JP7435958B2 - Composition for promoting mesenchymal stem cell proliferation and composition for improving cognitive function - Google Patents
Composition for promoting mesenchymal stem cell proliferation and composition for improving cognitive function Download PDFInfo
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- JP7435958B2 JP7435958B2 JP2019022458A JP2019022458A JP7435958B2 JP 7435958 B2 JP7435958 B2 JP 7435958B2 JP 2019022458 A JP2019022458 A JP 2019022458A JP 2019022458 A JP2019022458 A JP 2019022458A JP 7435958 B2 JP7435958 B2 JP 7435958B2
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Description
本発明は、間葉系幹細胞の増殖、特に生体内での間葉系幹細胞の増殖を促進するための組成物、及び哺乳動物、特にヒトの認知機能を改善するための組成物に関する。 The present invention relates to a composition for promoting proliferation of mesenchymal stem cells, particularly in vivo, and a composition for improving cognitive function in mammals, particularly humans.
高齢化が急速に進む現代社会において、高齢者における認知機能の低下は社会問題となっている。アルツハイマー病等を発症原因とするいわゆる認知症による機能低下は、患者本人のQOLの低下に留まらず、介護等の周囲への負担の増大及び医療費の増大を招く原因となっている。また、自然な老化に伴う比較的軽度な認知機能の低下であっても、当人が日常生活を営む上で様々な支障の原因となり、特に高齢化と共にその影響はより深刻なものとなり得る。そのため、医療費等の社会福祉費用の軽減及び対象者のQOL向上の観点から、認知機能の低下を予防する又は認知機能を改善することのできる手段への期待は高い。 In modern society where the population is rapidly aging, the decline in cognitive function among the elderly has become a social problem. Functional decline due to so-called dementia, which is caused by Alzheimer's disease, etc., not only reduces the quality of life of the patient but also increases the burden on those around them, such as nursing care, and increases medical costs. Furthermore, even a relatively mild decline in cognitive function that accompanies natural aging can cause various problems in a person's daily life, and the effects can become more serious as the person ages. Therefore, from the perspective of reducing social welfare costs such as medical expenses and improving the QOL of subjects, there are high expectations for means that can prevent or improve cognitive function.
医学的に認知症と診断された患者に対しては、アセチルコリンエステラーゼ阻害作用を示すドネペジルやガランタミン等の適応が行われている。しかし、これらの薬物による治療は対症療法であり、また副作用の懸念がある。 For patients medically diagnosed with dementia, drugs such as donepezil and galantamine, which have an acetylcholinesterase inhibitory effect, are indicated. However, treatment with these drugs is symptomatic treatment, and there are concerns about side effects.
認知機能の改善に有効な食品中の機能性成分として、イチョウ葉フラボノイド配糖体・テルペンラクトン（コリン作動性の神経伝達物質の利用効率向上）、鶏由来プラズマローゲン（海馬の神経細胞の新生促進、アミロイドβの蓄積抑制、神経炎症抑制作用）、魚やオーランチオキトリウム由来DHA（海馬での神経細胞新生の促進、アミロイドβタンパク質凝集の抑制、シナプス膜流動性促進による神経伝達物質NMDA（N-メチル-D-アスパラギン酸）の受容体の活性化、脳血流量増加による脳への酸素供給の促進）、大豆由来ホスファチジルセリン（ホスファチジルセリン誘導D-セリンのNMDA型グルタミン酸受容体の活性化）等が報告されており、機能性表示食品として販売されている。 Functional ingredients in foods that are effective in improving cognitive function include ginkgo biloba flavonoid glycosides and terpene lactones (improving the utilization efficiency of cholinergic neurotransmitters), and chicken-derived plasmalogen (promoting new generation of hippocampal nerve cells). , amyloid β accumulation inhibition, neuroinflammation inhibitory effect), DHA derived from fish and aurantiochytrium (promotes neurogenesis in the hippocampus, inhibits amyloid β protein aggregation, and promotes synaptic membrane fluidity to promote neurotransmitter NMDA (N- Activation of receptors for methyl-D-aspartate (promoting oxygen supply to the brain by increasing cerebral blood flow), soybean-derived phosphatidylserine (activation of NMDA-type glutamate receptors for phosphatidylserine-induced D-serine), etc. has been reported and is sold as a food with functional claims.
