JP6661115B2 - Allergy suppressant - Google Patents
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- JP6661115B2 JP6661115B2 JP2015173451A JP2015173451A JP6661115B2 JP 6661115 B2 JP6661115 B2 JP 6661115B2 JP 2015173451 A JP2015173451 A JP 2015173451A JP 2015173451 A JP2015173451 A JP 2015173451A JP 6661115 B2 JP6661115 B2 JP 6661115B2
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Description
本発明は、安全性の高いアレルギー抑制剤に関する。 The present invention relates to a highly safe allergy inhibitor.
現代の日本において、アレルギーを原因とする症状に苦しんでいる人は多い。くしゃみ、鼻炎、鼻水、皮膚のかゆみ、目のかゆみなどの不快感や、喘息、頭痛などでは不快感を通り越して、病的状態に陥り生命の危険に晒される場合もある。これらのアレルギーの原因としては、そばや卵、大豆、ピーナッツ、エビやカニなどの甲殻類など食物性のものや、花粉、ダニ、カビ、埃などの環境中に存在している物質など様々ある。健康な生活を営むために、アレルギーの症状の発症を抑える治療や抗ヒスタミン剤やステロイド剤などの薬剤投与などが行われている。また、薬剤に加えて、アレルギー抑制効果のある食品なども開発、市販されている。 In modern Japan, many people suffer from symptoms caused by allergies. Discomforts such as sneezing, rhinitis, runny nose, itchy skin, and itchy eyes, as well as asthma and headaches, may pass through the discomfort and lead to morbidity and endangerment. The causes of these allergies include various food substances such as buckwheat, eggs, soybeans, peanuts, crustaceans such as shrimp and crab, and pollutants, mites, mold, dust, and other substances present in the environment. In order to live a healthy life, treatments for suppressing the onset of allergic symptoms and administration of drugs such as antihistamines and steroids are performed. In addition to drugs, foods having an allergy suppressing effect have been developed and marketed.
アレルギーにはＩｇＥ依存型と非依存型が存在する。ＩｇＥ依存型ではまずアレルゲンが侵入し、アレルゲンを捕捉した樹状細胞が所属リンパ節あるいは粘膜下組織で、ＩＬ-４の存在下でＴｈ２細胞の分化を誘導することから始まる。Ｔｈ２細胞はＩＬ-４を産生し、ＩｇＥ産生Ｂ細胞の分化を誘導する。産生されたＩｇＥはマスト細胞上に発現するＩｇＥレセプター（ＦｃεＲＩ）に結合し感作が成立する。この後、アレルゲンの再侵入によりＩｇＥ-ＦｃεＲＩが架橋されると、マスト細胞はサイトカインやケミカルメディエーターを放出し、アレルギー性炎症を惹起する。 There are IgE-dependent and allergic allergies. In the IgE-dependent type, first, the allergen invades, and the dendritic cells capturing the allergen begin to induce Th2 cell differentiation in the regional lymph nodes or submucosa in the presence of IL-4. Th2 cells produce IL-4 and induce differentiation of IgE-producing B cells. The produced IgE binds to an IgE receptor (FcεRI) expressed on mast cells, and sensitization is established. Thereafter, when the IgE-FcεRI is cross-linked by re-entry of the allergen, the mast cells release cytokines and chemical mediators and cause allergic inflammation.
ＩｇＥ非依存型では、アレルゲン刺激を受けた上皮細胞がＴＳＬＰ、ＩＬ-２５などのサイトカインを産生しＴｈ２細胞の分化を誘導する。Ｔｈ２細胞がＩＬ-４、ＩＬ-５、ＩＬ-１３などのサイトカインを産生し好酸球の活性化を誘導する。さらに、獲得免疫系を介さない機序も存在する。上皮細胞が産生するＴＳＬＰ、ＩＬ-２５、ＩＬ-３３がマスト細胞や好塩基球、自然免疫リンパ球からＴｈ２サイトカインの産生を誘導し、自然免疫においてもアレルギー性炎症を誘導する。特にシステインプロテアーゼであるパパインをマウスに吸入させると、好酸球の浸潤を伴う気道炎症が惹起される。 In the IgE-independent type, epithelial cells stimulated with allergen produce cytokines such as TSLP and IL-25 to induce Th2 cell differentiation. Th2 cells produce cytokines such as IL-4, IL-5 and IL-13 and induce eosinophil activation. In addition, there are mechanisms that do not go through the acquired immune system. TSLP, IL-25 and IL-33 produced by epithelial cells induce the production of Th2 cytokines from mast cells, basophils and innate immune lymphocytes, and also induce allergic inflammation in innate immunity. In particular, inhalation of papain, a cysteine protease, into mice causes airway inflammation with eosinophil infiltration.
