JP2010013423A - Dipeptidyl peptidase-iv inhibitor - Google Patents
Dipeptidyl peptidase-iv inhibitor Download PDFInfo
- Publication number
- JP2010013423A JP2010013423A JP2008177138A JP2008177138A JP2010013423A JP 2010013423 A JP2010013423 A JP 2010013423A JP 2008177138 A JP2008177138 A JP 2008177138A JP 2008177138 A JP2008177138 A JP 2008177138A JP 2010013423 A JP2010013423 A JP 2010013423A
- Authority
- JP
- Japan
- Prior art keywords
- dipeptidyl peptidase
- food
- peptide
- inhibitor
- sample
- 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.)
- Pending
Links
Landscapes
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
本発明は、インスリン分泌増強作用などを有するグルカゴン様ペプチド−１を不活性化するジペプチジルペプチダーゼ−ＩＶ（以下、ＤＤＰ−ＩＶと記す場合もある）を阻害するジペプチジルベプチダーゼ−ＩＶ阻害剤に関するものである。 The present invention relates to a dipeptidyl peptidase-IV inhibitor that inhibits dipeptidyl peptidase-IV (hereinafter also referred to as DDP-IV) that inactivates glucagon-like peptide-1 having an insulin secretion enhancing action and the like. Is.
代謝異常症候群いわゆるメタボリックシンドロームは国民の４０歳代以上の男性の３人に一人は予備群であると、厚生労働省より発表されている。この代謝異常症候群の上流にある症状は肥満であり、特に内臓脂肪から生ずるアディポサイトカインによって高血圧、高脂血症、糖尿病を引き起こす。この中でも糖尿病は冠状心疾患、脳卒中、末梢血管疾患、高血圧、腎症、神経障害、アルツハイマー症及び網膜症を含めた大血管及び微小血管合併症を併発する危険性が高い。したがって、糖尿病を臨床的に管理、治療することが重要となる。 Metabolic syndrome, so-called metabolic syndrome, has been announced by the Ministry of Health, Labor and Welfare that one out of every three males in their 40s is a reserve group. The symptom upstream of this metabolic disorder syndrome is obesity, which causes hypertension, hyperlipidemia, and diabetes, especially by adipocytokines generated from visceral fat. Among them, diabetes has a high risk of complications of macrovascular and microvascular complications including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, Alzheimer's disease and retinopathy. Therefore, it is important to clinically manage and treat diabetes.
経口糖尿病治療薬は、その歴史を振り返ると、１９５０年代の第１世代スルホニル尿素(ＳＵ)剤、１９６０年代のビグアナイド剤、１９７０年代の第二世代ＳＵ剤というように、１０年に１種ずつの割合で導入されてきた。そして、１９９０年代では、α−グルコシダーゼ阻害剤、グリニド剤、第３世代ＳＵ剤、グリタゾン剤という４種類の血糖降下剤が実用化された。その後も、メカニズムが異なり、より性能の高い、副作用の低い経口糖尿病薬の開発に鎬が削られているのが現状である。このような状況の中、従来の市販薬にない作用メカニズムを持つ糖尿病治療薬として注目されているのが、「ジペプチジルペプチダーゼ−ＩＶ（ＤＰＰ−ＩＶ）阻害剤」である。 Looking back at the history of oral anti-diabetic drugs, the first generation sulfonylurea (SU) in the 1950s, the biguanide in the 1960s, and the second generation SU in the 1970s It has been introduced at a rate. In the 1990s, four types of hypoglycemic agents, α-glucosidase inhibitor, glinide agent, third generation SU agent, and glitazone agent, were put into practical use. Even after that, the current situation is that the mechanism is different, and the development of oral anti-diabetic drugs with higher performance and lower side effects is still underway. Under such circumstances, “dipeptidyl peptidase-IV (DPP-IV) inhibitors” are attracting attention as antidiabetic agents having a mechanism of action that is not found in conventional commercially available drugs.
通常、食物の摂取後に消化管から膵臓からのインスリン分泌を促進するホルモンであるインクレチンが放出されている。このインクレチンを分解する酵素がＤＰＰ−ＩＶであり、このＤＰＰ−ＩＶを阻害することで血糖値の上昇を押さえる治療薬が、上記ジペプチジルペプチダーゼ-ＩＶ（ＤＰＰ−ＩＶ）阻害剤である。 Normally, incretin, a hormone that promotes insulin secretion from the pancreas, is released from the digestive tract after food intake. The enzyme that degrades incretin is DPP-IV, and the therapeutic agent that suppresses the increase in blood glucose level by inhibiting DPP-IV is the dipeptidyl peptidase-IV (DPP-IV) inhibitor.
このようなメカニズムを持つ食品成分として報告されているのは、熟成ナチュラルチーズ成分中のペプチド（特許文献１）、（非特許文献１）や食肉の乳酸菌発酵物（非特許文献２）のみである。これらの成分を、糖尿病を治療する目的で摂取しようとした場合、チーズや食肉の乳酸菌発酵物のカロリーが高いため、糖尿病患者あるいは糖尿病予備群の患者が食品として長期的に摂取することは、却って食事による高血糖状態や肥満を引き起こす原因となりかねない。 Only the peptides (patent document 1) and (non-patent document 1) in ripened natural cheese ingredients and fermented lactic acid bacteria of meat (non-patent document 2) are reported as food components having such a mechanism. . When trying to take these ingredients for the purpose of treating diabetes, the calorie of lactic acid bacteria fermentation products of cheese and meat is high, so that diabetics or patients in the pre-diabetes group take it as food for a long time, It can cause hyperglycemia and obesity due to diet.
本発明は、上記従来の事情に鑑みてなされたものであって、その課題は、ＤＤＰ−ＩＶ阻害作用が強く、しかも、カロリーが低く、日常的に摂取して安全な飲食用素材由来の調製物を有効成分とするジペプチジルベプチダーゼ−ＩＶ阻害剤を提供することにある。 The present invention has been made in view of the above-described conventional circumstances, and the problem is that the DDP-IV inhibitory action is strong, and the calorie is low, and it is prepared from food and drink materials that are safe to eat on a daily basis. An object of the present invention is to provide a dipeptidyl beptidase-IV inhibitor containing a product as an active ingredient.
上述した課題を解決するために、本発明者らは、鋭意、実験、検討したところ、特定の飲食用素材由来の調製物、すなわち、蛋白質含有食品素材由来のピーク分子量が２０００以下のペプチド及び特定の植物の抽出物に、固形分濃度３．５ｍｇ/ｍＬ以下で６０％以上の高いＤＤＰ−ＩＶ阻害作用があることを知見するにいった。本発明は、係る知見に基づいてなされたものである。 In order to solve the above-mentioned problems, the present inventors diligently, experimented, and examined. As a result, a preparation derived from a specific food and drink material, that is, a peptide having a peak molecular weight of 2000 or less derived from a protein-containing food material and a specific The plant extract was found to have a high DDP-IV inhibitory effect of 60% or more at a solid content concentration of 3.5 mg / mL or less. The present invention has been made based on such knowledge.