一方、損傷を受けた脳機能を治療する又は改善する有効な手段として、間葉系幹細胞（Mesenchymal Stem Cell: MSC）を利用した再生医療が提唱されている。例えば、生体から採取して体外で培養、増殖させた間葉系幹細胞を、各種神経疾患モデル動物及びヒトに対して経静脈的に全身投与することで脳梗塞や脊髄損傷の後遺症を改善し得ることが報告されている（例として非特許文献１～５）。しかしながら、投与用の間葉系幹細胞の調製には特別な設備を要すること、自家移植の場合は投与前に当該患者から間葉系幹細胞を採取して培養する必要があること等の理由から、間葉系幹細胞の投与は既に発症した患者の治療の場面に留まっている。徐々に発症して経過が長期にわたるいわゆる慢性疾患、例えば神経変性疾患や慢性炎症性疾患等においても、間葉系幹細胞は、その組織修復作用、抗炎症作用及び線維化抑制作用等の様々な作用により発症の阻止や病態進行の抑制に寄与するものと期待されるが、これらの疾患に罹患した者に対してその明確な症状があらわれる前に治療的に間葉系幹細胞を投与すること、及びこれらの疾患に罹患するおそれがある者に対して予防的に間葉系幹細胞を投与することは、対象者の発見の困難性及び経済性の面で現実的ではない。 On the other hand, regenerative medicine using mesenchymal stem cells (MSCs) has been proposed as an effective means to treat or improve damaged brain function. For example, mesenchymal stem cells collected from a living body, cultured and proliferated outside the body can be intravenously administered systemically to various neurological disease model animals and humans to improve the aftereffects of cerebral infarction and spinal cord injury. It has been reported (for example, Non-Patent Documents 1 to 5). However, preparation of mesenchymal stem cells for administration requires special equipment, and in the case of autologous transplantation, it is necessary to collect mesenchymal stem cells from the patient and culture them before administration. Administration of mesenchymal stem cells remains limited to the treatment of patients who have already developed symptoms. Even in so-called chronic diseases that develop gradually and have a long course, such as neurodegenerative diseases and chronic inflammatory diseases, mesenchymal stem cells have various effects such as tissue repair, anti-inflammatory, and fibrosis-inhibiting effects. It is expected that mesenchymal stem cells will contribute to preventing the onset of these diseases and suppressing the progression of the disease, but it is important to administer mesenchymal stem cells therapeutically to people suffering from these diseases before their clear symptoms appear, and It is not practical to administer mesenchymal stem cells prophylactically to people who are at risk of suffering from these diseases, due to the difficulty in finding patients and the cost.
本発明は、間葉系幹細胞、特に生体内に存在する間葉系幹細胞の有効利用に資する新たな手段を提供することを目的とするものである。 An object of the present invention is to provide a new means that contributes to the effective utilization of mesenchymal stem cells, particularly mesenchymal stem cells existing in vivo.
本発明者らは、特定の成分を含有する食品が生体内での間葉系幹細胞の増殖を促進し、また前記食品が認知機能を改善するという新たな知見を見出し、以下の発明を完成させた。
（１）β-カロテン含有食品、ルチン含有食品、アントシアニン含有食品及びフラボノール含有食品よりなる群から選択される１又は２以上の食品を有効成分として含有する間葉系幹細胞増殖促進用組成物。
（２）β-カロテン含有食品がニンジンである、（１）に記載の組成物。
（３）ルチン含有食品がダッタンソバである、（１）に記載の組成物。
（４）アントシアニン含有食品が、茶品種サンルージュ（品種登録第21262号）及びその系統品種、バレイショ品種シャドークイーン（品種登録第17574号）及びその系統品種並びにバレイショ品種ノーザンルビー（品種登録第17447号）及びその系統品種よりなる群から選択される食品である、（１）に記載の組成物。
（５）アントシアニンのアグリコンが、デルフィニジン、シアニジン、ペチュニジン又はペラルゴニジンである、（１）又は（４）に記載の組成物。
（６）フラボノール含有食品が、茶品種サンルージュ（品種登録第21262号）又はその系統品種の茶である、（１）に記載の組成物。
（７）フラボノールが、ミリセチン、ケンフェロール又はケルセチンである、（１）又は（６）に記載の組成物。
（８）β-カロテン含有食品、ルチン含有食品、アントシアニン含有食品及びフラボノール含有食品よりなる群から選択される１又は２以上の食品を有効成分として含有する認知機能改善用組成物。