アレルギー治療のための薬剤は、頭痛や食欲不振、眠気を催すなどの副作用があり、医師による処方がないと入手できないため、手軽に服用することはできない。食品由来のアレルギー抑制効果を有するものが知られており、デーツに含まれているベラルゴニンやフェルラ酸（特許文献１）、シソ科抽出物（特許文献２、特許文献３）、西洋わさび、本わさび由来の６−メチルチオヘキシルイソチオシアネート（特許文献４）、乳酸菌ラクトバチルス・プランタラム（特許文献５）、クラミドモナス属藻類（特許文献６）、クスノキなどの由来のリグナン化合物（特許文献７）などがある。しかし、ベラルゴニンやフェルラ酸、リグナン化合物は非水溶性のため、食品に添加して摂取するには加工上制限があり、西洋わさび、本わさび由来の６−メチルチオヘキシルイソチオシアネートも非水溶性で揮発性が高いため、食品加工上制限があり、食品として摂取するには乳酸菌や藻類も問題があった。 Drugs for treating allergies have side effects such as headaches, anorexia, and drowsiness, and cannot be taken easily because they cannot be obtained without a prescription by a doctor. It is known to have a food-derived allergy-suppressing effect, and it contains belargonin and ferulic acid contained in dates (Patent Document 1), Labiatae extracts (Patent Documents 2 and 3), horseradish, and wasabi. 6-methylthiohexylisothiocyanate (Patent Document 4), lactic acid bacteria Lactobacillus plantarum (Patent Document 5), Chlamydomonas algae (Patent Document 6), lignan compounds derived from camphor tree (Patent Document 7), and the like. . However, since belargonin, ferulic acid, and lignan compounds are insoluble in water, their processing is limited when added to foods for ingestion, and horseradish and wasabi-derived 6-methylthiohexyl isothiocyanate is also insoluble and volatile. Due to its high potency, there are restrictions on food processing, and lactic acid bacteria and algae also have problems when taken as food.
本発明は、食品由来の安全で、食品として摂取できるアレルギー抑制効果が優れているアレルギー抑制剤を提供するものである。 The present invention provides an allergy inhibitor which is safe from food and has an excellent allergy inhibitory effect which can be taken as food.
上記課題を達成するために、本発明のアレルギー抑制剤は、プロテオグリカンのナトリウム塩、もしくはプロテオグリカンのマグネシウム塩の少なくとも一つを有効成分とする。 In order to achieve the above object, the allergy inhibitor of the present invention contains at least one of a sodium salt of proteoglycan and a magnesium salt of proteoglycan as an active ingredient.
本発明により、安全で、水溶性の優れたアレルギー抑制剤を提供できる。 According to the present invention, a safe and excellent water-soluble allergy inhibitor can be provided.
以下、実施の形態をより具体的に説明する。 Hereinafter, embodiments will be described more specifically.
本発明でいうプロテオグリカンは、グリコサミノグリカンとタンパク質の共有結合物の総称であり、一般の糖タンパク質に比べて、糖含量が極めて多いのが特徴である。プロテオグリカンは天然由来の高分子化合物であり、起源となる原料や抽出・製造条件により、分子量や含まれるアミノ酸や糖（中性糖、ウロン酸、アミノ糖など）の種類や量、比率も異なっており、さまざま分子種が存在する。一般的にプロテオグリカンの分子量は数十万から数百万である。プロテオグリカンの原料由来としては、牛、鶏、鯨などの哺乳類の軟骨や、鮭、鮫、エイなどの魚類の軟骨であり、その種類を問わないものであり、食されることも多い。また、プロテオグリカンの抽出薬剤についても、酢酸などの有機酸や酸、アルカリ、グアニジン塩酸など様々あるが、本発明では抽出薬剤や温度や時間などの抽出・製造の条件も限定しないものである。 The term "proteoglycan" as used in the present invention is a general term for a covalently bonded product of glycosaminoglycan and protein, and is characterized by an extremely high sugar content as compared with a general glycoprotein. Proteoglycans are naturally occurring high molecular compounds, and the molecular weight and the types, amounts, and ratios of amino acids and sugars (neutral sugars, uronic acids, amino sugars, etc.) differ depending on the raw materials and extraction / production conditions used as the source. And there are various molecular species. Generally, the molecular weight of proteoglycans is hundreds of thousands to millions. Raw materials of proteoglycans are cartilage of mammals such as cows, chickens and whales, and cartilage of fishes such as salmon, sharks and rays, and are irrelevant and often eaten. There are various proteoglycan extraction agents such as organic acids such as acetic acid and the like, acids, alkalis, guanidine hydrochloride, and the like. However, the present invention does not limit the extraction agent, extraction and production conditions such as temperature and time.