すなわち、本発明に係るジペプチジルベプチダーゼ−ＩＶ阻害剤は、固形分濃度３．５ｍｇ／ｍＬ以下でのジペプチジルペプチダーゼＩＶ阻害率が６０％以上の飲食用素材由来の調製物を有効成分として含有することを特徴とする。 That is, the dipeptidyl peptidase-IV inhibitor according to the present invention contains, as an active ingredient, a preparation derived from a food and beverage material having a dipeptidyl peptidase IV inhibition rate of 60% or more at a solid content concentration of 3.5 mg / mL or less. It is characterized by doing.
また、本発明に係るジペプチジルペプチダーゼ−ＩＶ阻害剤は、ジペプチジルペプチダーゼＩＶ阻害のＩＣ５０（５０％阻害濃度）が固形分濃度で３．５ｍｇ/ｍＬ以下である飲食用素材由来の調製物を有効成分として含有することを特徴とする。 In addition, the dipeptidyl peptidase-IV inhibitor according to the present invention is effective for a preparation derived from a food and beverage material having an IC50 (50% inhibitory concentration) of dipeptidyl peptidase IV inhibition of 3.5 mg / mL or less in solid content concentration. It is contained as a component.
前記構成において、前記飲食用素材由来の調製物は、蛋白質含有食品素材由来のピーク分子量が２０００以下のペプチドであるか、海藻、茶類、クルミ、ザクロ、ブドウ種子、黄杞葉、カカオ、ブドウ新芽、グアバ、生コーヒー豆、コタラヒムブツ、タマリンドの各抽出物から選ばれる少なくとも一種である。 In the above configuration, the preparation derived from the food and drink material is a peptide having a peak molecular weight of 2000 or less derived from a protein-containing food material, or a seaweed, tea, walnut, pomegranate, grape seed, yellow leaves, cacao, grape shoot, It is at least one selected from each extract of guava, green coffee beans, kotara humbutsu, and tamarind.
前記蛋白質含有食品素材としては、乳、魚、豆類、小麦、豚から選ばれた少なくとも一種であることが、好ましい。 The protein-containing food material is preferably at least one selected from milk, fish, beans, wheat, and pigs.
または、前記ペプチドは、カゼインペプチド、コラーゲンペプチド、大豆ペプチド、緑豆ペプチド、小麦グルテンから選ばれた少なくとも一種であることが、好ましい。 Alternatively, the peptide is preferably at least one selected from casein peptide, collagen peptide, soybean peptide, mung bean peptide, and wheat gluten.
本発明に係るジペプチジルベプチダーゼ−ＩＶ阻害剤は、ＤＤＰ−ＩＶ阻害作用が強く、しかも、カロリーが低く、飲食用素材由来であるために、日常的に摂取して安全であり、各種医薬品、特定用保健食品、機能性食品、飲用物などへの利用が可能である。 The dipeptidyl beptidase-IV inhibitor according to the present invention has a strong DDP-IV inhibitory action, is low in calories, and is derived from food and drink. It can be used for specific health foods, functional foods, and drinks.
本発明に係るジペプチジルベプチダーゼ−ＩＶ阻害剤は、前述のように、固形分濃度３．５ｍｇ／ｍＬ以下でのジペプチジルペプチダーゼＩＶ阻害率が６０％以上の飲食用素材由来の調製物を有効成分として含有する。あるいは、本発明に係るジペプチジルペプチダーゼ−ＩＶ阻害剤は、ジペプチジルペプチダーゼＩＶ阻害のＩＣ５０（５０％阻害濃度）が固形分濃度で３．５ｍｇ/ｍＬ以下である飲食用素材由来の調製物を有効成分として含有する。前記飲食用素材由来の調製物は、蛋白質含有食品素材由来のピーク分子量が２０００以下のペプチドであるか、海藻、茶類、クルミ、ザクロ、ブドウ種子、黄杞葉、カカオ、ブドウ新芽、グアバ、生コーヒー豆、コタラヒムブツ、タマリンドの各抽出物から選ばれる少なくとも一種である。 As described above, the dipeptidyl peptidase-IV inhibitor according to the present invention is effective as a preparation derived from a food and beverage material having a dipeptidyl peptidase IV inhibition rate of 60% or more at a solid content concentration of 3.5 mg / mL or less. Contains as a component. Alternatively, the dipeptidyl peptidase-IV inhibitor according to the present invention is effective for a preparation derived from a food and drink material having an IC50 (50% inhibition concentration) of dipeptidyl peptidase IV inhibition of 3.5 mg / mL or less in solid content concentration. Contains as a component. The preparation derived from the food and drink material is a peptide having a peak molecular weight of 2000 or less derived from a protein-containing food material, or is a seaweed, tea, walnut, pomegranate, grape seed, yellow leaf, cacao, grape shoot, guava, fresh coffee It is at least one selected from each extract of beans, Kotara Himubutsu, and tamarind.
本発明に係るジペプチジルベプチダーゼ−ＩＶ阻害剤は、経口的に投与して、生体におけるＤＤＰ−ＩＶを阻害することにより血糖値を低下させることができる。経口投与に用いる本発明のＤＤＰ−ＩＶ阻害剤の剤形は、錠剤、カプセル剤、細粒剤、散剤、タブレット剤、トローチ剤、舌下剤、液剤などが可能である。また、各種食品、各種飲料に添加して用いることもできる。 The dipeptidyl beptidase-IV inhibitor according to the present invention can be administered orally to inhibit blood glucose level by inhibiting DDP-IV in a living body. The dosage form of the DDP-IV inhibitor of the present invention used for oral administration can be tablets, capsules, fine granules, powders, tablets, troches, sublinguals, liquids and the like. Moreover, it can also add and use for various foodstuffs and various drinks.
本発明に係るジペプチジルベプチダーゼ−ＩＶ阻害剤の経口投与量としては、治療や予防の目的、投与対象の症状、体重、年齢、性別などの諸条件を考慮して、適宜に決定されるが、通常、成人を対象とした場合、一日あたり、有効成分量として、５ｍｇ〜５０００ｍｇとすれば、有効である。 The oral dose of the dipeptidyl beptidase-IV inhibitor according to the present invention is appropriately determined in consideration of various conditions such as the purpose of treatment and prevention, symptoms of the subject of administration, body weight, age, and sex. In general, in the case of adults, it is effective if the amount of active ingredient is 5 mg to 5000 mg per day.
以下に、本発明にかかるジペプチジルベプチダーゼ−ＩＶ阻害剤の実施例を詳細に説明する。なお、この実施例によりこの発明が限定されるものではない。 Examples of dipeptidyl beptidase-IV inhibitors according to the present invention will be described in detail below. Note that the present invention is not limited to the embodiments.
（実施例１）
この実施例１では、飲食用素材由来の調製物として、蛋白質含有食品素材由来のペプチドについて、検討した。
Example 1
In Example 1, peptides derived from protein-containing food materials were examined as preparations derived from food and drink materials.
蛋白質含有食品素材由来のペプチドとして、（表１）に示す１５種のペプチドを用意した。これら１５種のペプチドサンプルに対して、ピーク分子量の測定と、ＤＤＰ−ＩＶ阻害率を測定した。 As peptides derived from protein-containing food materials, 15 types of peptides shown in (Table 1) were prepared. The peak molecular weight and DDP-IV inhibition rate were measured for these 15 peptide samples.
