明によれば、老人性痴呆症（アルツハイマー病）やパーキンソン病、ハンチントン病に代表される神経変性疾患の予防および／または治療に有効なキノコ由来の新規な小胞体ストレス抑制剤を提供することができる。 The present invention provides a novel endoplasmic reticulum stress inhibitor derived from mushrooms that is effective in the prevention and / or treatment of neurodegenerative diseases represented by senile dementia (Alzheimer's disease), Parkinson's disease, and Huntington's disease. Can do.
本発明の小胞体ストレス抑制剤は、桑黄由来の脂溶性抽出成分を有効成分とすることを特徴とするものである。本発明の小胞体ストレス抑制剤は、その小胞体ストレス抑制活性に基づき、神経変性疾患の予防および／または治療に有効である。なお、本発明において、小胞体ストレスとは、細胞内部に存在する粗面小胞体における機能異常を指し、タンパク質構造に異常をきたすことにより引き起こされる異常タンパク質の蓄積ストレスを意味する。そして、この小胞体ストレスを抑制する活性を小胞体ストレス抑制活性と規定する。また、本発明において、神経変性疾患とは、神経細胞がアポトーシス（プログラム細胞死）を起こし、神経が正常な状態を維持できなくなることに起因する疾患を意味する。具体的には、例えば、老人性痴呆症（アルツハイマー病）、パーキンソン病、ハンチントン病、ＡＬＳ（筋萎縮性側索硬化症）、プリオン病、その他の各種痴呆疾患（例えば、脳血管性痴呆、正常圧水頭症、脳外傷後痴呆、慢性硬膜下血腫、脳腫瘍）が挙げられる。神経細胞のアポトーシスは、主に小胞体ストレスによって引き起こされる。従って、本発明の小胞体ストレス抑制剤は、その小胞体ストレス抑制活性に基づいて、小胞体ストレスにより引き起こされる神経細胞のアポトーシスを抑制する活性を有する。 The endoplasmic reticulum stress inhibitor of the present invention is characterized by using a fat-soluble extract component derived from mulberry yellow as an active ingredient. The endoplasmic reticulum stress-suppressing agent of the present invention is effective for the prevention and / or treatment of neurodegenerative diseases based on its endoplasmic reticulum stress-suppressing activity. In the present invention, the endoplasmic reticulum stress refers to a functional abnormality in the rough endoplasmic reticulum existing inside the cell, and means an abnormal protein accumulation stress caused by an abnormality in the protein structure. And the activity which suppresses this endoplasmic reticulum stress is prescribed | regulated as endoplasmic reticulum stress suppression activity. Further, in the present invention, the neurodegenerative disease means a disease caused by a nerve cell undergoing apoptosis (programmed cell death) and the nerve cannot maintain a normal state. Specifically, for example, senile dementia (Alzheimer's disease), Parkinson's disease, Huntington's disease, ALS (Amyotrophic lateral sclerosis), prion disease, and other various dementia diseases (eg, cerebrovascular dementia, normal Hydrocephalus, post-traumatic dementia, chronic subdural hematoma, brain tumor). Neuronal apoptosis is mainly caused by endoplasmic reticulum stress. Therefore, the endoplasmic reticulum stress inhibitor of this invention has the activity which suppresses the apoptosis of the nerve cell caused by endoplasmic reticulum stress based on the endoplasmic reticulum stress inhibitory activity.
