JP2021065139A - Nuclear receptor-activating food composition and production method of the same - Google Patents
Nuclear receptor-activating food composition and production method of the same Download PDFInfo
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Images
Abstract
Description
本発明が関係するのは、核内受容体活性化用食品組成物及びその製造方法である。 The present invention relates to a food composition for activating nuclear receptors and a method for producing the same.
核内受容体は様々な生体機能に関与していることから、その活性の制御に関わる因子が注目され、盛んに研究が行われている。核内受容体とは、細胞内に存在するタンパク質であり、リガンドと結合することで核内に移行し、ＤＮＡに結合し転写を制御することが知られている。核内受容体として、ＲＡＲ、ＲＸＲ、ＰＰＡＲ、ＥＲ等がよく知られており、これらは生体内において種々の機能を担っていることが分かっている。 Since nuclear receptors are involved in various biological functions, factors involved in the regulation of their activities have attracted attention and are being actively studied. A nuclear receptor is a protein that exists in a cell, and is known to translocate into the nucleus by binding to a ligand, bind to DNA, and control transcription. RAR, RXR, PPAR, ER and the like are well known as nuclear receptors, and it is known that they have various functions in vivo.
核内受容体であるＲＡＲα及びＲＡＲβの選択的アゴニストのタミバロテンにより、空腹時血糖や空腹時インスリン濃度を低下させる効果があることが報告されている（非特許文献１）。また、核内受容体であるＲＡＲαは、膵臓β細胞膜上でグルコース輸送を担うグルコーストランスポーター２（ＧＬＵＴ２）の誘導、及び膵臓β細胞内のグルコースのリン酸化を触媒し、グルコース恒常性を保つ役割を担うグルコキナーゼ（ＧＣＫ）の発現を誘導し、インスリン産生β細胞の機能を維持すること、並びに、核内受容体であるＲＡＲβ２のアゴニストは、高脂肪食で肥満及び２型糖尿病を誘導させた通常マウス、遺伝的に操作された肥満及び２型糖尿病のモデルマウスの何れにおいても、肝臓、膵臓、及び腎臓においてインスリン感受性を改善し、血清グルコース及びインスリンレベルを低下させることが報告されている（非特許文献２）。これらのことから、核内受容体の活性化により、空腹時血糖値を正常化することが考えられている。
It has been reported that tamibarotene, a selective agonist of RARα and RARβ, which are nuclear receptors, has an effect of lowering fasting blood glucose and fasting insulin concentration (Non-Patent Document 1). In addition, RARα, which is a nuclear receptor, acts to maintain glucose homeostasis by inducing glucose transporter 2 (GLUT2), which is responsible for glucose transport on the pancreatic β-cell membrane, and catalyzing glucose phosphorylation in pancreatic β-cells. Inducing the expression of glucokinase (GCK), which is responsible for glucose, and maintaining the function of insulin-producing β-cells, and the agonist of the nuclear receptor RARβ2 induced obesity and
核内受容体であるＲＡＲを活性化するＲＡＲアゴニストによって医療適応できる疾患として、皮膚の炎症性疾患、角化症、光老化や色素沈着が報告されており、核内受容体（ＲＡＲ）の活性化により、それらが抑制されるとされていることから（非特許文献３）、核内受容体の活性化により、皮膚の炎症性疾患、皮膚の角化症、皮膚の光老化、及び、皮膚の色素沈着が抑制されることが考えられている。 Skin inflammatory diseases, keratosis, photoaging and pigmentation have been reported as diseases that can be medically indicated by RAR agonists that activate the nuclear receptor RAR, and the activity of the nuclear receptor (RAR). Since it is said that they are suppressed by the formation of skin (Non-Patent Document 3), activation of nuclear receptors causes inflammatory diseases of the skin, keratinization of the skin, photoaging of the skin, and skin. It is believed that the pigmentation of the skin is suppressed.
核内受容体であるＲＡＲαの活性化を介して、前駆脂肪細胞の分化の決定因子である亜鉛フィンガータンパク質４２３（Ｚｆｐ４２３）の発現を阻害することで、白色脂肪生成を阻害することが報告されている（非特許文献４)。このことから、核内受容体の活性化により、脂肪蓄積が抑制されることが考えられている。 It has been reported that white adipose tissue production is inhibited by inhibiting the expression of zinc finger protein 423 (Zfp423), which is a determinant of preadipocyte differentiation, through activation of the nuclear receptor RARα. (Non-Patent Document 4). From this, it is considered that fat accumulation is suppressed by activation of nuclear receptors.
ビタミンＡの誘導体である全トランス型レチノイン酸（ａｔＲＡ）は、核内受容体であるＲＡＲα及びＲＡＲβを介して、肥満誘導性脂肪肝を抑制する肝細胞由来ホルモンであるＦＧＦ２１の発現を誘導すること、核内受容体であるＲＡＲαによって、高中性脂肪（ＴＧ）血症発症の中心因子として知られる肝臓アポリポタンパクＣＩＩＩ（Ａｐｏ-ＣＩＩＩ）の発現が抑制され、肝臓と血中のＴＧレベルが低下することが報告されていることから（非特許文献２）、核内受容体の活性化により、脂肪肝が抑制されることが考えられている。 Total trans retinoic acid (atRA), a derivative of vitamin A, induces the expression of FGF21, a hepatocyte-derived hormone that suppresses obesity-induced fatty liver, via the nuclear receptors RARα and RARβ. , Nuclear receptor RARα suppresses the expression of liver apolipoprotein CIII (Apo-CIII), which is known as a central factor in the development of hypertriglycerid (TG)emia, and lowers TG levels in the liver and blood. Since it has been reported (Non-Patent Document 2), it is considered that fatty liver is suppressed by activation of nuclear receptors.
核内受容体であるＲＡＲγによりマクロファージのＡＴＰ結合カセットトランスポーター１（ＡＢＣＡ１）が誘導されること（非特許文献５）、及び、ＡＢＣＡ１は細胞外のアポリポタンパク質Ａ-Ｉ（ａｐｏＡ-Ｉ）に対して細胞内のコレステロール及びリン脂質を搬出し、ａｐｏＡ−Ｉとそれらが結合することでＨＤＬコレステロールが形成されること（非特許文献６）が報告されている。これらのことから、核内受容体の活性化により、マクロファージ泡沫細胞からのコレステロールの排出及びＨＤＬコレステロール形成が促進され、血中ＨＤＬコレステロールが高められることが考えられる。 RARγ, a nuclear receptor, induces macrophage ATP-binding cassette transporter 1 (ABCA1) (Non-Patent Document 5), and ABCA1 is associated with extracellular apolipoprotein AI (apoA-I). It has been reported that HDL cholesterol is formed by carrying out intracellular cholesterol and phospholipids and binding to apoAI-I (Non-Patent Document 6). From these facts, it is considered that activation of nuclear receptors promotes cholesterol excretion and HDL cholesterol formation from macrophage foam cells and enhances blood HDL cholesterol.
このように、核内受容体の活性化は、空腹時血糖値の正常化、皮膚の炎症性疾患抑制、皮膚の角化症抑制、皮膚の光老化抑制、皮膚の色素沈着抑制、脂肪の蓄積抑制、脂肪肝の抑制、及び、血中ＨＤＬコレステロールの増加につながると考えられている。 Thus, activation of nuclear receptors normalizes fasting blood glucose levels, suppresses inflammatory diseases of the skin, suppresses keratosis of the skin, suppresses photoaging of the skin, suppresses pigmentation of the skin, and accumulates fat. It is thought to lead to suppression, suppression of fatty liver, and increase in blood HDL cholesterol.
本発明が解決しようとする課題は、新規な核内受容体活性化用食品組成物を提供することである。 An object to be solved by the present invention is to provide a novel food composition for activating nuclear receptors.