（蛋白質食品素材からのペプチドの調製方法）
ペプチド素材の調製方法としては、慣用の方法が多種あるが、蛋白質の分解には酵素を用いた方法あるいは加水分解を用いた方法が一般的である。蛋白質の分解の後、酵素の失活や中和、濾過の後、凍結乾燥やスプレードライを用いて粉末化する。しかし、どのような調製方法を用いた場合でも、原料となる食品素材と分子量により、ＤＰＰ−ＩＶ阻害活性が依存する。したがって、ペプチド素材の調製方法は、特に限定されない。
(Method for preparing peptides from protein food materials)
As a method for preparing a peptide material, there are a variety of conventional methods. For protein degradation, a method using an enzyme or a method using hydrolysis is generally used. After protein degradation, the enzyme is inactivated, neutralized, filtered, and then pulverized using freeze drying or spray drying. However, whatever preparation method is used, the DPP-IV inhibitory activity depends on the food material and molecular weight as the raw material. Therefore, the method for preparing the peptide material is not particularly limited.
（分子量ピークの測定）
ペプチドの分子量ピークを測定する方法については、種々の測定方法があるが、ゲル濾過法を用いた測定が迅速で、正確な値が得られる。すなわち、分子篩機能をもった充填剤を充填したカラムを用いてた高速液体クロマトグラフィー（High Performance Liquid Chromatography：以下、ＨＰＬＣと記す場合もある）にて、２８０μｍの吸収を測定することによりペプチドサンプルの分子量分布カーブを求め、その中で最も高いピークの頂点の分子量を分子量ピークの値とする。
(Measurement of molecular weight peak)
There are various measurement methods for measuring the molecular weight peak of the peptide, but the measurement using the gel filtration method is quick and an accurate value can be obtained. That is, by measuring absorption at 280 μm by high performance liquid chromatography (hereinafter sometimes referred to as HPLC) using a column packed with a filler having a molecular sieve function, A molecular weight distribution curve is obtained, and the molecular weight at the apex of the highest peak is taken as the molecular weight peak value.
（阻害活性測定用サンプルの調製）
（表１）に示した１５種のペプチドサンプル（粉末状固形物）を５０ｍＭトリス塩酸緩衝液（ｐＨ７．５）に１０ｍｇ／ｍＬの濃度で溶解し、０．４５μｍのメンブランフィルター処理を行った後、ＤＰＰ−ＩＶ阻害活性測定に供した。ＤＤＰ−ＩＶ阻害活性は、以下の測定方法Ａにより測定した。
(Preparation of inhibitory activity measurement sample)
After 15 peptide samples (powdered solid) shown in (Table 1) were dissolved in 50 mM Tris-HCl buffer (pH 7.5) at a concentration of 10 mg / mL and subjected to 0.45 μm membrane filter treatment Then, it was subjected to DPP-IV inhibitory activity measurement. The DDP-IV inhibitory activity was measured by the following measuring method A.
（ジペプチジルペプチダーゼ-ＩＶ（ＤＰＰ−ＩＶ）阻害活性測定方法Ａ）
各ペプチドサンプルについて、ＤＤＰ−ＩＶ阻害活性測定キット（バイオモル社製、商品名「DPPIV Drug Discovery Kit-AK-499」)を用いて、ＤＰＰ−ＩＶ阻害活性の測定を行った。ペプチドサンプル基質として、Ｈ−Ｇｌｙ−Ｐｌｏ−７−アミノ−４−メチルクマリン（バイオモル社製、商品名「Ｐ１８９−９０９０ ＡＭＣ基質」)を用い、酵素はＤＰＰ−ＩＶ（バイオモル社製、商品名「Ｅ４３４−９０９０ ＤＤＰＩＶ酵素；ヒト組み替え体」）を用いた。また、対照阻害剤としてＰ３２／９８（（バイオモル社製、商品名「ＰＩ１４２−９０９０」）を使用した。
(Dipeptidyl peptidase-IV (DPP-IV) inhibitory activity measurement method A)
About each peptide sample, DPP-IV inhibitory activity was measured using the DDP-IV inhibitory activity measuring kit (The biomol company make, brand name "DPPIV Drug Discovery Kit-AK-499"). As a peptide sample substrate, H-Gly-Plo-7-amino-4-methylcoumarin (trade name “P189-9090 AMC substrate” manufactured by Biomol) was used, and the enzyme was DPP-IV (trade name “Biomol”, product name “ E434-9090 DDPIV enzyme; human recombinant ")". Further, P32 / 98 (manufactured by Biomol, trade name “PI142-9090”) was used as a control inhibitor.
具体的には、１００μＬ、９６穴白色マイクロプレートに、阻害率測定用サンプル３５μＬ、１／５０希釈ＤＰＰ−ＩＶ酵素１５μＬ、１／５０希釈のＡＭＣ基質溶液５０μＬを添加した。得られたサンプルの固形分濃度は３．５ｍｇ／ｍＬとなった。このサンプルのＤＤＰ−ＩＶ阻害活性を、励起波長３８０ｎｍ、測定波長４６０ｎｍにて、１分間置きに６０分まで測定し、値が直線性を維持する範囲での傾きの値を、サンプル無添加の値を１００％として、各サンプルの相対的な活性を算出した。各サンプルについてＤＰＰ−ＩＶ阻害率を２回測定して平均値を求めた。その結果を（表１）に併記した。 Specifically, 35 μL of inhibition rate measurement sample, 15 μL of 1/50 diluted DPP-IV enzyme, and 50 μL of 1/50 diluted AMC substrate solution were added to 100 μL, 96-well white microplate. The solid content concentration of the obtained sample was 3.5 mg / mL. The DDP-IV inhibitory activity of this sample was measured up to 60 minutes every other minute at an excitation wavelength of 380 nm and a measurement wavelength of 460 nm, and the value of the slope in the range where the value maintains linearity is the value with no sample added. Was 100%, and the relative activity of each sample was calculated. For each sample, the DPP-IV inhibition rate was measured twice to obtain an average value. The results are also shown in (Table 1).
＊２：森永乳業株式会社製、商品名「ペプチドＣＵ２５００」
＊３：森永乳業株式会社製、商品名「ペプチドＣＰＯＰ」
＊４：不二製油株式会社製、商品名「ハイニュートＡＭ」
＊５：ＤＭＶ社製、商品名「ＷＧＥ８０ＧＰＡ」
＊６：ＤＭＶ社製、商品名「ＷＧＥ８０ＧＰＮ」
＊７：ゼライス株式会社製、商品名「ＨＡＣＰ−０１」
＊８：ゼライス株式会社製、商品名「ＨＡＣＯ−Ｕ２」
＊９：ＤＭＶ社製、商品名「Ｃ１２ＡＳＥ」
＊１０：ＤＭＶ社製、商品名「Ｃ１２ＰＥＰＴＩＯＮＢ」
＊１１：株式会社ニチロ製、商品名「マリンコラーゲンペプチドＯＭ」
＊１２：森永乳業株式会社製、商品名「エマルアップ」
＊１３：協和発酵株式会社製、商品名「水溶性コラーゲンペプチドＰＡ」
＊１４：協和発酵株式会社製、商品名「水溶性コラーゲンペプチドＰＡ」
＊１５：協和発酵株式会社製、商品名「水溶性フィッシュコラーゲンペプチド」
* 2: Product name “Peptide CU2500” manufactured by Morinaga Milk Industry Co., Ltd.
* 3: Product name “Peptide CPOP” manufactured by Morinaga Milk Industry Co., Ltd.