本発明において、桑黄とは、広葉樹寄生する担子菌類であるキコブタケ属（Ｐｈｅｌｌｉｎｕｓ属）のキノコを意味する。具体的には、メシマコブ、キコブタケ、エゾキコブタケ、マツノカタワタケなどが挙げられる。キコブタケ属のキノコは、漢方薬として古くから利用されており、近年、その抗腫瘍効果などの機能性が注目されているが、神経変性疾患に対する作用についてはこれまで報告されたことはない。脂溶性抽出成分を得るために用いる桑黄は、子実体であっても菌糸体であってもよい。また、これらは、天然物であっても栽培物または培養物であってもよい。桑黄由来の脂溶性抽出成分は、桑黄の子実体や菌糸体、またはこれらの乾燥体の破砕物や粉砕物から有機溶媒を用いた抽出操作を経て得ることができる。有機溶媒としては、エタノール、メタノール、イソプロパノール、ブタノールなどのアルコールの他、ヘキサン、クロロホルム、ベンゼン、フェノール、酢酸エチル、ジエチルエーテル、アセトン、トルエン、ジクロロメタンなどを用いることができる。有機溶媒は単独で用いてもよいし、複数種類を混合して用いてもよい。また、複数種類の有機溶媒を連続して用いて抽出操作を行ってもよい。有機溶媒の使用量は、使用する有機溶媒の種類や抽出効率などに基づいて適宜決定すればよい。抽出操作方法の一例としては、クロロホルム：メタノールを７：３〜９：１の割合で混合して調製した溶媒を、桑黄の乾燥粉末１重量部に対して５重量部〜５０重量部用いて行う方法が挙げられる。脂溶性抽出成分は、このような抽出操作によって得られる抽出液を必要に応じて濾過を行った後、減圧濃縮などをすることで得ることができる。また、脂溶性抽出成分は、得られた抽出液をさらに分画精製して得られる脂溶性抽出画分であってもよい。 In the present invention, mulberry yellow means a mushroom of the genus Phellinus, which is a basidiomycete parasitic on hardwood. Specific examples include Meshima Cobb, Mushroom, Ezo Mushroom, and Matsuno Katatake. Mushrooms belonging to the genus Mushroom have long been used as traditional Chinese medicines, and in recent years, their antitumor effects and other functionalities have attracted attention. However, no action has been reported on neurodegenerative diseases. Mulberry yellow used for obtaining a fat-soluble extract component may be a fruit body or a mycelium. These may be natural products or cultivated or cultured products. The fat-soluble extractive component derived from mulberry yellow can be obtained from mulberry yellow fruit bodies and mycelia, or a crushed or pulverized product of these dried bodies through an extraction operation using an organic solvent. As the organic solvent, in addition to alcohols such as ethanol, methanol, isopropanol, and butanol, hexane, chloroform, benzene, phenol, ethyl acetate, diethyl ether, acetone, toluene, dichloromethane, and the like can be used. An organic solvent may be used independently and may be used in mixture of multiple types. Moreover, you may perform extraction operation using a multiple types of organic solvent continuously. What is necessary is just to determine the usage-amount of an organic solvent suitably based on the kind, extraction efficiency, etc. of the organic solvent to be used. As an example of the extraction operation method, a solvent prepared by mixing chloroform: methanol in a ratio of 7: 3 to 9: 1 is used in an amount of 5 to 50 parts by weight with respect to 1 part by weight of the dry powder of mulberry yellow. The method of performing is mentioned. The fat-soluble extraction component can be obtained by subjecting the extract obtained by such an extraction operation to filtration as necessary, followed by concentration under reduced pressure. Further, the fat-soluble extract component may be a fat-soluble extract fraction obtained by further fractionating and purifying the obtained extract.
桑黄由来の脂溶性抽出成分は、自体公知の方法によって顆粒剤や錠剤やカプセル剤などに製剤化し、服用することで、優れた小胞体ストレス抑制活性に基づく神経変性疾患の予防薬や治療薬などとして機能する。その服用量は、服用者の年齢、性別、体重、体調などによって適宜決定することができる。また、桑黄由来の脂溶性抽出成分は、種々の形態の食品（サプリメントを含む）に、小胞体ストレス抑制活性を発揮するに足る有効量を添加することで、神経変性疾患に対する予防効果や治療効果をもたらす機能性食品として食してもよい。 Mulberry yellow-derived fat-soluble extractive ingredients are formulated into granules, tablets, capsules, etc. by methods known per se, and are taken to prevent or treat neurodegenerative diseases based on excellent endoplasmic reticulum stress-inhibiting activity. Function as such. The dose can be appropriately determined according to the age, sex, weight, physical condition, etc. of the user. In addition, the fat-soluble extract component derived from mulberry yellow has a preventive effect and treatment for neurodegenerative diseases by adding an effective amount sufficient to exert endoplasmic reticulum stress inhibitory activity to various forms of foods (including supplements). You may eat as a functional food which brings about an effect.
以下、本発明の小胞体ストレス抑制剤について実施例によって更に詳細に説明するが、本発明は以下の記載に限定して解釈されるものではない。 Hereinafter, although the endoplasmic reticulum stress inhibitor of this invention is demonstrated still in detail by an Example, this invention is limited to the following description and is not interpreted.