本発明品のプロテオグリカンのナトリウム塩は、プロテオグリカンをナトリウムイオン型の強酸性陽イオン交換樹脂にて処理することにより製造することができる。また、プロテオグリカンを低温下で、１Ｍ以下の塩酸やクエン酸で処理し、加えた酸や遊離した低分子を除去し、その後、炭酸水素ナトリウムや炭酸ナトリウム、水酸化ナトリウム、酢酸ナトリウムなどを加えて中和しても製造できる。また、本発明品のプロテオグリカンのマグネシウム塩は、プロテオグリカンをマグネシウムイオン型の強酸性陽イオン交換樹脂にて処理することにより製造することができる。また、プロテオグリカンを低温下で、１Ｍ以下の塩酸やクエン酸で処理し、加えた酸や遊離した低分子を除去し、その後、塩化マグネシウムや酢酸マグネシウムなどを加えても製造できる。さらにプロテオグリカンの水溶液に高濃度の塩化ナトリウムや塩化マグネシウムを添加しても製造することができる。 The sodium salt of proteoglycan of the product of the present invention can be produced by treating proteoglycan with a sodium ion type strongly acidic cation exchange resin. In addition, proteoglycan is treated with hydrochloric acid or citric acid of 1M or less at a low temperature to remove the added acid and free small molecules, and then add sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, sodium acetate, and the like. Can be manufactured even after neutralization. Further, the magnesium salt of proteoglycan of the present invention can be produced by treating proteoglycan with a magnesium ion type strongly acidic cation exchange resin. Proteoglycan can also be produced by treating the proteoglycan with 1 M or less of hydrochloric acid or citric acid at a low temperature to remove the added acid or free low molecules, and then adding magnesium chloride or magnesium acetate. Further, it can be produced by adding a high concentration of sodium chloride or magnesium chloride to an aqueous solution of proteoglycan.
本発明品は、溶液の状態で飲料やドリンク剤の形態として、単独、または、他の健康補助成分と併用してもよい。 The product of the present invention may be used alone or in combination with other health-supporting ingredients in the form of a solution in the form of a beverage or a drink.
以下に実施例を示して本発明を具体的に説明するが、これは単に例示の目的で述べるものであり、本発明はこれらの実施例に限定されるものではない。 Hereinafter, the present invention will be described in detail with reference to examples. However, this is merely for illustrative purposes, and the present invention is not limited to these examples.
（プロテオグリカンのナトリウム塩の製造）
原料のプロテオグリカンは、市販の鮭由来プロテオグリカン（（株）角弘プロテオグリカン研究所）を購入し、用いた。強酸性陽イオン交換樹脂（商品名：ＡＧ ５０Ｗ−Ｘ８ ｒｅｓｉｎ、バイオラッド社）をガラス製カラムに充填し（内径２．５ｃｍ、高さ８．２ｃｍ）、樹脂を常法によりナトリウムイオン型に活性化した。原料の鮭由来プロテオグリカン０．４０ｇを脱イオン水３０ｍＬに溶解した溶液を、室温でカラム上方から添加・流下した。その後、樹脂に脱イオン水を１５０ｍＬ流下し、得られた溶出液約１８０ｍＬをエバポレーター（東京理科器械（株））にて濃縮した後、凍結乾燥（東京理科器械（株））し、０．３７ｇの白色綿状固体であるプロテオグリカンのナトリウム塩を得た。
(Production of sodium salt of proteoglycan)
As the raw material proteoglycan, a commercially available salmon-derived proteoglycan (Kadohiro Proteoglycan Research Institute Co., Ltd.) was purchased and used. A strongly acidic cation exchange resin (trade name: AG 50W-X8 resin, Bio-Rad) is packed in a glass column (inner diameter 2.5 cm, height 8.2 cm), and the resin is activated to a sodium ion type by a conventional method. It has become. A solution prepared by dissolving 0.40 g of the raw material salmon-derived proteoglycan in 30 mL of deionized water was added and allowed to flow down from above the column at room temperature. Thereafter, 150 mL of deionized water was allowed to flow into the resin, and about 180 mL of the obtained eluate was concentrated using an evaporator (Tokyo Rikakiki Co., Ltd.), followed by freeze-drying (Tokyo Rikakiki Co., Ltd.) to obtain 0.37 g. The sodium salt of proteoglycan was obtained as a white flocculent solid.