以上を踏まえて、本願発明者が鋭意検討して見出したのは、ベビーリーフとしてよく食されているスピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉又はその加工物が核内受容体活性化作用を有することである。すなわち、前述の葉又はその加工物が、複数の種類の核内受容体、具体的には、ＲＡＲ、ＲＸＲ、ＰＰＡＲ及びＥＲのうち、何れか１つ又は２つ以上を活性化することである。それにより、空腹時血糖値の正常化、皮膚の炎症性疾患抑制、皮膚の角化症抑制、皮膚の光老化抑制、皮膚の色素沈着抑制、脂肪の蓄積抑制、脂肪肝の抑制、及び、血中ＨＤＬコレステロールの増加が期待される。この観点から、本発明を定義すると、以下のとおりである。 Based on the above, the inventor of the present application has diligently studied and found one or more leaves of spinach, beet, arugula, red romaine, and green romaine, which are often eaten as baby leaf. Alternatively, the processed product has a nuclear receptor activating effect. That is, the leaf or its processed product activates one or more of a plurality of types of nuclear receptors, specifically RAR, RXR, PPAR and ER. .. As a result, fasting blood glucose level is normalized, skin inflammatory disease is suppressed, skin keratosis is suppressed, skin photoaging is suppressed, skin pigmentation is suppressed, fat accumulation is suppressed, fatty liver is suppressed, and blood. An increase in medium HDL cholesterol is expected. From this point of view, the present invention is defined as follows.
本発明に係る核内受容体活性化用食品組成物が含有するのは、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉又はその加工物である。つまり、核内受容体活性化に寄与する原料は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉又はその加工物である。核内受容体活性化に寄与する成分は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインに含まれる成分である。前述の葉は、発芽後３０日以内であることが好ましい。前記核内受容体はＲＡＲ、ＲＸＲ、ＰＰＡＲ又はＥＲのうち、何れか１つ又は２つ以上であることが好ましい。 The food composition for activating nuclear receptors according to the present invention contains leaves of any one or more of spinach, beet, arugula, red romaine, and green romaine, or processed products thereof. .. That is, the raw material that contributes to the activation of nuclear receptors is any one or more of spinach, beet, arugula, red romaine, and green romaine, or a processed product thereof. The components that contribute to the activation of nuclear receptors are those contained in spinach, beet, arugula, red romaine, and green romaine. The leaves are preferably within 30 days after germination. The nuclear receptor is preferably any one or two or more of RAR, RXR, PPAR or ER.
本発明に係る核内受容体活性化用食品組成物が含有するのは、ベビーリーフ又はその加工物である。前記ベビーリーフは、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の幼葉又はその加工物である。前記核内受容体はＲＡＲ、ＲＸＲ、ＰＰＡＲ又はＥＲのうち、何れか１つ又は２つ以上であることが好ましい。 The food composition for activating nuclear receptors according to the present invention contains baby leaf or a processed product thereof. The baby leaf is a young leaf of any one or more of spinach, beet, arugula, red romaine, and green romaine, or a processed product thereof. The nuclear receptor is preferably any one or two or more of RAR, RXR, PPAR or ER.
本発明に係る空腹時血糖値の正常化用食品組成物が含有するのは、核内受容体活性化寄与成分であり、その由来は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉である。前記核内受容体活性化寄与成分はＲＡＲ活性化寄与成分であることが好ましく、前述の葉は、発芽後３０日以内であることが好ましい。 The food composition for normalizing fasting blood glucose level according to the present invention contains a nuclear receptor activation contributing component, which is derived from spinach, beet, arugula, red romaine, and green romaine. Any one or more leaves. The nuclear receptor activation contributing component is preferably a RAR activation contributing component, and the leaves are preferably within 30 days after germination.
本発明に係る皮膚の炎症性疾患抑制用食品組成物が含有するのは、核内受容体活性化寄与成分であり、その由来は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉である。前記核内受容体活性化寄与成分はＲＡＲ活性化寄与成分であることが好ましく、前述の葉は、発芽後３０日以内であることが好ましい。 The food composition for suppressing inflammatory diseases of the skin according to the present invention contains a nuclear receptor activation contributing component, and its origin is any of spinach, beet, arugula, red romaine, and green romaine. Or one or more leaves. The nuclear receptor activation contributing component is preferably a RAR activation contributing component, and the leaves are preferably within 30 days after germination.
本発明に係る皮膚の角化症抑制用食品組成物が含有するのは、核内受容体活性化寄与成分であり、その由来は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉である。前記核内受容体活性化寄与成分はＲＡＲ活性化寄与成分であることが好ましく、前述の葉は、発芽後３０日以内であることが好ましい。 The food composition for suppressing keratoderma of the skin according to the present invention contains a nuclear receptor activation contributing component, and its origin is any of spinach, beet, arugula, red romaine, and green romaine. Or one or more leaves. The nuclear receptor activation contributing component is preferably a RAR activation contributing component, and the leaves are preferably within 30 days after germination.
本発明に係る皮膚の光老化抑制用食品組成物が含有するのは、核内受容体活性化寄与成分であり、その由来は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉である。前記核内受容体活性化寄与成分はＲＡＲ活性化寄与成分であることが好ましく、前述の葉は、発芽後３０日以内であることが好ましい。 The food composition for suppressing photoaging of the skin according to the present invention contains a nuclear receptor activation contributing component, and its origin is any of spinach, beet, arugula, red romaine, and green romaine. One or more leaves. The nuclear receptor activation contributing component is preferably a RAR activation contributing component, and the leaves are preferably within 30 days after germination.
本発明に係る皮膚の色素沈着抑制用食品組成物が含有するのは、核内受容体活性化寄与成分であり、その由来は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉である。前記核内受容体活性化寄与成分はＲＡＲ活性化寄与成分であることが好ましく、前述の葉は、発芽後３０日以内であることが好ましい。 The food composition for suppressing skin pigmentation according to the present invention contains a nuclear receptor activation contributing component, and its origin is any of spinach, beet, arugula, red romaine, and green romaine. One or more leaves. The nuclear receptor activation contributing component is preferably a RAR activation contributing component, and the leaves are preferably within 30 days after germination.
本発明に係る脂肪の蓄積抑制用食品組成物が含有するのは、核内受容体活性化寄与成分であり、その由来は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉である。前記核内受容体活性化寄与成分はＲＡＲ活性化寄与成分であることが好ましく、前述の葉は、発芽後３０日以内であることが好ましい。 The food composition for suppressing fat accumulation according to the present invention contains a nuclear receptor activation contributing component, the origin of which is any one of spinach, beet, arugula, red romaine, and green romaine. Seeds or leaves of two or more species. The nuclear receptor activation contributing component is preferably a RAR activation contributing component, and the leaves are preferably within 30 days after germination.
本発明に係る脂肪肝の抑制用食品組成物が含有するのは、核内受容体活性化寄与成分であり、その由来は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉である。前記核内受容体活性化寄与成分はＲＡＲ活性化寄与成分であることが好ましく、前述の葉は、発芽後３０日以内であることが好ましい。 The food composition for suppressing fatty liver according to the present invention contains a nuclear receptor activation contributing component, and its origin is any one of spinach, beet, arugula, red romaine, and green romaine. Seeds or leaves of two or more species. The nuclear receptor activation contributing component is preferably a RAR activation contributing component, and the leaves are preferably within 30 days after germination.
本発明に係る血中ＨＤＬコレステロールの増加用食品組成物が含有するのは、核内受容体活性化寄与成分であり、その由来は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉である前記核内受容体活性化寄与成分はＲＡＲ活性化寄与成分であることが好ましく、前述の葉は、発芽後３０日以内であることが好ましい。 The food composition for increasing blood HDL cholesterol according to the present invention contains a nuclear receptor activation contributing component, and its origin is any of spinach, beet, arugula, red romaine, and green romaine. The nuclear receptor activation contributing component, which is one or more leaves, is preferably a RAR activation contributing component, and the leaves are preferably within 30 days after germination.
本発明に係る核内受容体活性化用食品組成物の製造方法を構成するのは、少なくとも、抽出工程である。ここで、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉から抽出されるのは、核内受容体活性化寄与成分である。好ましくは、水、含水エタノール又は有機溶媒により抽出される。前述の葉は、発芽後３０日以内であることが好ましい。 At least an extraction step constitutes a method for producing a food composition for activating nuclear receptors according to the present invention. Here, among the spinach, beet, arugula, red romaine, and green romaine, what is extracted from the leaves of any one or more of them is a nuclear receptor activation contributing component. Preferably, it is extracted with water, hydrous ethanol or an organic solvent. The leaves are preferably within 30 days after germination.