実施例１：
（１）桑黄由来の脂溶性抽出成分の調製
キコブタケ子実体の乾燥粉末１重量部に対し、クロロホルム：メタノールを９：１の割合で混合して調製した溶媒を１０重量部加え、室温で２４時間振とうさせて脂溶性成分を抽出した。得られた抽出液を減圧下で濃縮し、キコブタケ由来の脂溶性抽出成分を乾燥粉末１ｇあたり４．１ｍｇ得た。
Example 1:
(1) Preparation of Mulberry Yellow-Derived Fat-soluble Extraction Ingredient 10 parts by weight of a solvent prepared by mixing chloroform: methanol in a ratio of 9: 1 to 1 part by weight of a dry powder of mushroom butterfly fruit body was added at room temperature. The fat-soluble component was extracted by shaking over time. The obtained extract was concentrated under reduced pressure to obtain 4.1 mg of a fat-soluble extract component derived from mushrooms per gram of dry powder.
（２）桑黄由来の脂溶性抽出成分の小胞体ストレス抑制効果の評価（その１）
（１）で得たキコブタケ由来の脂溶性抽出成分の小胞体ストレス抑制効果の評価を特許文献１の記載の方法に準じて以下のようにして行った。Ｎｅｕｒｏ−２ａ細胞（ヒューマンサイエンス研究資源バンク、ＩＦＯ５００８１）を神経細胞モデルとして使用した。培養培地には、１０％ウシ胎仔血清を添加したダルベッコ改変イーグル培地を使用した。細胞の培養は３７℃、ＣＯ2濃度は５％で行った。なお、小胞体ストレスモデルには、糖鎖の生合成を阻害し細胞死を誘導することが知られているツニカマイシン（ナカライテスク社製）を使用した。小胞体ストレス抑制効果の評価は、０．５μｇ／ｍＬツニカマイシンとキコブタケ由来の脂溶性抽出成分の存在下で、細胞を４８時間培養した時の細胞生存率から、細胞死緩和効果を評価することで行った。細胞生存率は、生細胞定量法のＭＴＴ（同仁化学社製）を用いるＭＴＴアッセイにより定量した。具体的には次のようにして行った。上記培養の終了後、培地を除去し細胞を２５０μｇ／ｍＬのＭＴＴの存在下でさらに２時間培養した。次いで反応停止液（２０％ＳＤＳおよび５０％ジメチルホルムアミドを含む）を加え反応を停止させた。生成物と細胞とを可溶化した後、５７０ｎｍでの吸光度を測定した。なお、コントロールとしては、Ｎｅｕｒｏ−２ａ細胞をツニカマイシンおよびキコブタケ由来の脂溶性抽出成分の非存在下で培養したものを用いた。これから得られた値を１００とし、ツニカマイシンおよびキコブタケ由来の脂溶性抽出成分の存在下での細胞生存率を比較した。なお、キコブタケ由来の脂溶性抽出成分の濃度は１００ｐｇ／ｍＬで行った。結果を図１に示す。なお、図１には、キコブタケ由来の脂溶性抽出成分と同様にして得た、アガリクス由来の脂溶性抽出成分（子実体乾燥粉末１ｇあたり４３．２ｍｇ取得）、カバノアナタケ由来の脂溶性抽出成分（子実体乾燥粉末１ｇあたり１２．９ｍｇ取得）を、キコブタケ由来の脂溶性抽出成分のかわりに用いて評価を行った結果と、ツニカマイシンのみを用いて評価を行った結果をあわせて示す。図１から明らかなように、キコブタケ由来の脂溶性抽出成分は、ツニカマイシンによって誘導される細胞死を緩和したことから、その小胞体ストレス抑制効果が確認できた。
(2) Evaluation of endoplasmic reticulum stress inhibitory effect of fat-soluble extract component derived from mulberry yellow (Part 1)
Evaluation of the endoplasmic reticulum stress inhibitory effect of the fat-soluble extract component derived from Mushrooms obtained in (1) was performed according to the method described in Patent Document 1 as follows. Neuro-2a cells (Human Science Research Resource Bank, IFO50081) were used as a neuronal cell model. As the culture medium, Dulbecco's modified Eagle medium supplemented with 10% fetal calf serum was used. Cells were cultured at 37 ° C. and CO 2 concentration at 5%. As the endoplasmic reticulum stress model, tunicamycin (manufactured by Nacalai Tesque), which is known to inhibit sugar chain biosynthesis and induce cell death, was used. Evaluation of endoplasmic reticulum stress-inhibiting effect is based on evaluation of cell death mitigation effect from cell viability when cells are cultured for 48 hours in the presence of 0.5 μg / mL tunicamycin and fat-soluble extract components derived from mushroom. went. The cell viability was quantified by MTT assay using MTT (manufactured by Dojindo), a live cell quantification method. Specifically, it was performed as follows. After completion of the above culture, the medium was removed and