* 4: Fuji Oil Co., Ltd., trade name “High Newt AM”
* 5: Product name “WGE80GPA” manufactured by DMV
* 6: Product name “WGE80GPN” manufactured by DMV
* 7: Product name “HACP-01” manufactured by Zerais Co., Ltd.
* 8: Product name “HACO-U2” manufactured by Zerais Co., Ltd.
* 9: Product name “C12ASE” manufactured by DMV
* 10: Product name “C12PEPTIONB” manufactured by DMV
* 11: Product name “Marine Collagen Peptide OM” manufactured by Nichiro Co., Ltd.
* 12: Morinaga Milk Industry Co., Ltd., trade name “Emal Up”
* 13: Product name “Water-soluble collagen peptide PA” manufactured by Kyowa Hakko Co., Ltd.
* 14: Product name "Water-soluble collagen peptide PA" manufactured by Kyowa Hakko Co., Ltd.
* 15: Product name “Water-soluble fish collagen peptide” manufactured by Kyowa Hakko Co., Ltd.
対照としたＤＤＰ−ＩＶ阻害薬である「Ｐ３２／９８」の１０μＭ品の阻害率が９３％、１μＭ品の阻害率が６７％であり、阻害率が６０％以上あれば、実用上の効果があると考え得る。 If the inhibition rate of the 10 μM product of “P32 / 98” which is the control DDP-IV inhibitor is 93%, the inhibition rate of the 1 μM product is 67%, and if the inhibition rate is 60% or more, there is a practical effect. I can think of it.
サンプル１の緑豆ペプチドのピーク分子量は１５０〜５００であり、サンプル２のカゼインペプチドのピーク分子量は９１であり、順次、最後のサンプル１５までピーク分子量が大きくなっていっており、最後のサンプル１５のピーク分子量は５０００であった。このピーク分子量の増加に比例して、各サンプルのＤＤＰ−ＩＶ阻害率は低下している。サンプル１の阻害率は９５％であり、医薬品である「Ｐ３２／９８」の１０μＭと同等の高い阻害率を有する。実用上有効であると見なすことのできる阻害率６０％までの阻害率を有するサンプルのうちの最も阻害率が低いものは、サンプル１１の６８％であり、サンプル１０〜サンプル１までは、６０％以上の高い阻害率を有している。 The peak molecular weight of the mung bean peptide of sample 1 is 150 to 500, the peak molecular weight of the casein peptide of sample 2 is 91, and the peak molecular weight increases sequentially until the last sample 15, The peak molecular weight was 5000. In proportion to the increase in the peak molecular weight, the DDP-IV inhibition rate of each sample decreases. The inhibition rate of sample 1 is 95%, and it has a high inhibition rate equivalent to 10 μM of “P32 / 98” which is a pharmaceutical product. Among samples having an inhibition rate of up to 60% that can be regarded as practically effective, the sample having the lowest inhibition rate is 68% of sample 11, and 60% of samples 10 to 1 It has the above high inhibition rate.
したがって、蛋白質含有食品素材由来のペプチドのうち、ピーク分子量が２０００以下のペプチドは、医薬品と同等の高いＤＤＰ−ＩＶ阻害作用があり、しかもカロリーが低く、日常的に摂取して安全であるので、日常的に常用可能な優れたＤＤＰ−ＩＶ阻害剤の有効成分として用いて好適であることが確認できた。 Therefore, among peptides derived from protein-containing food materials, peptides having a peak molecular weight of 2000 or less have a high DDP-IV inhibitory action equivalent to that of pharmaceuticals, and are low in calories and are safe to take on a daily basis. It has been confirmed that it is suitable for use as an active ingredient of an excellent DDP-IV inhibitor that can be routinely used.
（実施例２）
実施例１でＤＤＰ−ＩＶ阻害活性を測定したペプチドサンプルのうち、サンプル１，２，６，８，１０の５種について、５０％阻害濃度（ＩＣ５０）を求めた。
具体的には、各サンプルを５０ｍＭトリス塩酸緩衝液（ｐＨ７．５）に溶解し、更にその溶液を段階希釈して各々のＤＰＰ−ＩＶ阻害活性を求めた。ＤＰＰ−ＩＶ阻害活性は、下記測定方法Ｂにより測定した。
(Example 2)
Among the peptide samples whose DDP-IV inhibitory activity was measured in Example 1, the 50% inhibitory concentration (IC50) was determined for 5 types of samples 1, 2, 6, 8, and 10.
Specifically, each sample was dissolved in 50 mM Tris-HCl buffer (pH 7.5), and the solution was further serially diluted to determine each DPP-IV inhibitory activity. The DPP-IV inhibitory activity was measured by the following measurement method B.
（ジペプチジルペプチダーゼ−ＩＶ（ＤＤＰ−ＩＶ）阻害活性測定方法Ｂ）
サンプルについて、DPPIV Glo Protease Assay(プロメガ社製)を用いて、ＤＤＰ−ＩＶ阻害活性の測定を行った。基質として、DPPIV Glo Reagent (Cat.#G8350：プロメガ社製)を用い、酵素はＤＤＰ−ＩＶ（Cat.No.31763、ヒト組み替え体：カルビオケム社）を用いた。対照阻害剤としてＰ３２／９８(バイオモル社製、商品名「ＰＩ１４２−９０９０」)を使用した。
具体的操作としては、まず、１００μＬ、９６穴白色マイクロプレートに、阻害率測定用サンプル３５μＬ、ＤＤＰ−ＩＶ酵素（２ｎｇ／ｍＬ）５０μＬ、基質溶液５０μＬを添加し、混合した。３０分後に発光量を測定し、サンプル無添加の値を１００％として各サンプルの相対的な活性を算出した。
(Dipeptidyl peptidase-IV (DDP-IV) inhibitory activity measurement method B)
The sample was measured for DDP-IV inhibitory activity using DPPIV Glo Protease Assay (Promega). As a substrate, DPPIV Glo Reagent (Cat. # G8350: manufactured by Promega) was used, and as a enzyme, DDP-IV (Cat. No. 31763, human recombinant: Calbiochem) was used. P32 / 98 (manufactured by Biomol, trade name “PI142-9090”) was used as a control inhibitor.
Specifically, first, 35 μL of the inhibition rate measurement sample, 50 μL of DDP-IV enzyme (2 ng / mL), and 50 μL of the substrate solution were added to and mixed with 100 μL of a 96-well white microplate. The amount of luminescence was measured after 30 minutes, and the relative activity of each sample was calculated with the value of no sample being added as 100%.
上記阻害活性とサンプル濃度（固形分濃度）の対数の関係式から逆算して、各サンプルのＩＣ５０を求めた。その結果、各サンプル１，２，６，８，１０のＩＣ５０値は、それぞれ、サンプル１（大豆ペプチド）０．７ｍｇ／ｍＬ、サンプル２（カゼインペプチド）０．６ｍｇ／ｍＬ、サンプル６（グルタミンペプチド）２．２ｍｇ／ｍＬ、サンプル８（コラーゲンペプチド）０．９ｍｇ／ｍＬ、サンプル１０（カゼインペプチド）１．６ｍｇ／ｍＬであった。 IC50 of each sample was calculated by calculating backward from the logarithmic relational expression of the inhibitory activity and the sample concentration (solid content concentration). As a result, the IC50 values of Samples 1, 2, 6, 8, and 10 are respectively Sample 1 (soybean peptide) 0.7 mg / mL, Sample 2 (casein peptide) 0.6 mg / mL, and Sample 6 (glutamine peptide). ) 2.2 mg / mL, Sample 8 (collagen peptide) 0.9 mg / mL, and Sample 10 (casein peptide) 1.6 mg / mL.