本発明が可能にするのは、新規な核内受容体活性化用食品組成物を提供することである。すなわち、核内受容体活性化の寄与成分が提供されることにより、空腹時血糖値の正常化、皮膚の炎症性疾患抑制、皮膚の角化症抑制、皮膚の光老化抑制、皮膚の色素沈着抑制、脂肪の蓄積抑制、脂肪肝の抑制、及び、血中ＨＤＬコレステロールの増加に寄与する食品組成物が提供される。 What the present invention makes possible is to provide a novel nuclear receptor activation food composition. That is, by providing a contributing component for nuclear receptor activation, fasting blood glucose level is normalized, skin inflammatory disease is suppressed, skin keratosis is suppressed, skin photoaging is suppressed, and skin pigmentation is performed. Food compositions that contribute to suppression, suppression of fat accumulation, suppression of fatty liver, and increase in blood HDL cholesterol are provided.
＜本実施の形態に係る核内受容体活性化用食品組成物＞
本実施の形態に係る核内受容体活性化用食品組成物（以下、「本組成物」という。）の寄与成分は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉又はその加工物である。当該品目の葉及びその加工物の詳細は、後述する。
<Food composition for activating nuclear receptors according to this embodiment>
The contributing component of the food composition for activating nuclear receptors according to the present embodiment (hereinafter referred to as "this composition") is any one of spinach, beet, arugula, red romaine, and green romaine. Or two or more kinds of leaves or processed products thereof. Details of the leaves of the item and its processed products will be described later.
＜本実施の形態に係る葉＞
本実施の形態においては、使用する葉は発芽後９０日以内、好ましくは発芽後５０日以内の葉を使用することができる。一般的なベビーリーフは、発芽後１０〜３０日程度の葉菜（以下、「幼葉」という。）を意味し、発芽後３０日を超える葉菜（以下、「大人葉」という。）よりも好適に使用することができるが、発芽後１４〜２２日の幼葉を用いることが特に好ましい。なお、当該葉には、葉柄を含んでいてもよい。
ベビーリーフの種類は、特に限定されないが、例示すると、アブラナ科、ヒユ科、キク科、セリ科、ユリ科、アカザ科の野菜等である。具体例としては、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメイン、レッドオーク、ミズナ、ホウレンソウ、カラシナ、サニーレタス、グリーンカール、サラダナ、グリーンマスタード、赤高菜、ロメイン、ターサイ、小紅菜、ロロロッサ、レッドアジアンマスタード、ピノグリーン、ホワイトケール、レッドケール、デトロイト、パクチョイ等である。上記の中でも、核内受容体活性化作用を示すものとして、スピナッチ（Spinacia oleracea）、ビート（Beta vulgaris）、ルッコラ（Eruca vesicaria）、レッドロメイン（Lactuca sativa L. var. longifolia）又はグリーンロメイン（Lactuca sativa L. var. longifolia）のうち、何れか１つ又は２つ以上を用いることが好ましい。
<Leaf according to this embodiment>
In the present embodiment, the leaves to be used can be used within 90 days after germination, preferably within 50 days after germination. A general baby leaf means leafy vegetables about 10 to 30 days after germination (hereinafter referred to as "young leaves"), and from leafy vegetables exceeding 30 days after germination (hereinafter referred to as "adult leaves"). Can also be preferably used, but it is particularly preferable to use young leaves 14 to 22 days after germination. The leaf may contain a petiole.
The type of baby leaf is not particularly limited, but examples thereof include cruciferous, amaranthaceae, asteraceae, umbelliferae, liliaceae, and chenopodiaceae. Specific examples include spinach, beet, arugula, red romain, green romain, red oak, mizuna, spinach, mustard, sunny lettuce, green curl, salada, green mustard, red mustard, romain, tarsai, small red mustard, loro rossa, Red Asian mustard, pino green, white mustard, red mustard, detroit, pakchoi, etc. Among the above, those showing nuclear receptor activating action include spinach (Spinacia oleracea), beet (Beta vulgaris), arugula (Eruca vesicaria), red romaine (Lactuca sativa L. var. Longifolia) or green romaine (Lactuca). It is preferable to use any one or two or more of sativa L. var. Longifolia).
＜葉の加工物＞
葉の加工物の機能は、核内受容体の活性化である。葉の加工物の態様は特に限定されないが、抽出物であることが好ましく、植物の抽出に用いられる通常の抽出方法により得ることができる。抽出方法は適宜設定することができる。加工物の調製には、葉をそのまま又は乾燥粉砕して用いることができる。核内受容体の活性化に寄与するのは、葉及びその加工物が含有する成分であり、推察される寄与成分を例示すると、ルテイン、α-カロテン、β-カロテン、レチノイン酸、β−クリプトキサンチン、レスベラトロール、リコピン、リコピン代謝物等である。
<Processed leaf>
The function of leaf processed products is the activation of nuclear receptors. The mode of the processed leaf product is not particularly limited, but it is preferably an extract, and can be obtained by a usual extraction method used for plant extraction. The extraction method can be set as appropriate. For the preparation of the processed product, the leaves can be used as they are or after being dried and pulverized. It is the components contained in the leaves and their processed products that contribute to the activation of nuclear receptors. Examples of the inferred contributing components are lutein, α-carotene, β-carotene, retinoic acid, and β-crypto. Xanthin, resveratrol, lycopene, lycopene metabolites and the like.
葉の加工物の調製に用いる抽出溶液は、食用に用いる観点から水又は含水エタノールであることが好ましいが、これに限定されず、この種の抽出に通常用いられる溶媒から適宜選択することができる。例示すると、メタノール、エタノール、プロパノール、ブタノール等のアルコール類；エチレングリコール、プロピレングリコール、１，２−ブチレングリコール、１，３−ブチレングリコール、１，４−ブチレングリコール、２，３−ブチレングリコール等の多価アルコール類；アセトン、メチルエチルケトン等のケトン類；酢酸メチル、酢酸エチル等のエステル類；ジエチルエーテル、テトラヒドロフラン等の鎖状又は環状エーテル類；ポリエチレングリコール等のポリエーテル類；ジクロロメタン、ジクロロエタン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類；ペンタン、ヘキサン、シクロヘキサン、石油エーテル等の炭化水素類；ベンゼン、トルエン等の芳香族炭化水素類；ピリジン類；超臨界二酸化炭素；ナタネ油、大豆油等の食用油；モノアシルグリセロール、ジアシルグリセロール（ＤＡＧ）、トリアシルグリセロール（ＴＡＧ）等のグリセリンの脂肪酸エステル；炭素数８のカプリル酸、炭素数１０のカプリン酸等の炭素数が５〜１２の中鎖脂肪酸（ＭＣＴ）；スクワラン、スクワレン等の油脂、ワックス、その他オイル等が挙げられる。 The extraction solution used for preparing the processed leaf product is preferably water or hydrous ethanol from the viewpoint of edible use, but is not limited to this, and can be appropriately selected from the solvents usually used for this type of extraction. .. For example, alcohols such as methanol, ethanol, propanol and butanol; ethylene glycol, propylene glycol, 1,2-butylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, 2,3-butylene glycol and the like. Polyhydric alcohols; ketones such as acetone and methyl ethyl ketone; esters such as methyl acetate and ethyl acetate; chain or cyclic ethers such as diethyl ether and tetrahydrofuran; polyethers such as polyethylene glycol; dichloromethane, dichloroethane, chloroform, etc. Halogenized hydrocarbons such as carbon tetrachloride; hydrocarbons such as pentane, hexane, cyclohexane, petroleum ether; aromatic hydrocarbons such as benzene and toluene; pyridines; supercritical carbon dioxide; rapeseed oil, soybean oil, etc. Edible oils; fatty acid esters of glycerins such as monoacylglycerols, diacylglycerols (DAGs), and triacylglycerols (TAGs); Chain fatty acids (MCT); examples include fats and oils such as squalane and squalane, waxes, and other oils.
上記抽出物をそのまま用いてもよく、さらに適当な分離手段、例示すると、ゲル濾過、クロマトグラフィー、精密蒸留等により活性の高い画分を分画して用いることもできる。また、得られた抽出物を希釈、濃縮又は凍結乾燥した後、粉末又はペースト状に調製して用いることもできる。また、前述の方法により得られた抽出物を、前記抽出溶媒とは異なる溶媒で転溶して用いることもできる。 The above extract may be used as it is, or a highly active fraction may be fractionated and used by an appropriate separation means, for example, gel filtration, chromatography, precision distillation or the like. Further, the obtained extract can be diluted, concentrated or freeze-dried, and then prepared into a powder or a paste and used. Further, the extract obtained by the above-mentioned method can also be used by being transsolved in a solvent different from the extraction solvent.