the cells were cultured for an additional 2 hours in the presence of 250 μg / mL MTT. Then, a reaction stop solution (containing 20% SDS and 50% dimethylformamide) was added to stop the reaction. After solubilization of the product and cells, the absorbance at 570 nm was measured. As a control, Neuro-2a cells cultured in the absence of fat-soluble extract components derived from tunicamycin and mushrooms were used. The value obtained from this was set to 100, and the cell viability in the presence of fat-soluble extract components derived from tunicamycin and mushroom was compared. In addition, the density | concentration of the fat-soluble extraction component derived from Mushroom was performed at 100 pg / mL. The results are shown in FIG. In addition, in FIG. 1, the fat-soluble extraction component derived from Agaricus (obtained 43.2 mg per 1 g of dried fruit body), the fat-soluble extraction component derived from birch salmon (children) obtained in the same manner as the fat-soluble extraction component derived from Mushroom. The results of evaluation using 12.9 mg per 1 g of dry substance powder instead of the fat-soluble extract component derived from Mushroom butter and the results of evaluation using only tunicamycin are shown. As is clear from FIG. 1, the fat-soluble extract component derived from mushrooms alleviated the cell death induced by tunicamycin, so that its endoplasmic reticulum stress inhibitory effect could be confirmed.
実施例２：桑黄由来の脂溶性抽出成分の小胞体ストレス抑制効果の評価（その２）
桑黄に属するエゾキコブタケ由来の脂溶性抽出成分と、マツノカタワタケ由来の脂溶性抽出成分を、キコブタケ由来の脂溶性抽出成分と同様にして得た。前者の脂溶性抽出成分は子実体乾燥粉末１ｇあたり６．７ｍｇ得られ、後者の脂溶性抽出成分は子実体乾燥粉末１ｇあたり７．０ｍｇ得られた。これらの脂溶性抽出成分の小胞体ストレス抑制効果の評価を、キコブタケ由来の脂溶性抽出成分とともに、実施例１の評価と同様にして行った。結果を図２に示す。図２から明らかなように、いずれの脂溶性抽出成分にも小胞体ストレス抑制効果が確認できたが、その効果は、特にキコブタケ由来の脂溶性抽出成分において優れていた。
Example 2: Evaluation of endoplasmic reticulum stress inhibitory effect of fat-soluble extract component derived from mulberry yellow (Part 2)
A fat-soluble extract component derived from Mushroom butterfly belonging to Mulberry yellow and a fat-soluble extract component derived from Matsuno Katatake were obtained in the same manner as the fat-soluble extract component derived from Mushroom butterfly. The former fat-soluble extract component was obtained in an amount of 6.7 mg per 1 g of the fruit body dry powder, and the latter fat-soluble extract component was obtained in an amount of 7.0 mg per 1 g of the fruit body dry powder. Evaluation of the endoplasmic reticulum stress inhibitory effect of these fat-soluble extract components was performed in the same manner as the evaluation of Example 1 together with the fat-soluble extract components derived from Mushroom. The results are shown in FIG. As is apparent from FIG. 2, the effect of suppressing endoplasmic reticulum stress was confirmed in any of the fat-soluble extract components, but the effect was particularly excellent in the fat-soluble extract components derived from Mushroom.