測定したサンプル１，２，６，８，１０は、すべてピーク分子量が２０００以下のペプチドであり、しかも、上述のように、ＩＣ５０の値が０．６〜２．２ｍｇ／ｍＬの範囲に入っており、良好なＤＤＰ−ＩＶ阻害活性を有していることが分かる。特にサンプル１のＩＣ５０は０．７ｍｇ／ｍＬ、サンプル２のＩＣ５０は０．６ｍｇ／ｍＬであり、しかも、これらの阻害率は、前述のように、９０％を超える高い値を示している。したがって、サンプル１，２は、ＤＤＰ−ＩＶ阻害剤の有効成分として、特に好ましい。 The measured samples 1, 2, 6, 8, and 10 are all peptides having a peak molecular weight of 2000 or less, and as described above, the IC50 value falls within the range of 0.6 to 2.2 mg / mL. It can be seen that it has a good DDP-IV inhibitory activity. In particular, the IC50 of sample 1 is 0.7 mg / mL, and the IC50 of sample 2 is 0.6 mg / mL. Moreover, as described above, these inhibition rates show high values exceeding 90%. Therefore, samples 1 and 2 are particularly preferable as the active ingredient of the DDP-IV inhibitor.
（実施例３）
この実施例３では、飲食用素材由来の調製物として、特定の植物（海藻を含む）の抽出物について検討した。
(Example 3)
In Example 3, an extract of a specific plant (including seaweed) was examined as a preparation derived from a food and drink material.
植物の抽出物として、（表２）に示す２７種の植物（海藻を含む）の抽出物を用意した。これら２７種の抽出物（サンプル１６〜４２）に対して、ＤＤＰ−ＩＶ阻害率を測定した。 As plant extracts, extracts of 27 kinds of plants (including seaweed) shown in (Table 2) were prepared. The DDP-IV inhibition rate was measured for these 27 kinds of extracts (samples 16 to 42).
（植物あるいは海藻抽出物の調製方法）
植物あるいは海藻素材の調製方法は、慣用の多種の方法があるが、通常は素材を粉砕し、水あるいはエタノール、含水エタノール、その他の食品に用いることのできる有機溶媒で抽出することが一般的である。抽出の後、濾過、凍結乾燥やスプレードライを用いて粉末化する。しかし、どのような調製方法を用いた場合でも、ＤＤＰ−ＩＶ阻害活性は、原料となる食品素材の種類に依存する。したがって、植物抽出物の調製方法は、特に限定されない。
(Preparation method of plant or seaweed extract)
There are various conventional methods for preparing plant or seaweed materials. Usually, the materials are crushed and extracted with water or an organic solvent that can be used for ethanol, hydrous ethanol, or other foods. is there. After extraction, it is pulverized using filtration, freeze drying or spray drying. However, in any preparation method, the DDP-IV inhibitory activity depends on the type of food material used as a raw material. Therefore, the method for preparing the plant extract is not particularly limited.
（阻害活性測定用サンプルの調製）
（表２）に示した植物または海藻由来のサンプル（粉末状固形物）は、５０ｍＭトリス塩酸緩衝液（ｐＨ７．５）に１ｍｇ／ｍＬの濃度で溶解し、０．４５μｍのメンブランフィルター処理を行った後、ＤＤＰ−ＩＶ阻害活性測定に供した。ＤＤＰ−ＩＶ阻害活性は、以下の測定方法Ｃにより測定した。
(Preparation of inhibitory activity measurement sample)
The plant or seaweed-derived sample (powdered solid) shown in (Table 2) was dissolved in 50 mM Tris-HCl buffer (pH 7.5) at a concentration of 1 mg / mL and subjected to 0.45 μm membrane filter treatment. Then, it used for the DDP-IV inhibitory activity measurement. The DDP-IV inhibitory activity was measured by the following measuring method C.
（ジペプチジルペプチダーゼ−ＩＶ（ＤＤＰ−ＩＶ）阻害活性測定方法Ｃ）
植物抽出物サンプルについて、ＤＤＰ−ＩＶ阻害活性測定キット（バイオモル社製、商品名「DPPIV Drug Discovery Kit-AK-499」)を用いて、ＤＤＰ−ＩＶ阻害活性の測定を行った。基質として、Ｈ−Ｇｌｙ−Ｐｌｏ−７−アミノ−４−メチルクマリン（バイオモル社製、商品名「Ｐ１８９−９０９０ ＡＭＣ基質」)を用い、酵素はＤＰＰ−ＩＶ（バイオモル社製、商品名「Ｅ４３４−９０９０ ＤＤＰＩＶ酵素；ヒト組み替え体」）を用いた。また、対照阻害剤としてＰ３２／９８（（バイオモル社製、商品名「ＰＩ１４２−９０９０」）を使用した。
(Dipeptidyl peptidase-IV (DDP-IV) inhibitory activity measurement method C)
About the plant extract sample, DDP-IV inhibitory activity was measured using the DDP-IV inhibitory activity measuring kit (The product name "DPPIV Drug Discovery Kit-AK-499" by Biomol). As a substrate, H-Gly-Plo-7-amino-4-methylcoumarin (trade name “P189-9090 AMC substrate” manufactured by Biomol Co., Ltd.) was used, and the enzyme was DPP-IV (trade name “E434- manufactured by Biomol Co., Ltd.). 9090 DDPIV enzyme; human recombinant "). Further, P32 / 98 (manufactured by Biomol, trade name “PI142-9090”) was used as a control inhibitor.
具体的には、１００μＬ、９６穴白色マイクロプレートに、阻害率測定用サンプル３５μＬ、１／５０希釈ＤＰＰ−ＩＶ酵素１５μＬ、１／５０希釈のＡＭＣ基質溶液５０μＬを添加した。得られたサンプルの固形分濃度は３．５ｍｇ／ｍＬとなった。このサンプルのＤＤＰ−ＩＶ阻害活性を、励起波長３８０ｎｍ、測定波長４６０ｎｍにて、１分間置きに６０分まで測定し、値が直線性を維持する範囲での傾きの値を、サンプル無添加の値を１００％として、各サンプルの相対的な活性を算出した。各サンプルについてＤＰＰ−ＩＶ阻害率を２回測定して平均値を求めた。その結果を（表２）に併記した。 Specifically, 35 μL of inhibition rate measurement sample, 15 μL of 1/50 diluted DPP-IV enzyme, and 50 μL of 1/50 diluted AMC substrate solution were added to 100 μL, 96-well white microplate. The solid content concentration of the obtained sample was 3.5 mg / mL. The DDP-IV inhibitory activity of this sample was measured up to 60 minutes every other minute at an excitation wavelength of 380 nm and a measurement wavelength of 460 nm, and the value of the slope in the range where the value maintains linearity is the value with no sample added. Was 100%, and the relative activity of each sample was calculated. For each sample, the DPP-IV inhibition rate was measured twice to obtain an average value. The results are also shown in (Table 2).