＜核内受容体＞
核内受容体は、生体内の主に脂溶性低分子化合物をリガンドとするリガンド依存的な転写因子であり、リガンドが結合すると核内に移行してＤＮＡに結合し転写を制御する。発生や細胞増殖、分化、形態形成、代謝などの様々な生物学的現象を調節しており、様々な疾患の発症に関わっている。代表的な核内受容体として、レチノイン酸受容体（ＲＡＲ）、レチノイドＸ受容体（ＲＸＲ）、ペルオキシソーム増殖因子活性化受容体（ＰＰＡＲ）、エストロゲン受容体（ＥＲ）が挙げられる。
<Nuclear receptor>
The nuclear receptor is a ligand-dependent transcription factor whose ligand is mainly a lipophilic low molecular weight compound in the living body, and when the ligand binds, it translocates into the nucleus and binds to DNA to control transcription. It regulates various biological phenomena such as development, cell proliferation, differentiation, morphogenesis, and metabolism, and is involved in the development of various diseases. Representative nuclear receptors include retinoic acid receptor (RAR), retinoid X receptor (RXR), peroxisome proliferator-activated receptor (PPAR), and estrogen receptor (ER).
ＲＡＲは、主に発生や恒常性の維持、免疫において重要な役割を果たしていることが知られている。ＲＡＲには、ＲＡＲα、ＲＡＲβ、ＲＡＲγの３つのサブタイプが存在する。本組成物は、上記３つのサブタイプのうち、何れか１つ又は２つ以上を活性化させる。 RAR is known to play an important role mainly in development, maintenance of homeostasis, and immunity. There are three subtypes of RAR, RARα, RARβ, and RARγ. The composition activates any one or more of the above three subtypes.
ＲＸＲは、主に他の核内受容体とヘテロダイマーを形成し機能を促進する役割を果たしていることが知られている。ＲＸＲには、ＲＸＲα、ＲＸＲβ、ＲＸＲγの３つのサブタイプが存在する。本組成物は、上記３つのサブタイプのうち、何れか１つ又は２つ以上を活性化させる。 It is known that RXR mainly plays a role of forming a heterodimer with other nuclear receptors and promoting its function. There are three subtypes of RXR, RXRα, RXRβ, and RXRγ. The composition activates any one or more of the above three subtypes.
ＰＰＡＲは、主に脂質や糖代謝において重要な役割を果たしていることが知られている。ＰＰＡＲには、ＰＰＡＲα、ＰＰＡＲβ/δ、ＰＰＡＲγの３つのサブタイプが存在する。本組成物は、上記３つのサブタイプのうち、何れか１つ又は２つ以上を活性化させる。 PPAR is known to play an important role mainly in lipid and glucose metabolism. There are three subtypes of PPAR: PPARα, PPARβ / δ, and PPARγ. The composition activates any one or more of the above three subtypes.
ＥＲは、主に雌性の生殖や骨形成、更年期障害緩和などに関与することが知られている。ＥＲには、ＥＲα、ＥＲβの２つのサブタイプが存在する。本組成物は、上記２つのサブタイプのうち、ＥＲβを活性化させる。 ER is known to be mainly involved in female reproduction, bone formation, and alleviation of menopausal disorders. There are two subtypes of ER, ERα and ERβ. The composition activates ERβ of the above two subtypes.
＜核内受容体活性化剤＞
核内受容体活性化剤は、空腹時血糖値の正常化、皮膚の炎症性疾患抑制、皮膚の角化症抑制、皮膚の光老化抑制、皮膚の色素沈着抑制、脂肪の蓄積抑制、脂肪肝の抑制、及び、血中ＨＤＬコレステロールの増加に寄与する。
<Nuclear receptor activator>
Nuclear receptor activators normalize fasting blood glucose levels, suppress inflammatory diseases of the skin, suppress keratosis of the skin, suppress photoaging of the skin, suppress pigmentation of the skin, suppress fat accumulation, fatty liver. Contributes to the suppression of blood glucose and the increase of blood HDL cholesterol.
＜空腹時血糖値の正常化＞
空腹時血糖値とは、１０時間以上絶食の後、採血した静脈血による血糖値のことである。日本糖尿病学会の「科学的根拠に基づく糖尿病診断ガイドライン２０１３」によると、空腹時血糖値が１１０ ｍｇ/ｄＬ未満の場合は正常域とされることから、ヒトにおける空腹時血糖値の正常化とは、１１０ ｍｇ/ｄＬ以上の方が、正常域となることを指す。さらに、１００〜１０９ ｍｇ／ｄＬは正常高値とされるため、それらの方が１００ ｍｇ/ｄＬ未満となることも正常化に含む。
<Normalization of fasting blood glucose level>
The fasting blood glucose level is the blood glucose level due to venous blood collected after fasting for 10 hours or more. According to the "Scientific Basis-Based Diabetes Diagnosis Guideline 2013" of the Japan Diabetes Society, if the fasting blood glucose level is less than 110 mg / dL, it is considered to be in the normal range. , 110 mg / dL or more indicates that the normal range is reached. Furthermore, since 100 to 109 mg / dL is considered to be a normal high value, it is also included in the normalization that they are less than 100 mg / dL.
＜皮膚の炎症性疾患抑制＞
皮膚の炎症性疾患抑制とは、ニキビや酒さといった皮膚の炎症を伴う疾患の発生を抑制すること、又は症状を軽減することを指す。
<Suppression of inflammatory diseases of the skin>
Suppression of inflammatory diseases of the skin refers to suppressing the occurrence of diseases associated with skin inflammation such as acne and rosacea, or alleviating the symptoms.
＜皮膚の角化症抑制＞
皮膚の角化症抑制とは、掌蹠角化症、魚鱗癬、ダリエ病といった遺伝性の角化症や、乾癬、毛孔性紅色粃糠疹、苔癬といった後天性の角化症の発生を抑制すること、又は症状を軽減することを指す。
<Skin keratoderma suppression>
Suppression of skin keratosis suppresses the occurrence of hereditary keratosis such as palmoplantar keratosis, ichthyosis, and Darier's disease, and acquired keratosis such as psoriasis, keratosis pilaris, and moss. Refers to doing or alleviating symptoms.
＜皮膚の光老化抑制＞
皮膚の光老化抑制とは、紫外線などにより引き起こる、しわ、たるみ、乾燥などの光老化現象を抑制することを指す。
<Skin photoaging suppression>
Suppression of photoaging of the skin refers to suppressing photoaging phenomena such as wrinkles, sagging, and dryness caused by ultraviolet rays and the like.
＜皮膚の色素沈着抑制＞
皮膚の色素沈着抑制とは、皮膚の炎症後に生じるシミや紫外線により引き起こされるシミなどの皮膚への色素沈着を抑制することを指す。
<Skin pigmentation suppression>
Suppression of skin pigmentation refers to suppression of skin pigmentation such as age spots that occur after skin inflammation and age spots caused by ultraviolet rays.
＜脂肪の蓄積抑制＞
脂肪の蓄積抑制とは、内臓脂肪蓄積による肥満が糖尿病や脂質異常症等の生活習慣病を引き起こすため、脂肪の蓄積抑制については、内臓脂肪量の増加抑制や内臓脂肪について組織学的に判定した脂肪滴の減少が認められることを指す。
<Suppression of fat accumulation>
Suppression of fat accumulation means that obesity due to visceral fat accumulation causes lifestyle diseases such as diabetes and dyslipidemia. Therefore, regarding suppression of fat accumulation, suppression of increase in visceral fat mass and histological judgment of visceral fat were made. It means that a decrease in fat droplets is observed.
＜脂肪肝の抑制＞
脂肪肝は肝細胞の３０％以上に中性脂肪が溜まった状態であり、脂肪肝の抑制は肝細胞への中性脂肪の蓄積を抑制することを指す。
<Suppression of fatty liver>
Fatty liver is a state in which neutral fat is accumulated in 30% or more of hepatocytes, and suppression of fatty liver means suppression of accumulation of triglyceride in hepatocytes.