（プロテオグリカンのナトリウム塩の分析）
実施例１で得られたプロテオグリカンのナトリウム塩のタンパク質含量を、比色法であるローリー法にて、牛血清アルブミン（アクロス社）を標準物質とした検量線から求めたところ、５．７重量％であった。ウロン酸含量を、比色法であるカルバゾール硫酸法にて、グルクロン酸（シグマ社）を標準物質とした検量線から求めたところ、３５．５重量％であった。原料の鮭由来プロテオグリカンについて同様に分析したところ、タンパク質含量は６．５重量％、ウロン酸含量は３４．６重量％であった。これらの結果から、実施例１で得られたプロテオグリカンのナトリウム塩のタンパク質とウロン酸含量は、原料の鮭由来プロテオグリカンとほとんど差がないことが明らかとなった。
(Analysis of sodium salt of proteoglycan)
The protein content of the sodium salt of proteoglycan obtained in Example 1 was determined by a Lowry method as a colorimetric method from a calibration curve using bovine serum albumin (Across) as a standard substance, and found to be 5.7% by weight. Met. The uronic acid content was determined by a carbazole sulfate method, which is a colorimetric method, from a calibration curve using glucuronic acid (Sigma) as a standard substance, and was 35.5% by weight. When the raw material salmon-derived proteoglycan was similarly analyzed, the protein content was 6.5% by weight and the uronic acid content was 34.6% by weight. From these results, it was clarified that the protein and uronic acid content of the sodium salt of proteoglycan obtained in Example 1 had almost no difference from the salmon-derived proteoglycan as a raw material.
各プロテオグリカンの水分含量は、以下の方法により測定した。熱天秤装置（Ｔｈｅｒｍｏ Ｐｌｕｓ ＴＧ８２１０、（株）リガク製）にて、１２５℃で試料重量が恒量となるまで加熱し、重量減少分を試料に含まれていた水分として計算した。その結果、実施例１で得られたプロテオグリカンのナトリウム塩の水分含量は１３重量％であり、原料の鮭由来プロテオグリカンの水分含量は１７重量％であった。 The water content of each proteoglycan was measured by the following method. The sample was heated at 125 ° C. until the weight of the sample became a constant weight using a thermobalance device (Thermo Plus TG8210, manufactured by Rigaku Corporation), and the weight loss was calculated as the moisture contained in the sample. As a result, the water content of the sodium salt of proteoglycan obtained in Example 1 was 13% by weight, and the water content of the raw material salmon-derived proteoglycan was 17% by weight.
実施例１で得られたプロテオグリカンのナトリウム塩のナトリウムとカルシウムの含量を、キャピラリー電気泳動装置（Ａｇｉｌｅｎｔ７１００ キャピラリー電気泳動システム、アジレント・テクノロジー（株）製）を用いて定量した。各金属の定量法については、ＵＶ吸収を有する緩衝液で満たしたキャピラリーカラムに、試料を注入して電圧をかけることで、試料中の各金属イオンを分離しながら移動させ、ＵＶ検出部を通過する時のＵＶ吸収の減少分により検出する間接吸光法を採用した。カラムにバブルセルフューズドシリカキャピラリー（内径５０μｍ、有効長５６ｃｍ、アジレント・テクノロジー（株）製）、緩衝液に陽イオン分析バッファ（ＰａｒｔＮｏ．５０６４−８２０３、アジレント・テクノロジー（株）製）を用い、電圧２５ｋＶで、陽イオン標準液（５〜１００ｐｐｍ、ＰａｒｔＮｏ．５０６４−８２０５、アジレント・テクノロジー（株）製）から作成した検量線より、ナトリウおよびカルシウム含量を求めた。実施例１で得られたプロテオグリカンのナトリウム塩については、乾燥重量を基にして０．１７４重量％水溶液で測定したため、作成した検量線による各金属含量の測定下限は０．２９重量％であった。測定の結果、実施例１で得られたプロテオグリカンのナトリウム塩のナトリウム含量は６．５重量％であり、カルシウム含量は０．５１重量％であった。原料の鮭由来プロテオグリカンについては、乾燥重量を基にして０．１６６重量％水溶液で測定したため、作成した検量線による各金属含量の測定下限は０．３０重量％であった。原料の鮭由来プロテオグリカンについて同様に分析したところ、ナトリウム含量は１．８重量％、カルシウム含量は５．６重量％であった。なお、上記金属含量は、実施例１で得られたプロテオグリカンのナトリウム塩中に含まれる水分含量（１３重量％）および原料の鮭由来プロテオグリカンに含まれる水分含量（１７重量％）をそれぞれ除去した乾燥重量を基に計算した。 