＊１７：常盤植物化学研究所社製、商品名「ティアカロン90S」
＊１８：オリザ油化社製、商品名「クルミホ゜リフェノールP30」
＊１９：常盤植物化学研究所社製、商品名「ティアカロン30」
＊２０：丸善製薬社製、商品名「甜茶エキスM粉末」
＊２１：キッコーマン社製、商品名「サ゛クロエラク゛酸」
＊２２：キッコーマン社製、商品名「ク゛ラウ゛ィノールSL」
＊２３：丸善製薬社製、商品名「黄杞葉エイキスハ゜ウタ゛ーMF」
＊２４：オリザ油化社製、商品名「カカオエキスP」
＊２５：サンブライト社製、商品名「VINEATROL20M」
＊２６：キッコーマン社製、商品名「ク゛ラウ゛ィノール」
＊２７：サウスプロダクト社製、商品名「ク゛アハ゛エキス末」
＊２８：丸善製薬社製、商品名「ウーロン茶エキスM粉末」
＊２９：オリザ油化社製、商品名「クルミホ゜リフェノールP10」
＊３０：オリザ油化社製、商品名「生コーヒー豆エキスPS1」
＊３１：AOAコーポレーション社製、商品名「スーハ゜ーコタラヒム」
＊３２：オリザ油化社製、商品名「生コーヒー豆エキスP」
＊３３：丸善製薬社製、商品名「インテ゛ィアンテ゛ーツエキスハ゜ウタ゛ーMF」
＊３４：TSトレーディング社製、商品名「XANTHIGEN-5」
＊３５：常盤植物化学研究所社製、商品名「朝鮮アサ゛ミ乾燥エキス」
＊３６：丸善製薬社製、商品名「ヒハツエキスME」
＊３７：丸善製薬社製、商品名「純ク゛リチミンY」
＊３８：サウスプロダクト社製、商品名「フコイタ゛ン」
＊３９：オリザ油化社製、商品名「温州みかんエキスP」
＊４０：サウスプロダクト社製、商品名「シークワーサーエキス末」
＊４１：常盤植物化学研究所社製、商品名「アイソマックス-80」
＊４２：サウスプロダクト社製、商品名「コ゛ーヤーエキス末」
* 17: Tokiwa Plant Chemistry Research Institute, trade name “Tiacalon 90S”
* 18: Product name “walnut polyphenol P30” manufactured by Oriza Oil Chemical Co., Ltd.
* 19: Tokiwa Plant Chemistry Research Institute, trade name “Tiacalon 30”
* 20: Maruzen Pharmaceutical Co., Ltd., trade name “Ochacha Extract M Powder”
* 21: Product name “Cycloeradic Acid” manufactured by Kikkoman Corporation
* 22: Product name “Glauinol SL” manufactured by Kikkoman Corporation
* 23: Maruzen Pharmaceutical Co., Ltd., trade name: “Yellow Leaves Aikishooter MF”
* 24: Product name “Cacao Extract P” manufactured by Oriza Oil Chemical Co., Ltd.
* 25: Product name "VINEATROL20M" manufactured by Sun Bright
* 26: Product name "Glauinol" manufactured by Kikkoman Corporation
* 27: Made by South Products, trade name “Guava extract powder”
* 28: Product name “Oolong tea extract M powder” manufactured by Maruzen Pharmaceutical Co., Ltd.
* 29: Product name “walnut polyphenol P10”, manufactured by Oriza Oil Chemical Co., Ltd.
* 30: Product name “Raw Coffee Bean Extract PS1” manufactured by Oriza Oil Chemical Co., Ltd.
* 31: Product name "Suha Kotarahim" manufactured by AOA Corporation
* 32: Product name “Raw Coffee Bean Extract P”, manufactured by Oriza Oil Chemical Co., Ltd.
* 33: Made by Maruzen Pharmaceutical Co., Ltd., trade name “Indian Arts Extract Super MF”
* 34: Product name “XANTHIGEN-5” manufactured by TS Trading
* 35: Made by Tokiwa Phytochemical Laboratories, Inc., trade name “Korean Asami Dry Extract”
* 36: Product name “Hihatsu Extract ME” manufactured by Maruzen Pharmaceutical Co., Ltd.
* 37: Product name “Pure Glytimin Y” manufactured by Maruzen Pharmaceutical Co., Ltd.
* 38: Product name “Fuco Dan”, manufactured by South Products
* 39: Product name “Wenzhou mandarin orange extract P” manufactured by Oriza Oil Chemical Co., Ltd.
* 40: Product name "SEIKWASER EXTRACT" manufactured by South Products
* 41: Tokiwa Plant Chemistry Laboratory, trade name “ISOMAX-80”
* 42: Made by South Product Co., Ltd., trade name “Coyer Extract Powder”
対照としたＤＤＰ−ＩＶ阻害薬である「Ｐ３２／９８」の１０μＭ品の阻害率が９３％、１μＭ品の阻害率が６７％であり、阻害率が６０％以上あれば、実用上の効果があると考え得る。 If the inhibition rate of the 10 μM product of “P32 / 98” which is the control DDP-IV inhibitor is 93%, the inhibition rate of the 1 μM product is 67%, and if the inhibition rate is 60% or more, there is a practical effect. I can think of it.
サンプル１６の海藻（アスコフィラム）抽出物の阻害率は９８％であり、医薬品である「Ｐ３２／９８」の１０μＭと同等以上の高い阻害率を有する。実用上有効であると見なすことのできる阻害率６０％までの阻害率を有するサンプルのうちの最も阻害率が低いものは、サンプル３４の海藻（ワカメ）抽出物の６２％であり、サンプル３４〜サンプル１６までは、６０％以上の高い阻害率を有している。 The inhibition rate of the seaweed (Ascofilum) extract of Sample 16 is 98%, and has a high inhibition rate equivalent to or higher than 10 μM of the pharmaceutical “P32 / 98”. Of the samples having an inhibition rate of up to 60% that can be regarded as practically effective, the lowest inhibition rate is 62% of the seaweed extract of sample 34. Samples up to 16 have a high inhibition rate of 60% or more.
したがって、飲食用素材である植物抽出物のうち、サンプル１６〜３４の特定の植物（海藻を含む）の抽出物は、医薬品と同等もしくは同等以上の高いＤＤＰ−ＩＶ阻害作用があり、しかもカロリーが低く、日常的に摂取して安全であるので、日常的に常用可能な優れたＤＤＰ−ＩＶ阻害剤の有効成分として用いて好適であることが確認できた。 Therefore, among the plant extracts that are food and drink materials, the extracts of the specific plants (including seaweed) of Samples 16 to 34 have a high DDP-IV inhibitory action equivalent to or higher than that of pharmaceuticals, and also have calories. Since it is low and safe to take on a daily basis, it was confirmed that it is suitable for use as an active ingredient of an excellent DDP-IV inhibitor that can be routinely used.
（実施例４）
実施例３でＤＤＰ−ＩＶ阻害活性を測定した植物抽出物サンプルのうち、サンプル１６，１８，３４の３種について、５０％阻害濃度（ＩＣ５０）を求めた。
具体的には、各サンプルを５０ｍＭトリス塩酸緩衝液（ｐＨ７．５）に溶解し、更にその溶液を段階希釈して各々のＤＰＰ−ＩＶ阻害活性を求めた。ＤＰＰ−ＩＶ阻害活性は、下記測定方法Ｃにより測定した。
Example 4
Among the plant extract samples whose DDP-IV inhibitory activity was measured in Example 3, the 50% inhibitory concentration (IC50) was determined for three types of samples 16, 18, and 34.