＜血中ＨＤＬコレステロールの増加＞
血中ＨＤＬコレステロールは、血液中の余分なコレステロールを肝臓に運ぶ役割を担っており、その血中濃度が高いほど動脈硬化性疾患にかかりにくいため「善玉コレステロール」と呼ばれている。ヒトにおいて、血中ＨＤＬコレステロール値の正常範囲は４０ｍｇ／ｄＬ以上であることから、ヒトにおける血中ＨＤＬコレステロールの増加とは、４０ｍｇ／ｄｌ未満から、４０ｍｇ／ｄｌに値が近づくこと、又は、４０ｍｇ／ｄｌ以上となることを指す。
<Increase in blood HDL cholesterol>
Blood HDL cholesterol plays a role of transporting excess cholesterol in the blood to the liver, and the higher the blood concentration, the less likely it is to suffer from arteriosclerosis, so it is called "good cholesterol". Since the normal range of blood HDL cholesterol level in humans is 40 mg / dL or more, the increase in blood HDL cholesterol level in humans means that the value approaches 40 mg / dl from less than 40 mg / dl, or 40 mg. It means that it becomes / dl or more.
＜本組成物の製造方法の概要＞
本組成物の製造方法（以下、「本製法」という。）の流れは、以下のとおりである。本製法を構成するのは、主に、抽出である。
<Outline of manufacturing method of this composition>
The flow of the method for producing the present composition (hereinafter referred to as "the present production method") is as follows. The main constituent of this manufacturing method is extraction.
＜抽出＞
抽出により、葉から抽出物を調製する目的は、寄与成分の濃縮である。抽出する方法は、公知の方法で良く、例示すると水や有機溶媒等を用いた振盪抽出等である。
<Extraction>
The purpose of preparing the extract from the leaves by extraction is to concentrate the contributing components. The extraction method may be a known method, and examples thereof include shaking extraction using water, an organic solvent, or the like.
核内受容体の活性化に寄与するのは、抽出された葉の加工物が含有する成分であり、推定される寄与成分を例示すると、ルテイン、α-カロテン、β-カロテン、レチノイン酸、β−クリプトキサンチン、レスベラトロール、リコピン、リコピン代謝物等である。 It is the components contained in the extracted leaf processed product that contribute to the activation of nuclear receptors. Examples of the estimated contributing components are lutein, α-carotene, β-carotene, retinoic acid, and β. -Cryptoxanthin, resveratrol, lycopene, lycopene metabolites, etc.
＜核内受容体活性化用食品組成物＞
本組成物は、食品、飲料、飼料、ペットフードに添加又はこれらと混合して使用することができる。或いは、核内受容体活性化により、予防又は改善しうる疾患又は状態について、その旨を表示した飲食品、すなわち、健康食品、機能性表示食品、病者用食品及び特定保健用食品等に添加又は配合して使用することができる。具体的には、細粒剤、錠剤、顆粒剤、散剤、カプセル剤、シロップ剤、液剤、流動食等の各種製剤形態として使用することができる。製剤形態の食品は、賦形剤、結合剤、崩壊剤、滑沢剤、抗酸化剤、着色剤、矯味剤等の添加材を必要に応じて使用することができる。また、前記寄与成分と、食品として許容できる担体、例えば適当な賦形剤等とを混合した後、慣用の手段を用いて製造することができる。さらに、そのままのものを食品とすることも可能であり、その種類及び形態は特に限定されないが、例示すると、スープ類、ジュース類、野菜飲料、果実飲料、野菜果実飲料、牛乳、乳飲料、乳清飲料、乳酸菌飲料、茶飲料、アルコール飲料、コーヒー飲料、炭酸飲料、清涼飲料水、水飲料、ココア飲料、ゼリー状飲料、スポーツ飲料、ダイエット飲料などの液状食品組成物、プリン、ヨーグルトなどの半固形食品組成物、パン類、麺類、菓子類、スプレッド類、調味料等に添加又はこれらと混合することができる。
<Food composition for activating nuclear receptors>
The composition can be added to or mixed with foods, beverages, feeds and pet foods. Alternatively, for diseases or conditions that can be prevented or ameliorated by activating nuclear receptors, they are added to foods and drinks that indicate that fact, that is, health foods, foods with functional claims, foods for the sick, foods for specified health use, etc. Alternatively, it can be used in combination. Specifically, it can be used as various pharmaceutical forms such as fine granules, tablets, granules, powders, capsules, syrups, liquids, and liquid foods. Additives such as excipients, binders, disintegrants, lubricants, antioxidants, colorants, and flavoring agents can be used as necessary for the food in the pharmaceutical form. Further, after mixing the contributing component with a carrier acceptable as a food product, for example, a suitable excipient, etc., it can be produced by a conventional means. Further, it is also possible to use the food as it is, and the type and form thereof are not particularly limited, but for example, soups, juices, vegetable drinks, fruit drinks, vegetable fruit drinks, milk, milk drinks, milk. Liquid food compositions such as soft drinks, lactic acid bacteria drinks, tea drinks, alcoholic drinks, coffee drinks, carbonated drinks, soft drinks, water drinks, cocoa drinks, jelly-like drinks, sports drinks, diet drinks, half of pudding, yogurt, etc. It can be added to or mixed with solid food compositions, breads, noodles, confectionery, spreads, seasonings and the like.
＜実施例１＞
土壌で栽培した発芽後１６〜２０日（幼葉）及び発芽後３６〜４０日（大人葉）のスピナッチ（品種名：グリーンスピナッチ）、水耕栽培した発芽後１６〜２０日（幼葉）及び発芽後３６〜４０日（大人葉）のビート（品種名：デトロイト）、土壌で栽培した発芽後１４〜１８日（幼葉）及び発芽後３６〜４０日（大人葉）のルッコラ（品種名：ルッコラ（ロケット））、水耕栽培した発芽後１８〜２２日（幼葉）及び発芽後３８〜４２日（大人葉）のレッドロメイン（品種名：レッドロメイン）、水耕栽培した発芽後１８〜２２日（幼葉）及び発芽後３８〜４２日（大人葉）のグリーンロメイン（品種名：グリーンロメイン）の葉柄をハサミで切断し、これら生葉を−８０℃ の超低温冷凍庫（アズワン（株））内で予備凍結した。その後速やかに真空凍結乾燥機（ラブコンコ社、ＦＺ−６ＢＴ）に移して５〜７日間真空乾燥した。乾燥は、真空室の弁とコールドトラップの弁を締め、設定した真空度０．０４０ｍｂａｒから２０〜３０分間変化が認められないことを確認したことで乾燥終了とした。その後、粉砕機（東京ユニコム、ハイスピードミルＴ−３５１）で粉砕処理し、凍結乾燥したサンプルを得た。次いで、粉末化したサンプルを抽出処理に供した。最終サンプル１ ｍｌあたりの粉末サンプル量（ｇ）は、幼葉については表１、大人葉については表２のとおりである。抽出の具体的な方法は、後述する。
<Example 1>
Spinatch (variety name: green spinach) cultivated in soil 16 to 20 days after germination (young leaves) and 36 to 40 days after germination (adult leaves), 16 to 20 days after germination (young leaves) cultivated hydroponicly, and Beet (variety name: Detroit) 36-40 days after germination (adult leaf), Luccola (variety name: Detroit) 14-18 days (young leaf) after germination and 36-40 days (adult leaf) after germination cultivated in soil. Luccola (rocket)), 18 to 22 days after germination (young leaves) and 38 to 42 days (adult leaves) after germination, red romaine (variety name: red romaine), 18 to 18 to after germination, hydrocultivated. The leaf stalks of green romaine (variety name: green romaine) on the 22nd (young leaves) and 38 to 42 days after germination (adult leaves) were cut with scissors, and these fresh leaves were cut at an ultra-low temperature freezer at -80 ° C (Aswan Co., Ltd.). Pre-frozen in. Then, it was immediately transferred to a vacuum freeze dryer (Loveconco, FZ-6BT) and vacuum dried for 5 to 7 days. Drying was completed by closing the valve of the vacuum chamber and the valve of the cold trap and confirming that no change was observed for 20 to 30 minutes from the set vacuum degree of 0.040 mbar. Then, it was pulverized by a pulverizer (Tokyo Unicom, High Speed Mill T-351) to obtain a freeze-dried sample. The powdered sample was then subjected to an extraction process. The powder sample amount (g) per 1 ml of the final sample is shown in Table 1 for young leaves and Table 2 for adult leaves. The specific method of extraction will be described later.