The sodium and calcium contents of the sodium salt of proteoglycan obtained in Example 1 were quantified using a capillary electrophoresis apparatus (Agilent 7100 capillary electrophoresis system, manufactured by Agilent Technologies). Regarding the method for quantifying each metal, a sample is injected into a capillary column filled with a buffer solution having UV absorption, and a voltage is applied, whereby each metal ion in the sample is moved while being separated, and passes through a UV detection unit. An indirect absorption method that detects the decrease in UV absorption at the time was employed. Using a bubble self-used silica capillary (inner diameter 50 μm, effective length 56 cm, manufactured by Agilent Technologies, Inc.) for the column and a cation analysis buffer (Part No. 5064-8203, manufactured by Agilent Technologies, Inc.) for the buffer, At a voltage of 25 kV, the contents of sodium and calcium were determined from a calibration curve prepared from a cation standard solution (5 to 100 ppm, Part No. 5064-8205, manufactured by Agilent Technologies). Since the sodium salt of proteoglycan obtained in Example 1 was measured with a 0.174% by weight aqueous solution based on the dry weight, the lower limit of measurement of each metal content by the created calibration curve was 0.29% by weight. . As a result of the measurement, the sodium content of the sodium salt of proteoglycan obtained in Example 1 was 6.5% by weight, and the calcium content was 0.51% by weight. Since the raw material salmon-derived proteoglycan was measured in a 0.166% by weight aqueous solution based on the dry weight, the lower limit of measurement of each metal content by the created calibration curve was 0.30% by weight. When the raw material salmon-derived proteoglycan was similarly analyzed, the sodium content was 1.8% by weight and the calcium content was 5.6% by weight. The metal content was determined by removing the moisture content (13% by weight) contained in the sodium salt of proteoglycan obtained in Example 1 and the moisture content (17% by weight) contained in the salmon-derived proteoglycan as a raw material. Calculated based on weight.
（プロテオグリカンのマグネシウム塩の製造）
原料のプロテオグリカンは、市販の鮭由来プロテオグリカン（（株）角弘プロテオグリカン研究所）を購入し、用いた。強酸性陽イオン交換樹脂（商品名：ダイヤイオンＳＫ１Ｂ（三菱化学（株）））をガラス製カラムに充填し（内径２ｃｍ、高さ８ｃｍ）、樹脂を定法によりマグネシウムイオン型に活性化した。原料の鮭由来プロテオグリカン０．５０ｇを脱イオン水４０ｍＬに溶解した溶液を、室温でカラム上方から添加・流下した。その後、樹脂に脱イオン水を１６０ｍＬ流下し、得られた溶出液約２００ｍＬをエバポレーター（東京理科器械（株））にて濃縮した後、凍結乾燥（東京理科器械（株））し、０．４８ｇの白色綿状固体であるプロテオグリカンのマグネシウム塩を得た。
(Production of magnesium salt of proteoglycan)
As the raw material proteoglycan, a commercially available salmon-derived proteoglycan (Kadohiro Proteoglycan Research Institute Co., Ltd.) was purchased and used. A strongly acidic cation exchange resin (trade name: Diaion SK1B (Mitsubishi Chemical Corporation)) was packed in a glass column (inner diameter 2 cm, height 8 cm), and the resin was activated to a magnesium ion type by a conventional method. A solution prepared by dissolving 0.50 g of salmon-derived proteoglycan as a raw material in 40 mL of deionized water was added and allowed to flow down from above the column at room temperature. Thereafter, 160 mL of deionized water was allowed to flow down into the resin, and about 200 mL of the obtained eluate was concentrated by an evaporator (Tokyo Rika Instruments) and freeze-dried (Tokyo Rika Instruments) to obtain 0.48 g To obtain a magnesium salt of proteoglycan as a white flocculent solid.