実施例３：桑黄由来の脂溶性抽出成分の小胞体ストレス抑制効果の評価（その３）
実施例１の（１）で得たキコブタケ由来の脂溶性抽出成分７００ｍｇをシリカゲルカラムクロマトグラフィーで分画した。２×３０ｃｍのガラスクロマト管にシリカゲル（Ｍｅｒｃｋ社製：Ｋｉｅｓｅｌｇｅｌ６０Ｆ254）を約２０ｇ詰め、展開溶媒にはクロロホルム−アセトンおよびアセトン−メタノールを用いた。なお、展開溶媒の混合比は順次変えて行った。即ち、まず、クロロホルム−アセトンを１０：０、９：１、８：２、７：３、６：４、２：８、０：１０の割合で混合した溶媒をそれぞれ２００ｍｌ、２００ｍｌ、７０ｍｌ、１５０ｍｌ、５０ｍｌ、７０ｍｌ、１５０ｍｌずつ用いて展開した。その後、さらに、アセトン−メタノールを９：１、７：３の割合で混合した溶媒をそれぞれ２００ｍｌ、３００ｍｌずつ用いて展開した。分画液を約２０ｍｌずつ集め、その分画物をＴＬＣ（Ｍｅｒｃｋ社製：Ｓｉｌｉｃａｇｅｌ６０Ｆ254）で展開し、類似成分とみなしうるスポットを含む分画物を混合して同一の粗精製画分とした。以上の操作により、実施例１の（１）で得たキコブタケ由来の脂溶性抽出成分７００ｍｇから、ＴＬＣ（同上）にスポットし、ジエチルエーテル：メタノール＝９：１の割合で混合した溶媒で展開してリンモリブデン酸試薬により発色させることで、Ｒｆ値が０．３８、０．５１である２つの異なるスポットを有する、メタノールによって溶出される粗精製画分２４ｍｇを得た。この粗精製画分の小胞体ストレス抑制効果の評価を、実施例１の評価と同様にして行った（ただしその濃度は１０ｐｇ／ｍＬとした）。その結果、図３に示したように、この粗精製画分は優れた小胞体ストレス抑制効果をもつことが確認できた。
Example 3: Evaluation of the endoplasmic reticulum stress inhibitory effect of a fat-soluble extract component derived from mulberry yellow (Part 3)
700 mg of the fat-soluble extract component derived from Mushrooms obtained in (1) of Example 1 was fractionated by silica gel column chromatography. Silica gel glass chromatographic tubes 2 × 30 cm (Merck Co.: Kieselgel 60 254) to about 20g filling, the developing solvent chloroform - methanol was used - acetone and acetone. The mixing ratio of the developing solvent was changed sequentially. That is, first, 200 ml, 200 ml, 70 ml, and 150 ml of a solvent prepared by mixing chloroform-acetone in a ratio of 10: 0, 9: 1, 8: 2, 7: 3, 6: 4, 2: 8, and 0:10, respectively. , 50 ml, 70 ml and 150 ml each. Thereafter, further, 200 ml and 300 ml of a solvent in which acetone-methanol was mixed at a ratio of 9: 1 and 7: 3 were developed. Collected fractionated liquid by about 20 ml, a fraction thereof to TLC (Merck Co.: Silicagel60F 254) and developed with, and the same crude fraction by mixing the fractions containing the spots can be considered similar component . By the above operation, spotted on TLC (same as above) from 700 mg of the fat-soluble extract component derived from mushrooms obtained in (1) of Example 1, and developed with a solvent mixed in a ratio of diethyl ether: methanol = 9: 1. The color was developed with a phosphomolybdic acid reagent to obtain 24 mg of a crudely purified fraction eluted with methanol having two different spots with Rf values of 0.38 and 0.51. Evaluation of the endoplasmic reticulum stress inhibitory effect of this crudely purified fraction was performed in the same manner as in Example 1 (however, the concentration was 10 pg / mL). As a result, as shown in FIG. 3, it was confirmed that this crudely purified fraction had an excellent endoplasmic reticulum stress suppressing effect.
実施例４：桑黄由来の脂溶性抽出成分の小胞体ストレス抑制効果の評価（その４）
キコブタケ子実体のかわりにメシマコブ子実体を用いること以外は実施例１と同様にしてメシマコブ由来の脂溶性抽出成分の小胞体ストレス抑制効果を確認した。
Example 4: Evaluation of endoplasmic reticulum stress inhibitory effect of fat-soluble extract component derived from mulberry yellow (Part 4)
The endoplasmic reticulum stress inhibitory effect of the fat-soluble extract component derived from Meshimakobu was confirmed in the same manner as in Example 1 except that Meshimakobu fruit body was used in place of the fruit body.
製剤例１：錠剤
キコブタケ由来の脂溶性抽出成分４ｇ、乳糖７６ｇ、ステアリン酸マグネシウム２０ｇ、合計１００ｇを均一に混合し、常法に従って錠剤とした。
Formulation Example 1: Tablets 4 g of a fat-soluble extract component derived from mushrooms, 76 g of lactose, 20 g of magnesium stearate, and a total of 100 g were uniformly mixed to obtain tablets according to a conventional method.