抽出後のサンプルについて、核内受容体であるＰＰＡＲα、ＰＰＡＲδ、ＰＰＡＲγ、ＲＸＲα、ＲＸＲβ、ＲＸＲγ、ビタミンＤ受容体（ＶＤＲ）、アンドロゲン受容体（ＡＲ）、グルココルチコイド受容体（ＧＲ）、プロゲステロン受容体（ＰＲ）、甲状腺ホルモン受容体α（ＴＲα）は、ＣＶ−１細胞（ＪＣＲＢ細胞バンク、国立研究開発法人 医薬基盤・健康・栄養研究所より購入）を用いて、後述のレポーターアッセイにより評価した。核内受容体であるＲＡＲα、ＲＡＲβ、ＲＡＲγ、ＥＲα、ＥＲβ、ＥＲＲα、ＥＲＲβ、ＥＲＲγは、ＣＯＳ−７細胞（ＡＴＣＣ（Ａｍｅｒｉｃａｎ Ｔｙｐｅ Ｃｕｌｔｕｒｅ Ｃｏｌｌｅｃｔｉｏｎ）より購入）を用いて、後述のレポーターアッセイにより評価した。核内受容体であるプレグナン受容体（ＰＸＲ）、ファルネソイドＸ受容体（ＦＸＲ）、肝臓Ｘ受容体α（ＬＸＲα）、肝臓Ｘ受容体β（ＬＸＲβ）、肝細胞核因子４α（ＨＮＦ−４α）、ＲＡＲオーファン受容体α（ＲＯＲα）、及び、ＣＮＣファミリーに属する転写因子（Ｎｒｆ２）は、Ｈｅｐ Ｇ２細胞（理化学研究所バイオリソース研究センター（理研ＢＲＣ）より購入）を用いて、後述のレポーターアッセイにより評価した。評価結果は、幼葉については図１、大人葉については図２に示す。核内受容体及びＮｒｆ２活性の詳細な測定方法及び図の説明は、後述する。 For the sample after extraction, the nuclear receptors PPARα, PPARδ, PPARγ, RXRα, RXRβ, RXRγ, vitamin D receptor (VDR), androgen receptor (AR), glucocorticoid receptor (GR), progesterone receptor (PR) and thyroid hormone receptor α (TRα) were evaluated using CV-1 cells (purchased from JCRB cell bank, National Institute of Pharmaceutical Sciences, Health and Nutrition) by the reporter assay described later. The nuclear receptors RARα, RARβ, RARγ, ERα, ERβ, ERRα, ERRβ, and ERRγ were evaluated using COS-7 cells (purchased from ATCC (American Type Culture Collection)) by the reporter assay described below. Nuclear receptors such as pregnane receptor (PXR), farnesoid X receptor (FXR), liver X receptor α (LXRα), liver X receptor β (LXRβ), hepatocyte nuclear factor 4α (HNF-4α), RR Orphan receptor α (RORα) and transcription factor (Nrf2) belonging to the CNC family were evaluated using Hep G2 cells (purchased from the Bioresource Research Center of the Institute of Physical and Chemical Research (RIKEN BRC)) by the reporter assay described later. .. The evaluation results are shown in FIG. 1 for young leaves and FIG. 2 for adult leaves. A detailed measurement method and a description of the drawings of the nuclear receptor and Nrf2 activity will be described later.
＜水抽出＞
スピナッチ及びビートの葉の粉末サンプルに５０ ｍｇ／ｍｌになるように滅菌水を添加し、ルッコラ、レッドロメイン、グリーンロメインの葉の粉末サンプルには１００ ｍｇ／ｍｌになるように滅菌水を添加した。４℃において２４時間振盪し、遠心分離（２２０×ｇ、１０〜３０分）した後、上清を孔径０．２ μｍのメンブレンフィルターで濾過滅菌した。
<Water extraction>
Sterilized water was added to spinach and beet leaf powder samples to 50 mg / ml, and sterilized water was added to arugula, red romaine, and green romaine leaf powder samples to 100 mg / ml. .. The mixture was shaken at 4 ° C. for 24 hours, centrifuged (220 × g, 10 to 30 minutes), and the supernatant was filtered and sterilized with a membrane filter having a pore size of 0.2 μm.
＜エタノール抽出＞
粉末サンプルを、７０％エタノールに１００ ｍｇ/ｍｌ（ｗ/ｖ）となるようそれぞれ浮遊し、室温で３時間シェーカーで振盪した。孔径０．２ μｍ のメンブレンフィルターで濾過後、濾液を常温で減圧乾燥した。得られた乾固物は２００ ｍｇ/ｍｌ或いは４００ ｍｇ/ｍｌとなるようジメチルスルホキシド（ＤＭＳＯ）に溶解した。
<Ethanol extraction>
The powder samples were each suspended in 70% ethanol at a concentration of 100 mg / ml (w / v) and shaken at room temperature for 3 hours with a shaker. After filtering through a membrane filter having a pore size of 0.2 μm, the filtrate was dried under reduced pressure at room temperature. The obtained dry matter was dissolved in dimethyl sulfoxide (DMSO) to a concentration of 200 mg / ml or 400 mg / ml.
＜混合溶媒抽出＞
粉末サンプルを、ヘキサン：エタノール：アセトン：トルエン混液 （以後 混合溶媒）に１００ ｍｇ／ｍｌとなるよう添加し、室温において３時間シェーカーで振盪した。その後、遠心分離（８９０×ｇ、１０〜３０分）し、上清を回収した。孔径０．２ μｍのメンブレンフィルターにて濾過滅菌した後、濾液を常温で減圧乾燥した。得られた乾固物は、２００ ｍｇ／ｍｌ或いは４００ ｍｇ／ｍｌになるようにＤＭＳＯに溶解した。
<Mixed solvent extraction>
The powder sample was added to a mixed solution of hexane: ethanol: acetone: toluene (hereinafter referred to as mixed solvent) at a concentration of 100 mg / ml, and the mixture was shaken with a shaker at room temperature for 3 hours. Then, it was centrifuged (890 × g, 10 to 30 minutes), and the supernatant was collected. After sterilizing by filtration through a membrane filter having a pore size of 0.2 μm, the filtrate was dried under reduced pressure at room temperature. The obtained dry matter was dissolved in DMSO to 200 mg / ml or 400 mg / ml.
＜核内受容体活性及びＮｒｆ２の測定方法；レポーターアッセイ＞
アフリカミドリザル腎由来細胞株ＣＶ−１、ＣＯＳ−７、ヒト肝ガン細胞株Ｈｅｐ Ｇ２をそれぞれ２ｘ１０５ ｃｅｌｌｓ/ｗｅｌｌとなるよう、６穴プレートに播種し、ＤＭＥＭ（１０％ 血清）中で1日培養した。Ｇａｌ４のＤＮＡ結合ドメイン（Ｇａｌ４−ＤＢＤ）と核内受容体のリガンド結合ドメイン(ＮＲ−ＬＢＤ)のキメラタンパク質発現プラスミド、Ｇａｌ４ ＤＮＡ応答配列とホタルルシフェラーゼ遺伝子を含むレポータープラスミド（ｐＧａｌ４−Ｌｕｃ）及び内部標準用としてウミシイタケルシフェラーゼ遺伝子の上流に遺伝子構成的発現プロモーター（ＣＭＶ、ＳＶ４０）を連結した内部標準プラスミド（ｐＧＬ４．７５ｈＲｌｕｃ−ＣＭＶ又はｐＧＬ４．７３ｈＲｌｕｃ−ＳＶ４０）を重量比１：０．９：０．１の割合で混合し、Ｏｐｔｉ−ＭＥＭに１０ μｇ/ｍｌ（総ＤＮＡ量）の濃度で溶解した。
<Measurement method of nuclear receptor activity and Nrf2; reporter assay>
African green monkey kidney-derived cell lines CV-1, COS-7, and human liver cancer cell line Hep G2 were seeded in 6-well plates so as to have 2x10 5 cells / well, respectively, and cultured in DMEM (10% serum) for 1 day. did. Chimeric protein expression plasmid for Gal4 DNA binding domain (Gal4-DBD) and nuclear receptor ligand binding domain (NR-LBD), reporter plasmid (pGal4-Luc) containing Gal4 DNA response sequence and firefly luciferase gene, and internal standard An internal standard plasmid (pGL4.75hRluc-CMV or pGL4.73hRluc-SV40) in which a gene-constituting expression promoter (CMV, SV40) is ligated upstream of the sea urchin cercipherase gene is used in a weight ratio of 1: 0.9: 0.1. Was mixed and dissolved in Opti-MEM at a concentration of 10 μg / ml (total DNA amount).