（プロテオグリカンのマグネシウム塩の分析）
実施例３で得られたプロテオグリカンのマグネシウム塩のタンパク質含量を、比色法であるローリー法にて、牛血清アルブミン（アクロス社）を標準物質とした検量線から求めたところ、４．４重量％であった。ウロン酸含量を、比色法であるカルバゾール硫酸法にて、グルクロン酸（シグマ社）を標準物質とした検量線から求めたところ、３１．３重量％であった。原料の鮭由来プロテオグリカンについて同様に分析したところ、タンパク質含量は６．５重量％、ウロン酸含量は３４．６重量％であった。実施例３で得られたプロテオグリカンのマグネシウム塩のタンパク質とウロン酸含量は、原料の鮭由来プロテオグリカンとほとんど差がないことが明らかとなった。
(Analysis of magnesium salt of proteoglycan)
The protein content of the magnesium salt of proteoglycan obtained in Example 3 was determined by a Lowry method as a colorimetric method from a calibration curve using bovine serum albumin (Across) as a standard substance, and found to be 4.4% by weight. Met. The uronic acid content was determined by a carbazole sulfate method as a colorimetric method from a calibration curve using glucuronic acid (Sigma) as a standard substance, and was 31.3% by weight. When the raw material salmon-derived proteoglycan was similarly analyzed, the protein content was 6.5% by weight and the uronic acid content was 34.6% by weight. It became clear that the protein and uronic acid content of the magnesium salt of proteoglycan obtained in Example 3 had almost no difference from the salmon-derived proteoglycan as a raw material.
実施例３で得られたプロテオグリカンのマグネシウム塩の水分含量を、上記実施例２と同様に分析したところ、２３重量％であった。同様に、原料の鮭由来プロテオグリカンの水分含量について分析したところ、１７重量％であった。 When the water content of the magnesium salt of proteoglycan obtained in Example 3 was analyzed in the same manner as in Example 2, it was 23% by weight. Similarly, when the water content of the raw material salmon-derived proteoglycan was analyzed, it was 17% by weight.
実施例３で得られたプロテオグリカンのマグネシウム塩のマグネシウムとカルシウムの含量を、キャピラリー電気泳動装置（Ａｇｉｌｅｎｔ７１００ キャピラリー電気泳動システム、アジレント・テクノロジー（株）製）を用いて定量した。各金属の定量法については、実施例２と同様の方法を採用した。カラムにフューズドシリカキャピラリー（内径５０μｍ、有効長５６ｃｍ、アジレント・テクノロジー（株）製）、緩衝液に陽イオン分析バッファ（ＰａｒｔＮｏ．５０６４−８２０３、アジレント・テクノロジー（株）製）を用い、電圧２５ｋＶで、陽イオン標準液（５〜１００ｐｐｍ、ＰａｒｔＮｏ．５０６４−８２０５、アジレント・テクノロジー（株）製）から作成した検量線より、カルシウムおよびマグネシウム含量を求めた。実施例３で得られたプロテオグリカンのマグネシウム塩については、乾燥重量を基にして０．０７７重量％水溶液で測定したため、作成した検量線による各金属含量の測定下限は０．６５重量％であった。測定の結果、実施例３で得られたプロテオグリカンのマグネシウム塩のマグネシウム含量は５．３重量％であり、カルシウムは検量線より低い濃度であったため０．６５重量％未満であった。原料の鮭由来プロテオグリカンについては、乾燥重量を基にして０．１６６重量％水溶液で測定したため、作成した検量線による各金属含量の測定下限は０．３０重量％であった。原料の鮭由来プロテオグリカンの測定の結果、カルシウム含量は５．６重量％であり、マグネシウムは検量線より低い濃度であったため０．３０重量％未満であった。なお、上記金属含量は、実施例３で得られたプロテオグリカンのマグネシウム塩中に含まれる水分含量（２３重量％）および原料の鮭由来プロテオグリカンに含まれる水分含量（１７重量％）をそれぞれ除去した乾燥重量を基に計算した。 The magnesium and calcium contents of the magnesium salt of proteoglycan obtained in Example 3 were quantified using a capillary electrophoresis apparatus (Agilent 7100 capillary electrophoresis system, manufactured by Agilent Technologies). The same method as in Example 2 was employed for the determination of each metal. A fused silica capillary (inner diameter 50 μm, effective length 56 cm, manufactured by Agilent Technologies, Inc.) is used for the column, and a cation analysis buffer (Part No. 5064-8203, manufactured by Agilent Technologies, Inc.) is used for the buffer, and the voltage is 25 kV. The calcium and magnesium contents were determined from a calibration curve prepared from a cation standard solution (5 to 100 ppm, Part No. 5064-8205, manufactured by Agilent Technologies, Inc.). The magnesium salt of proteoglycan obtained in Example 3 was measured with a 0.077% by weight aqueous solution based on the dry weight. Therefore, the lower limit of measurement of each metal content by the created calibration curve was 0.65% by weight. . As a result of the measurement, the magnesium content of the magnesium salt of proteoglycan obtained in Example 3 was 5.3% by weight, and calcium was less than 0.65% by weight because the concentration was lower than the calibration curve. Since the raw material salmon-derived proteoglycan was measured in a 0.166% by weight aqueous solution based on the dry weight, the lower limit of measurement of each metal content by the created calibration curve was 0.30% by weight. As a result of measuring salmon-derived proteoglycan as a raw material, the calcium content was 5.6% by weight, and magnesium was less than 0.30% by weight because the concentration was lower than the calibration curve. The metal content was determined by removing the moisture content (23% by weight) contained in the magnesium salt of proteoglycan obtained in Example 3 and the moisture content (17% by weight) contained in the salmon-derived proteoglycan as a raw material, respectively. Calculated based on weight.