Specifically, each sample was dissolved in 50 mM Tris-HCl buffer (pH 7.5), and the solution was further serially diluted to determine each DPP-IV inhibitory activity. The DPP-IV inhibitory activity was measured by the following measurement method C.
（ジペプチジルペプチダーゼ−ＩＶ（ＤＤＰ−ＩＶ）阻害活性測定方法Ｃ）
植物抽出物サンプルについて、DPPIV Glo Protease Assay(プロメガ社製)を用いて、ＤＤＰ−ＩＶ阻害活性の測定を行った。基質として、DPPIV Glo Reagent (Cat.#G8350：プロメガ社製)を用い、酵素はＤＤＰ−ＩＶ（Cat.No.31763、ヒト組み替え体：カルビオケム社）を用いた。対照阻害剤としてＰ３２／９８(バイオモル社製、商品名「ＰＩ１４２−９０９０」)を使用した。
具体的操作としては、まず、１００μＬ、９６穴白色マイクロプレートに、阻害率測定用サンプル３５μＬ、ＤＤＰ−ＩＶ酵素（２ｎｇ／ｍＬ）５０μＬ、基質溶液５０μＬを添加し、混合した。３０分後に発光量を測定し、サンプル無添加の値を１００％として各サンプルの相対的な活性を算出した。
(Dipeptidyl peptidase-IV (DDP-IV) inhibitory activity measurement method C)
About a plant extract sample, DDP-IV inhibitory activity was measured using DPPIV Glo Protease Assay (made by Promega). As a substrate, DPPIV Glo Reagent (Cat. # G8350: manufactured by Promega) was used, and as a enzyme, DDP-IV (Cat. No. 31763, human recombinant: Calbiochem) was used. P32 / 98 (manufactured by Biomol, trade name “PI142-9090”) was used as a control inhibitor.
Specifically, first, 35 μL of the inhibition rate measurement sample, 50 μL of DDP-IV enzyme (2 ng / mL), and 50 μL of the substrate solution were added to and mixed with 100 μL of a 96-well white microplate. The amount of luminescence was measured after 30 minutes, and the relative activity of each sample was calculated with the value of no sample being added as 100%.
上記阻害活性とサンプル濃度（固形分濃度）の対数の関係式から逆算して、各サンプルのＩＣ５０を求めた。その結果、各サンプル１６，１８，３４のＩＣ５０値は、それぞれ、サンプル１（大豆ペプチド）０．７ｍｇ／ｍＬ、サンプル１６（海藻（アスコフィラム）抽出物）０．６ｍｇ／ｍＬ、サンプル１８（クルミ抽出物）０．７ｍｇ／ｍＬ、サンプル３４（海藻（ワカメ）抽出物）０．６ｍｇ／ｍＬであった。 IC50 of each sample was calculated by calculating backward from the logarithmic relational expression of the inhibitory activity and the sample concentration (solid content concentration). As a result, the IC50 values of the samples 16, 18, and 34 are respectively 0.7 mg / mL for sample 1 (soybean peptide), 0.6 mg / mL for sample 16 (ascophyllum extract), and 18 for sample (walnut extraction). Product) 0.7 mg / mL, sample 34 (seaweed (seaweed) extract) 0.6 mg / mL.
測定したサンプル１６，１８，３４は、ＩＣ５０の値が０．６〜０．７ｍｇ／ｍＬの範囲に入っており、良好なＤＤＰ−ＩＶ阻害活性を有していることが分かる。特に、サンプル１６，１８の阻害率は、前述のように、９０％を超える高い値を示している。したがって、サンプル１６，１８は、ＤＤＰ−ＩＶ阻害剤の有効成分として、特に好ましい。 The measured samples 16, 18, and 34 have IC50 values in the range of 0.6 to 0.7 mg / mL, indicating that they have good DDP-IV inhibitory activity. In particular, the inhibition rates of Samples 16 and 18 show high values exceeding 90% as described above. Therefore, samples 16 and 18 are particularly preferable as an active ingredient of the DDP-IV inhibitor.
以上のように、本発明にかかるジペプチジルベプチダーゼ−ＩＶ阻害剤は、ＤＤＰ−ＩＶ阻害作用が強く、しかも、カロリーが低く、飲食用素材由来であるために、日常的に摂取して安全であり、各種医薬品、特定用保健食品、機能性食品、飲用物などへの利用に適している。 As described above, the dipeptidyl beptidase-IV inhibitor according to the present invention has a strong DDP-IV inhibitory action, has low calories, and is derived from food and drink. Yes, it is suitable for use in various medicines, special health foods, functional foods and drinks.
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008177138A JP2010013423A (en) | 2008-07-07 | 2008-07-07 | Dipeptidyl peptidase-iv inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2008177138A JP2010013423A (en) | 2008-07-07 | 2008-07-07 | Dipeptidyl peptidase-iv inhibitor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2010013423A true JP2010013423A (en) | 2010-01-21 |
Family
ID=41699880
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2008177138A Pending JP2010013423A (en) | 2008-07-07 | 2008-07-07 | Dipeptidyl peptidase-iv inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2010013423A (en) |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011190248A (en) * | 2010-02-18 | 2011-09-29 | Kobayashi Pharmaceutical Co Ltd | Glp-1 activity enhancer |
| JP2013023450A (en) * | 2011-07-15 | 2013-02-04 | Maruzen Pharmaceut Co Ltd | Dipeptidyl peptidase iv inhibitor |
| WO2014017474A1 (en) * | 2012-07-25 | 2014-01-30 | 株式会社ニッピ | Collagen peptide composition production method, dpp-4 inhibitor, and antihyperglycemic agent |
| US9061003B2 (en) | 2011-01-27 | 2015-06-23 | Nitta Gelatin Inc. | Therapeutic or preventive agent for diabetes |
| US9340579B2 (en) | 2011-11-04 | 2016-05-17 | Nippi, Incorporated | DPP-4 inhibitor |
| WO2017010133A1 (en) * | 2015-07-16 | 2017-01-19 | サントリーホールディングス株式会社 | Composition that contains plant- or animal-derived peptide and inhibits serum carnosinase |
| JP2017031105A (en) * | 2015-08-03 | 2017-02-09 | 森永乳業株式会社 | Agent for promoting suppression of postprandial blood sugar level increase |
| JP2017508801A (en) * | 2014-03-10 | 2017-03-30 | フィトテック エクストラクツ ピーヴイティー リミテッド | Water-soluble bunjiro leaf extract with standardized phytochemicals |
| JP2018513838A (en) * | 2015-02-27 | 2018-05-31 | コグニティヴ クラリティ インコーポレイテッド | Compositions and methods for the treatment of "plaques and tangles" in humans and animals |
| CN110800858A (en) * | 2019-11-22 | 2020-02-18 | 中国农业大学 | Sturgeon protein peptide powder and preparation method and application thereof |
| CN111549085A (en) * | 2020-05-18 | 2020-08-18 | 江南大学 | Method for preparing dipeptidyl peptidase IV inhibiting active peptide by using walnut meal and application thereof |
| JP2021095345A (en) * | 2019-12-13 | 2021-06-24 | 国立大学法人鳥取大学 | Bean fermentation products having high dipeptidyl peptidase iv-inhibiting activity and methods of making thereof |
| CN114805479A (en) * | 2022-04-13 | 2022-07-29 | 锡林郭勒职业学院 | Bioactive peptide with dipeptidyl peptidase IV inhibitory activity |
| US11491201B2 (en) | 2018-12-12 | 2022-11-08 | Cognitive Clarity Inc. | Compositions and methods for the treatment of “plaques and tangles” in humans and animals |
-
2008
- 2008-07-07 JP JP2008177138A patent/JP2010013423A/en active Pending