転写因子であるＮｒｆ２については、Ｎｒｆ２の標的遺伝子の１つであるグルタチオンＳ―トランスフェラーゼＡ２（ＧＳＴＡ２）のプロモーター領域とホタルルシフェラーゼ遺伝子を含むレポータープラスミド（ＧＳＴＡ２−Ｌｕｃ）、及び内部標準用としてウミシイタケルシフェラーゼ遺伝子の上流に遺伝子構成的発現プロモーター（ＳＶ４０）を連結した内部標準プラスミド（ｐＧＬ４．７３ｈＲｌｕｃ−ＳＶ４０）を重量比１．９：０．１の割合で混合し、Ｏｐｔｉ−ＭＥＭに１０ μｇ/ｍｌ（総ＤＮＡ量）の濃度で溶解した。 Regarding Nrf2, which is a transcription factor, a reporter plasmid (GSTA2-Luc) containing the promoter region of glutathione S-transferase A2 (GSTA2), which is one of the target genes of Nrf2, and the firefly luciferase gene, and sea urchin cercipherase for internal standard. An internal standard plasmid (pGL4.73hRluc-SV40) in which a gene-constituting expression promoter (SV40) was ligated upstream of the gene was mixed at a weight ratio of 1.9: 0.1, and 10 μg / ml (10 μg / ml) was added to Opti-MEM. It was lysed at a concentration of (total DNA amount).
同時に遺伝子導入試薬（Ｘ−ｔｒｅｍｅＧＥＮＥ ＨＰ； Ｒｏｃｈｅ）を１/４３量添加し、１５分間静置後、本混合液を２００ μlずつ各ウェルに添加し、６時間培養することによって遺伝子を導入した。各受容体のアッセイに使用した細胞株及びプラスミドを表３に示した。 At the same time, a gene transfer reagent (X-tremeGENE HP; Roche) was added in an amount of 1/43, allowed to stand for 15 minutes, 200 μl of this mixture was added to each well, and the gene was introduced by culturing for 6 hours. The cell lines and plasmids used in the assay for each receptor are shown in Table 3.
遺伝子導入細胞をトリプシンにより分散し、９６ｗｅｌｌ ｐｌａｔｅにそれぞれ１．６ｘ１０４ ｃｅｌｌｓ/ｗｅｌｌ （ＣＶ−１）、２．０ｘ１０４ｃｅｌｌｓ/ｗｅｌｌ （ＣＯＳ−７、Ｈｅｐ Ｇ２）となるよう再度播種した。この際、培養液をｐｈｅｎｏｌ ｒｅｄ不含のＤＭＥＭ培地（１０％活性炭処理ＦＢＳ）に交換した。１時間後に、各濃度の被験物質を含む上記と同様のＤＭＥＭ培地をそれぞれのウェルへ添加した。陰性コントロール（溶媒コントロール）としては最終濃度０．５％ＤＭＳＯ（７０％エタノール抽出, 混合溶媒抽出）、１０％超純水（水抽出）を用いた。 The transgenic cells were dispersed with trypsin and reseeded in 96 -well plates to 1.6x10 4 cells / well (CV-1) and 2.0x10 4 cells / well (COS-7, Hep G2), respectively. At this time, the culture medium was replaced with DMEM medium (10% activated carbon-treated FBS) containing no phenol red. After 1 hour, DMEM medium similar to the above containing each concentration of test substance was added to each well. As a negative control (solvent control), a final concentration of 0.5% DMSO (70% ethanol extraction, mixed solvent extraction) and 10% ultrapure water (water extraction) were used.
各サンプルにおける試験濃度は、事前のＣＶ−１細胞、ＣＯＳ−７細胞及びＨｅｐ Ｇ２細胞に対する細胞毒性試験により、細胞毒性を示さない最高濃度から設定した。 The test concentration in each sample was set from the highest concentration showing no cytotoxicity by a prior cytotoxicity test on CV-1 cells, COS-7 cells and Hep G2 cells.
ＣＯ２インキュベーター中で４８時間培養後、リン酸緩衝生理食塩水（ＰＢＳ）にて細胞を洗浄し、デュアルルシフェラーゼアッセイシステム（Ｐｒｏｍｅｇａ社）を用いて細胞を溶解した。さらにルシフェリンを含む基質溶液を加え、プレートリーダー（Ｌｕｍｉｎｅｓｃｅｎｃｅｒ, ＡＢ−２３５０ＥＸ , ＡＴＴＯ社）にてホタル及びウミシイタケルシフェラーゼ活性を各々測定した。以上の操作は、１サンプル（陽性、陰性コントロールを含む）につき３ウェルを用いて実施し、３ウェルの平均値をデータとして採用した。なお、本実験の精度管理に用いた陽性コントロールは表４のとおりである。表４の物質添加には溶媒としてＤＭＳＯ（終濃度０．５％）を用いた。 After culturing in a CO 2 incubator for 48 hours, the cells were washed with phosphate buffered saline (PBS) and lysed using a dual luciferase assay system (Promega). Further, a substrate solution containing luciferin was added, and firefly and shiitake mushroom cipherase activities were measured with a plate reader (Luminescener, AB-2350EX, ATTO), respectively. The above operation was performed using 3 wells per sample (including positive and negative controls), and the average value of 3 wells was adopted as data. Table 4 shows the positive controls used for quality control in this experiment. DMSO (final concentration 0.5%) was used as a solvent for the addition of the substances in Table 4.
＜データ解析＞
核内受容体或いは転写因子依存的な遺伝子の転写活性（ルシフェラーゼ活性の内部標準補正値）は、以下のように定義した。
<Data analysis>
The transcriptional activity of a nuclear receptor or transcription factor-dependent gene (internal standard correction of luciferase activity) was defined as follows.
（内部標準補正値）＝（Ｇａｌ４-Ｌｕｃ或いはＧＳＴＡ２-Ｌｕｃによるホタルルシフェラーゼ活性）/（ｈＲｌｕｃ-ＣＭＶ又はｈＲｌｕｃ-ＳＶ４０によるウミシイタケルシフェラーゼ活性）
活性の評価は陰性コントロールとの比（サンプルにおける活性値／陰性コントロールにおける活性値）で表し、細胞に顕著な障害が認められず（ウミシイタケルシフェラーゼ活性値の顕著な低下が認められない）、本数値（陰性コントロール比）が２．０以上となる場合を、有意な活性と定義した。ただし、Ｇａｌ４−Ｌｕｃによるホタルルシフェラーゼ活性のみの数値から、活性が認められないものは、内部標準補正値が２．０以上でも活性なしとした。
(Internal standard correction value) = (Firefly luciferase activity by Gal4-Luc or GSTA2-Luc) / (Umi-shiitake luciferase activity by hRluc-CMV or hRluc-SV40)
The evaluation of activity was expressed by the ratio to the negative control (activity value in the sample / activity value in the negative control), and no significant damage was observed in the cells (no significant decrease in the luciferase activity value was observed). When the numerical value (negative control ratio) was 2.0 or more, it was defined as significant activity. However, from the values of only the firefly luciferase activity by Gal4-Luc, those in which no activity was observed were regarded as inactive even if the internal standard correction value was 2.0 or more.
図１及び図２は、それぞれ幼葉及び大人葉についての、核内受容体活性化能を比較した結果をまとめたものである。陰性コントロールと比べて、３＋は１０１倍以上（下線は５００倍以上）、２＋は５１〜１００倍、１＋は２〜５０倍（下線は１０倍以上）とした。アッセイで得られた最高値を用いて分類を行った。 FIGS. 1 and 2 summarize the results of comparing the nuclear receptor activation abilities of young leaves and adult leaves, respectively. Compared with the negative control, 3+ was 101 times or more (underlined 500 times or more), 2+ was 51 to 100 times, and 1+ was 2 to 50 times (underlined 10 times or more). Classification was performed using the highest value obtained in the assay.