（発明品の安全性）
発明品の安全性の確認に用いる試料は、実施例１で用いた市販の鮭由来プロテオグリカン（（株）角弘プロテオグリカン研究所）、実施例１で得られたプロテオグリカンのナトリウム塩、および実施例３で得られたプロテオグリカンのマグネシウム塩を使用した。それぞれ蒸留水で０．２ｍｇ／ｍＬとなるように希釈したものを使用した。対照として蒸留水を用いた。１群を８匹として、評価用のマウスには、６週齢のＣ５７ＢＬ／６マウス（ＣＬＥＡ Ｊａｐａｎ製）を各群（対照群、鮭由来プロテオグリカン群、実施例１で得られたプロテオグリカンのナトリウム塩群および実施例３で得られたプロテオグリカンのマグネシウム塩群）に用いた。恒温、恒湿の一定環境の飼育室で、試料を自由飲水させ、固形飼料（ＣＥ―２、ＣＬＥＡ Ｊａｐａｎ製）を自由摂取させ飼育した。なお、実験動物の取り扱いは弘前大学動物実験委員会により承認され、弘前大学動物実験に関する規程に従った。
(Safety of invention)
The samples used for confirming the safety of the invention product were the commercially available salmon-derived proteoglycan (Kadohiro Proteoglycan Research Institute Co., Ltd.) used in Example 1, the sodium salt of proteoglycan obtained in Example 1, and the sample in Example 3. The obtained magnesium salt of proteoglycan was used. Each diluted with distilled water to a concentration of 0.2 mg / mL was used. Distilled water was used as a control. Assuming that each group consisted of 8 mice, 6-week-old C57BL / 6 mice (manufactured by CLEA Japan) were used for each group (control group, salmon-derived proteoglycan group, sodium salt of proteoglycan obtained in Example 1). Group and the magnesium salt group of proteoglycan obtained in Example 3). In a breeding room in a constant environment of constant temperature and constant humidity, the sample was allowed to freely drink water, and solid feed (CE-2, manufactured by CLEA Japan) was freely taken and bred. The handling of experimental animals was approved by the Hirosaki University Animal Experiment Committee, and was in accordance with the rules on animal experiments at Hirosaki University.
各群のマウスを１０日間飼育し、体重の変化、体表の様子を観察したが、いずれの試料も対照群との違いはなかった。なお、摂取飲水量は、４群とも一匹あたり一日約４ｍＬで差はなかった。 The mice in each group were bred for 10 days, and changes in body weight and body surface were observed, but none of the samples was different from the control group. In addition, the intake drinking water amount was about 4 mL per animal per day in all four groups, and there was no difference.