Cited By (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011190248A (en) * | 2010-02-18 | 2011-09-29 | Kobayashi Pharmaceutical Co Ltd | Glp-1 activity enhancer |
| US9061003B2 (en) | 2011-01-27 | 2015-06-23 | Nitta Gelatin Inc. | Therapeutic or preventive agent for diabetes |
| JP2013023450A (en) * | 2011-07-15 | 2013-02-04 | Maruzen Pharmaceut Co Ltd | Dipeptidyl peptidase iv inhibitor |
| US9340579B2 (en) | 2011-11-04 | 2016-05-17 | Nippi, Incorporated | DPP-4 inhibitor |
| WO2014017474A1 (en) * | 2012-07-25 | 2014-01-30 | 株式会社ニッピ | Collagen peptide composition production method, dpp-4 inhibitor, and antihyperglycemic agent |
| JPWO2014017474A1 (en) * | 2012-07-25 | 2016-07-11 | 株式会社ニッピ | Method for producing collagen peptide composition |
| US9486491B2 (en) | 2012-07-25 | 2016-11-08 | Nippi, Incorporated | Collagen peptide composition production method, DPP-4 inhibitor, and antihyperglycemic agent |
| JP2017508801A (en) * | 2014-03-10 | 2017-03-30 | フィトテック エクストラクツ ピーヴイティー リミテッド | Water-soluble bunjiro leaf extract with standardized phytochemicals |
| US11376300B2 (en) | 2015-02-27 | 2022-07-05 | Cognitive Clarity Inc. | Compositions and methods for the treatment of plaques and tangles in humans and animals |
| JP2018513838A (en) * | 2015-02-27 | 2018-05-31 | コグニティヴ クラリティ インコーポレイテッド | Compositions and methods for the treatment of "plaques and tangles" in humans and animals |
| WO2017010133A1 (en) * | 2015-07-16 | 2017-01-19 | サントリーホールディングス株式会社 | Composition that contains plant- or animal-derived peptide and inhibits serum carnosinase |
| WO2017010538A1 (en) * | 2015-07-16 | 2017-01-19 | サントリーホールディングス株式会社 | Composition that contains plant- or animal-derived peptide and inhibits serum carnosinase |
| JP2017031105A (en) * | 2015-08-03 | 2017-02-09 | 森永乳業株式会社 | Agent for promoting suppression of postprandial blood sugar level increase |
| US11491201B2 (en) | 2018-12-12 | 2022-11-08 | Cognitive Clarity Inc. | Compositions and methods for the treatment of “plaques and tangles” in humans and animals |
| CN110800858A (en) * | 2019-11-22 | 2020-02-18 | 中国农业大学 | Sturgeon protein peptide powder and preparation method and application thereof |
| JP2021095345A (en) * | 2019-12-13 | 2021-06-24 | 国立大学法人鳥取大学 | Bean fermentation products having high dipeptidyl peptidase iv-inhibiting activity and methods of making thereof |
| JP7453662B2 (en) | 2019-12-13 | 2024-03-21 | 国立大学法人鳥取大学 | Fermented legumes with high dipeptidyl peptidase IV inhibitory activity and method for producing the same |
| CN111549085A (en) * | 2020-05-18 | 2020-08-18 | 江南大学 | Method for preparing dipeptidyl peptidase IV inhibiting active peptide by using walnut meal and application thereof |
| CN111549085B (en) * | 2020-05-18 | 2023-07-21 | 江南大学 | Method for preparing dipeptidyl peptidase IV inhibitory active peptide by using walnut meal and application thereof |
| CN114805479A (en) * | 2022-04-13 | 2022-07-29 | 锡林郭勒职业学院 | Bioactive peptide with dipeptidyl peptidase IV inhibitory activity |
| CN114805479B (en) * | 2022-04-13 | 2024-02-13 | 锡林郭勒职业学院 | Bioactive peptide with dipeptidyl peptidase IV inhibition activity |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2010013423A (en) | Dipeptidyl peptidase-iv inhibitor | |
| KR101412221B1 (en) | Composition of antiobesity containing Lycium chinensis leaf extract powder and betaine as effective ingredients | |
| JP5690028B1 (en) | Uric acid level lowering agent | |
| AU2015275507A1 (en) | Cyclic dipeptide-containing composition | |
| Parthsarathy et al. | Boarfish (Capros aper) protein hydrolysate has potent insulinotropic and GLP‐1 secretory activity in vitro and acute glucose lowering effects in mice | |
| CN104323231A (en) | Liver-protecting sobering-up natural composition, liver-protecting sobering-up natural product and preparation method thereof | |
| KR101651908B1 (en) | Composition for Prevention or Treatment diabetes comprising Tenebrio molitor larva or extract suspension of Tenebrio molitor larva | |
| KR101695848B1 (en) | A composition comprising ginsenoside f2 for preventing or treating non-alcoholic liver disease | |
| Kausar et al. | Effect of apple cider vinegar on glycemic control, hyperlipidemia and control on body weight in type 2 diabetes patients | |
| JP6445686B2 (en) | Anti-diabetic effect of dipenoside 75 | |
| KR102054597B1 (en) | Composition for Improvement of Exercise Performance Using an Extract of Ishige okamurae | |
| JP4921681B2 (en) | Preventive drugs | |
| CN103446166B (en) | Hepatic function remedial agent | |
| JP2019210269A (en) | Composition for treating diabetic disease | |
| KR101797926B1 (en) | Composition for preventing or treating obesity or obesity-realated metabolic syndrome comprising formic acid or pharmaceutically acceptable salt thereof as an active ingredient | |
| JP2006232781A (en) | Hypoglycemic composition comprising substance derived from bark of genus acacia | |
| JP2014239699A (en) | Blood adiponectin amount increasing agent | |
| JP2010030950A (en) | Prophylactic and therapeutic agent for metabolic syndrome and functional food | |
| JP2008074734A (en) | Ameliorating agent for insulin resistance | |
| JP2010043036A (en) | Saccharometabolism promoter | |
| Ling et al. | Health benefits of vinegars | |
| JP2018070569A (en) | Hepatic stellate cell activation inhibitor and food composition for inhibiting hepatic stellate cell activation | |
| JP2006193501A (en) | Adiponectin regulating agent and food, drink, food additive and medicine containing the same | |
| JP2019052122A (en) | Adiponectin secretion enhancer, lipid progenitor cell differentiation-promoting agent, as well as pharmaceutical compositions, foods, and feeds comprising the same | |
| EP3235510A1 (en) | Nutritional compositions for the management of glucose metabolism |