製剤例２：顆粒剤
メシマコブ由来の脂溶性抽出成分１６ｇ、澱粉２９ｇ、乳糖５５ｇ、合計１００ｇを均一に混合し、常法に従って顆粒剤とした。
Formulation Example 2: Granule 16 g of fat-soluble extract component derived from Meshima Kobu, 29 g of starch, and 55 g of lactose were mixed uniformly to obtain a granule according to a conventional method.
製剤例３：ビスケット
薄力粉３２ｇ、全卵１８ｇ、バター１４ｇ、砂糖２４ｇ、水１０ｇ、ベーキングパウダー１ｇ、マツノカタワタケ由来の脂溶性抽出成分１ｇ、合計１００ｇを用い、常法に従ってビスケットとした。
Formulation Example 3: Biscuit Biscuits were prepared according to a conventional method using 32 g of soft flour, 18 g of whole eggs, 14 g of butter, 24 g of sugar, 10 g of water, 1 g of baking powder, 1 g of fat-soluble extract components derived from matsuno Katatake and 100 g in total.
本発明は、老人性痴呆症（アルツハイマー病）やパーキンソン病、ハンチントン病に代表される神経変性疾患の予防および／または治療に有効なキノコ由来の新規な小胞体ストレス抑制剤を提供することができる点において産業上の利用可能性を有する。 The present invention can provide a novel endoplasmic reticulum stress inhibitor derived from mushrooms that is effective in the prevention and / or treatment of neurodegenerative diseases represented by senile dementia (Alzheimer's disease), Parkinson's disease, and Huntington's disease. In terms of industrial applicability.
Claims (6)
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| JP2009256248A (en) * | 2008-04-17 | 2009-11-05 | Api Co Ltd | Cyclopentane compound, its manufacturing method and neurotropic factor-like agent |
| WO2013100717A2 (en) * | 2011-12-30 | 2013-07-04 | Park Hyoung Jin | Composition for preventing and treating multiple sclerosis and autoimmune diseases, containing phellinus igniarius extract |
| CN116251129A (en) * | 2021-12-09 | 2023-06-13 | 葡萄王生技股份有限公司 | Use of Phellinus linteus GKPl mycelium for preparing composition for improving obesity and obesity related metabolic diseases |
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| JP2002235084A (en) * | 2001-02-08 | 2002-08-23 | Ishikawa Tennen Yakko Busshitsu Kenkyu Center | Antioxidant |
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| JP2002235084A (en) * | 2001-02-08 | 2002-08-23 | Ishikawa Tennen Yakko Busshitsu Kenkyu Center | Antioxidant |
| KR20030034420A (en) * | 2001-10-23 | 2003-05-09 | 주식회사 엘컴사이언스 | Pharmaceutical preparations containing cultured basidiocarps of Phellinus linteus extract for prevention and treatment of neurodegenerative disease |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2009256248A (en) * | 2008-04-17 | 2009-11-05 | Api Co Ltd | Cyclopentane compound, its manufacturing method and neurotropic factor-like agent |
| WO2013100717A2 (en) * | 2011-12-30 | 2013-07-04 | Park Hyoung Jin | Composition for preventing and treating multiple sclerosis and autoimmune diseases, containing phellinus igniarius extract |
| KR20130078395A (en) * | 2011-12-30 | 2013-07-10 | 박형진 | A composition comprising extract of a mushroom, phellinus igniarius, for prevention and treatment of multiple sclerosis and other autoimmune diseases |
| WO2013100717A3 (en) * | 2011-12-30 | 2013-08-22 | Park Hyoung Jin | Composition for preventing and treating multiple sclerosis and autoimmune diseases, containing phellinus igniarius extract |
| KR101713166B1 (en) | 2011-12-30 | 2017-03-07 | 박형진 | A composition comprising extract of a mushroom, Phellinus igniarius, for prevention and treatment of multiple sclerosis and other autoimmune diseases |
| CN116251129A (en) * | 2021-12-09 | 2023-06-13 | 葡萄王生技股份有限公司 | Use of Phellinus linteus GKPl mycelium for preparing composition for improving obesity and obesity related metabolic diseases |
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