（９）β-カロテン含有食品がニンジンである、（８）に記載の組成物。
（１０）ルチン含有食品がダッタンソバである、（８）に記載の組成物。
（１１）アントシアニン含有食品が、茶品種サンルージュ（品種登録第21262号）及びその系統品種、バレイショ品種シャドークイーン（品種登録第17574号）及びその系統品種並びにバレイショ品種ノーザンルビー（品種登録第17447号）及びその系統品種よりなる群から選択される食品である、（８）に記載の組成物。
（１２）アントシアニンのアグリコンが、デルフィニジン、シアニジン、ペチュニジン又はペラルゴニジンである、（８）又は（１１）に記載の組成物。
（１３）フラボノール含有食品が、茶品種サンルージュ（品種登録第21262号）又はその系統品種の茶である、（８）に記載の組成物。
（１４）フラボノールが、ミリセチン、ケンフェロール又はケルセチンである、（８）又は（１３）に記載の組成物。
（１５）β-カロテン、ルチン、アントシアニン及びフラボノールよりなる群から選択される１又は２以上の物質を有効成分として含有する間葉系幹細胞増殖促進用組成物。
（１６）アントシアニンのアグリコンが、デルフィニジン、シアニジン、ペチュニジン又はペラルゴニジンである、（１５）に記載の組成物。
（１７）フラボノールが、ミリセチン、ケンフェロール又はケルセチンである、（１５）に記載の組成物。
（１８）β-カロテン、ルチン、アントシアニン及びフラボノールよりなる群から選択される１又は２以上の物質を有効成分として含有する認知機能改善用組成物。
（１９）アントシアニンのアグリコンが、デルフィニジン、シアニジン、ペチュニジン又はペラルゴニジンである、（１８）に記載の組成物。
（２０）フラボノールが、ミリセチン、ケンフェロール又はケルセチンである、（１８）に記載の組成物。
The present inventors have discovered new findings that foods containing specific ingredients promote the proliferation of mesenchymal stem cells in vivo, and that the foods improve cognitive function, and have completed the following invention. Ta.
(1) A composition for promoting mesenchymal stem cell proliferation, which contains as an active ingredient one or more foods selected from the group consisting of β-carotene-containing foods, rutin-containing foods, anthocyanin-containing foods, and flavonol-containing foods.
(2) The composition according to (1), wherein the β-carotene-containing food is carrot.
(3) The composition according to (1), wherein the rutin-containing food is Duttan buckwheat.
(4) Anthocyanin-containing foods include the tea variety Sun Rouge (variety registration No. 21262) and its pedigree, the potato variety Shadow Queen (variety registration No. 17574) and its pedigree, and the potato variety Northern Ruby (variety registration No. 17447). ) and its lineage varieties.
(5) The composition according to (1) or (4), wherein the aglycone of anthocyanin is delphinidin, cyanidin, petunidin, or pelargonidin.
(6) The composition according to (1), wherein the flavonol-containing food is tea of the tea variety Sunrouge (variety registration No. 21262) or its lineage varieties.
(7) The composition according to (1) or (6), wherein the flavonol is myricetin, kaempferol or quercetin.
(8) A composition for improving cognitive function containing as an active ingredient one or more foods selected from the group consisting of β-carotene-containing foods, rutin-containing foods, anthocyanin-containing foods, and flavonol-containing foods.
(9) The composition according to (8), wherein the β-carotene-containing food is carrot.
(10) The composition according to (8), wherein the rutin-containing food is Duttan buckwheat.
(11) Anthocyanin-containing foods include the tea variety Sun Rouge (variety registration No. 21262) and its pedigree, the potato variety Shadow Queen (variety registration No. 17574) and its pedigree, and the potato variety Northern Ruby (variety registration No. 17447). ) and its line varieties, the composition according to (8).
(12) The composition according to (8) or (11), wherein the aglycone of anthocyanin is delphinidin, cyanidin, petunidin, or pelargonidin.