本発明が有用な分野は、健康食品、機能性表示食品の製造である。 Areas in which the present invention is useful are the production of health foods and foods with functional claims.
Claims (33)
それが含有するのは、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉又はその加工物である。 A food composition for activating nuclear receptors,
It contains spinach, beet, arugula, red romaine, green romaine, any one or more leaves or processed products thereof.
前記葉は、発芽後３０日以内である。 The food composition for activating nuclear receptors according to claim 1.
The leaves are within 30 days after germination.
それが含有するのは、ベビーリーフ又はその加工物である。 A food composition for activating nuclear receptors,
It contains baby leaf or its processed products.
前記核内受容体がＲＡＲ、ＲＸＲ、ＰＰＡＲ又はＥＲのうち、何れか１つ又は２つ以上である。 A food composition for activating a nuclear receptor according to any one of claims 1 to 3.
The nuclear receptor is any one or two or more of RAR, RXR, PPAR or ER.
前記ＲＡＲが、ＲＡＲα、ＲＡＲβ又はＲＡＲγのうち、何れか１つ又は２つ以上であり、
前記ＲＸＲが、ＲＸＲα、ＲＸＲβ又はＲＸＲγのうち、何れか１つ又は２つ以上であり、
前記ＰＰＡＲが、ＰＰＡＲα、ＰＰＡＲγ、ＰＰＡＲδのうち、何れか１つ又は２つ以上であり、
前記ＥＲが、ＥＲβである。 A food composition for activating a nuclear receptor according to any one of claims 1 to 4.
The RAR is any one or two or more of RARα, RARβ, and RARγ.
The RXR is any one or two or more of RXRα, RXRβ, and RXRγ.
The PPAR is any one or two or more of PPARα, PPARγ, and PPARδ.
The ER is ERβ.
前記核内受容体が、ＲＡＲである。 A food composition for activating a nuclear receptor according to any one of claims 1 to 5.
The nuclear receptor is RAR.
それが含有するのは、核内受容体活性化寄与成分であり、
その由来は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉である。 A food composition for normalizing fasting blood glucose levels.
It contains nuclear receptor activation contributors,
Its origin is the leaves of any one or more of spinach, beet, arugula, red romaine, and green romaine.
前記核内受容体活性化寄与成分は、ＲＡＲ活性化寄与成分である。 The food composition of claim 7.
The nuclear receptor activation contributing component is a RAR activation contributing component.
前記葉は、発芽後３０日以内である。 The food composition of claim 7 or 8.
The leaves are within 30 days after germination.
それが含有するのは、核内受容体活性化寄与成分であり、
その由来は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉である。 A food composition for suppressing inflammatory diseases of the skin.
It contains nuclear receptor activation contributors,
Its origin is the leaves of any one or more of spinach, beet, arugula, red romaine, and green romaine.
前記核内受容体活性化寄与成分は、ＲＡＲ活性化寄与成分である。 The food composition of claim 10.
The nuclear receptor activation contributing component is a RAR activation contributing component.
前記葉は、発芽後３０日以内である。 The food composition of claim 10 or 11.
The leaves are within 30 days after germination.
それが含有するのは、核内受容体活性化寄与成分であり、
その由来は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉である。 A food composition for suppressing keratoderma of the skin.
It contains nuclear receptor activation contributors,
Its origin is the leaves of any one or more of spinach, beet, arugula, red romaine, and green romaine.
前記核内受容体活性化寄与成分は、ＲＡＲ活性化寄与成分である。 The food composition of claim 13.
The nuclear receptor activation contributing component is a RAR activation contributing component.
前記葉は、発芽後３０日以内である。 The food composition according to claim 13 or 14.
The leaves are within 30 days after germination.
それが含有するのは、核内受容体活性化寄与成分であり、
その由来は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉である。 A food composition for suppressing photoaging of the skin.
It contains nuclear receptor activation contributors,
Its origin is the leaves of any one or more of spinach, beet, arugula, red romaine, and green romaine.
前記核内受容体活性化寄与成分は、ＲＡＲ活性化寄与成分である。 The food composition of claim 16.
The nuclear receptor activation contributing component is a RAR activation contributing component.
前記葉は、発芽後３０日以内である。 The food composition of claim 16 or 17.
The leaves are within 30 days after germination.
それが含有するのは、核内受容体活性化寄与成分であり、
その由来は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉である。 A food composition for suppressing skin pigmentation,
It contains nuclear receptor activation contributors,
Its origin is the leaves of any one or more of spinach, beet, arugula, red romaine, and green romaine.
前記核内受容体活性化寄与成分は、ＲＡＲ活性化寄与成分である。 The food composition of claim 19.
The nuclear receptor activation contributing component is a RAR activation contributing component.
前記葉は、発芽後３０日以内である。 The food composition of claim 19 or 20
The leaves are within 30 days after germination.
それが含有するのは、核内受容体活性化寄与成分であり、
その由来は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉である。 A food composition for suppressing fat accumulation
It contains nuclear receptor activation contributors,
Its origin is the leaves of any one or more of spinach, beet, arugula, red romaine, and green romaine.
前記核内受容体活性化寄与成分は、ＲＡＲ活性化寄与成分である。 The food composition of claim 22
The nuclear receptor activation contributing component is a RAR activation contributing component.
前記葉は、発芽後３０日以内である。 The food composition of claim 22 or 23.
The leaves are within 30 days after germination.
それが含有するのは、核内受容体活性化寄与成分であり、
その由来は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉である。 A food composition for suppressing fatty liver,
It contains nuclear receptor activation contributors,
Its origin is the leaves of any one or more of spinach, beet, arugula, red romaine, and green romaine.
前記核内受容体活性化寄与成分は、ＲＡＲ活性化寄与成分である。 The food composition of claim 25.
The nuclear receptor activation contributing component is a RAR activation contributing component.
前記葉は、発芽後３０日以内である。 The food composition of claim 25 or 26.
The leaves are within 30 days after germination.
それが含有するのは、核内受容体活性化寄与成分であり、
その由来は、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉である。 A food composition for increasing blood HDL cholesterol.
It contains nuclear receptor activation contributors,
Its origin is the leaves of any one or more of spinach, beet, arugula, red romaine, and green romaine.
前記核内受容体活性化寄与成分は、ＲＡＲ活性化寄与成分である。 The food composition of claim 28.
The nuclear receptor activation contributing component is a RAR activation contributing component.
前記葉は、発芽後３０日以内である。 The food composition of claim 28 or 29.
The leaves are within 30 days after germination.
抽出：ここで抽出されるのは、核内受容体活性化寄与成分であり、スピナッチ、ビート、ルッコラ、レッドロメイン、グリーンロメインのうち、何れか１種又は２種以上の葉から抽出される。 A method for producing a food composition for activating nuclear receptors, which comprises at least the following constitutions:
Extraction: What is extracted here is a nuclear receptor activation contributing component, which is extracted from the leaves of any one or more of spinach, beet, arugula, red romaine, and green romaine.
前記核内受容体活性化寄与成分は、水、含水エタノール又は有機溶媒により抽出される。 The manufacturing method according to claim 31.
The nuclear receptor activation contributing component is extracted with water, hydrous ethanol or an organic solvent.
前記葉は発芽後３０日以内である。 The manufacturing method according to claim 31 or 32.
The leaves are within 30 days after germination.
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| US20070184060A1 (en) * | 2006-02-08 | 2007-08-09 | Josep Bassaganya-Riera | Method of using abscisic acid to treat and prevent diseases and disorders |
| JP2010106001A (en) * | 2008-10-31 | 2010-05-13 | Theravalues Corp | Ppar activator |
| JP2018080148A (en) * | 2016-11-18 | 2018-05-24 | 株式会社東洋新薬 | Composition for preventing and/or improving climacteric symptom |
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| JP2002326945A (en) * | 2001-05-02 | 2002-11-15 | Aoa Japan:Kk | Prophylactic agent for ultraviolet hazard |
| US20070184060A1 (en) * | 2006-02-08 | 2007-08-09 | Josep Bassaganya-Riera | Method of using abscisic acid to treat and prevent diseases and disorders |
| JP2010106001A (en) * | 2008-10-31 | 2010-05-13 | Theravalues Corp | Ppar activator |
| JP2018080148A (en) * | 2016-11-18 | 2018-05-24 | 株式会社東洋新薬 | Composition for preventing and/or improving climacteric symptom |
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