（アレルギー抑制試験）
アレルギー抑制作用の測定に用いる試料は、市販の鮭由来プロテオグリカン、実施例１で得られたプロテオグリカンのナトリウム塩、および実施例３で得られたプロテオグリカンのマグネシウム塩で実施例５と同じものを使用した。それぞれ蒸留水で０．２ｍｇ／ｍＬとなるように希釈したものを使用した。対照として蒸留水を用いた。１群を８匹として、作用評価用のマウスには、６週齢のＣ５７ＢＬ／６マウス（ＣＬＥＡ Ｊａｐａｎ製）を各群（対照群、鮭由来プロテオグリカン群、実施例１で得られたプロテオグリカンのナトリウム塩群および実施例３で得られたプロテオグリカンのマグネシウム塩群）に用いた。恒温、恒湿の一定環境の飼育室で、試料を自由飲水させ、固形飼料（ＣＥ―２、ＣＬＥＡ Ｊａｐａｎ製）を自由摂取させ飼育した。なお、実験動物の取り扱いは弘前大学動物実験委員会により承認され、弘前大学動物実験に関する規程に従った。
(Allergy suppression test)
The same samples as those used in Example 5 were used as the samples used for the measurement of the allergy-suppressing action, with commercially available salmon-derived proteoglycan, the sodium salt of proteoglycan obtained in Example 1, and the magnesium salt of proteoglycan obtained in Example 3. . Each diluted with distilled water to a concentration of 0.2 mg / mL was used. Distilled water was used as a control. Assuming that each group consisted of 8 mice, 6-week-old C57BL / 6 mice (manufactured by CLEA Japan) were used as mice for action evaluation (control group, salmon-derived proteoglycan group, sodium of proteoglycan obtained in Example 1). Salt group and the magnesium group of proteoglycan obtained in Example 3). In a breeding room in a constant environment of constant temperature and constant humidity, the sample was allowed to freely drink water, and solid feed (CE-2, manufactured by CLEA Japan) was freely taken and bred. The handling of experimental animals was approved by the Hirosaki University Animal Experiment Committee, and was in accordance with the rules on animal experiments at Hirosaki University.
各群のマウスの鼻腔に、麻酔下で０．２５ｍｇ／ｍＬパパイン溶液を４０μＬ接種した。７日後、同様に各群のマウスの鼻腔に、麻酔下で０．２５ｍｇ／ｍＬパパイン溶液を４０μＬ接種した。この３日後に、大腿部より採血を行い、頸椎脱臼により屠殺した。気管にリン酸緩衝生理食塩水を注入、回収し気管支肺胞洗浄液とした。気管支肺胞洗浄液をスライドグラスに塗抹し、メイギムザ染色法により細胞を染色した。白血球数と好酸球数を、顕微鏡下、目視で計測し、好酸球の肺胞内への浸潤を観察した。 The mice of each group were inoculated in the nasal cavity with 40 μL of a 0.25 mg / mL papain solution under anesthesia. Seven days later, 40 μL of a 0.25 mg / mL papain solution was similarly inoculated into the nasal cavity of each group of mice under anesthesia. Three days later, blood was collected from the thigh and sacrificed by cervical dislocation. Phosphate buffered saline was injected into the trachea, collected, and used as bronchoalveolar lavage fluid. Bronchoalveolar lavage fluid was smeared on a slide glass, and cells were stained by May-Giemsa staining. The number of leukocytes and the number of eosinophils were visually measured under a microscope, and the infiltration of eosinophils into the alveoli was observed.
測定された白血球数から、各作用評価用のマウス群における好酸球率を以下の式を用いて算出すると、対照群で６６．７±１２．７％、市販の鮭由来プロテオグリカン群で４３．０±１４．２％、実施例１で得られたプロテオグリカンのナトリウム塩群で１７．０±５．７％、実施例３で得られたプロテオグリカンのマグネシウム塩群で１９．０±６．１％であった。
好酸球率（％）＝好酸球数／白血球総数×１００
なお、統計処理には、Ｔｕｋｅｙ法を用いた。対照-実施例１で得られたプロテオグリカンのナトリウム塩間および対照-実施例３で得られたプロテオグリカンのマグネシウム塩間でＰ値が０．０５未満で有意差が認められた。なお、摂取飲水量は、４群とも一匹あたり一日約４ｍＬで差はなかった。
From the measured leukocyte count, the eosinophil ratio in the mouse group for each effect evaluation was calculated using the following formula, and found to be 66.7 ± 12.7% in the control group and 43.67% in the commercial salmon-derived proteoglycan group. 0 ± 14.2%, 17.0 ± 5.7% for the sodium salt group of proteoglycan obtained in Example 1, and 19.0 ± 6.1% for the magnesium salt group of proteoglycan obtained in Example 3. Met.
Eosinophil ratio (%) = Number of eosinophils / Total number of white blood cells × 100
The Tukey method was used for the statistical processing. A significant difference was observed between the sodium salt of the proteoglycan obtained in the control-Example 1 and the magnesium salt of the proteoglycan obtained in the control-Example 3 when the P value was less than 0.05. In addition, the intake drinking water amount was about 4 mL per animal per day in all four groups, and there was no difference.
プロテオグリカンは、様々な機能を有すことが報告されており、本発明によりアレルギーが抑制されることにより、健康食品の分野や医薬品分野で広く利用されることが可能である。 Proteoglycans are reported to have various functions, and can be widely used in the field of health foods and pharmaceuticals by suppressing allergies according to the present invention.
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