(13) The composition according to (8), wherein the flavonol-containing food is a tea variety Sunrouge (variety registration No. 21262) or a tea strain thereof.
(14) The composition according to (8) or (13), wherein the flavonol is myricetin, kaempferol, or quercetin.
(15) A composition for promoting proliferation of mesenchymal stem cells, which contains as an active ingredient one or more substances selected from the group consisting of β-carotene, rutin, anthocyanin, and flavonol.
(16) The composition according to (15), wherein the anthocyanin aglycone is delphinidin, cyanidin, petunidin, or pelargonidin.
(17) The composition according to (15), wherein the flavonol is myricetin, kaempferol or quercetin.
(18) A composition for improving cognitive function containing as an active ingredient one or more substances selected from the group consisting of β-carotene, rutin, anthocyanin, and flavonol.
(19) The composition according to (18), wherein the aglycone of anthocyanin is delphinidin, cyanidin, petunidin, or pelargonidin.
(20) The composition according to (18), wherein the flavonol is myricetin, kaempferol or quercetin.
本発明の間葉系幹細胞増殖促進用組成物は、これを投与された又は摂取した哺乳動物の体内で間葉系幹細胞数を増加させることができ、これにより様々な疾患に対する予防的及び／又は治療的な効果を発揮することが期待される。また本発明の間葉系幹細胞増殖促進用組成物は、これを含む適当な培地中で間葉系幹細胞を培養することで細胞数を増加させることができる。間葉系幹細胞の培養における細胞数の増加は、間葉系幹細胞を含有する医薬の製造において有利である。さらに、本発明の認知機能改善用組成物は、これを投与された又は摂取した哺乳動物の認知機能を改善することができる。 The composition for promoting proliferation of mesenchymal stem cells of the present invention can increase the number of mesenchymal stem cells in the body of a mammal that has been administered or ingested it, thereby providing preventive and/or effective treatment against various diseases. It is expected to have therapeutic effects. Furthermore, the composition for promoting proliferation of mesenchymal stem cells of the present invention can increase the number of cells by culturing mesenchymal stem cells in an appropriate medium containing the composition. Increasing the number of cells in culture of mesenchymal stem cells is advantageous in the production of medicinal products containing mesenchymal stem cells. Furthermore, the composition for improving cognitive function of the present invention can improve the cognitive function of a mammal that has been administered or ingested it.
本発明は、β-カロテン含有食品、ルチン含有食品、アントシアニン含有食品及びフラボノール含有食品よりなる群から選択される１又は２以上の食品を有効成分として含有する間葉系幹細胞増殖促進用組成物に関する。 The present invention relates to a composition for promoting proliferation of mesenchymal stem cells, which contains as an active ingredient one or more foods selected from the group consisting of β-carotene-containing foods, rutin-containing foods, anthocyanin-containing foods, and flavonol-containing foods. .
間葉系幹細胞は、間葉系組織の間質細胞の中に存在する多分化能および自己複製能を有する幹細胞である。間葉系幹細胞は、骨芽細胞、軟骨細胞、脂肪細胞、筋細胞といった間葉系に属する細胞に分化するだけでなく、神経細胞や肝細胞などにも胚葉を超えて分化することが知られている。 Mesenchymal stem cells are stem cells with multipotency and self-renewal ability that reside within the stromal cells of mesenchymal tissues. Mesenchymal stem cells are known to not only differentiate into mesenchymal cells such as osteoblasts, chondrocytes, adipocytes, and muscle cells, but also to differentiate beyond the germ layer into nerve cells and hepatocytes. ing.
本発明の間葉系幹細胞増殖用組成物は、間葉系幹細胞の増殖を促進する作用、すなわち間葉系幹細胞の増殖能を向上させ、その数を増加させる作用を有する。本発明の間葉系幹細胞増殖用組成物は、骨髄、末梢血、脂肪、脳など体組織に存在しているいずれの間葉系幹細胞に対しても使用することができ、好ましくは骨髄由来又は末梢血由来の間葉系幹細胞、特に骨髄由来の間葉系幹細胞に対して使用することができる。 The composition for proliferation of mesenchymal stem cells of the present invention has an effect of promoting the proliferation of mesenchymal stem cells, that is, an effect of improving the proliferative ability of mesenchymal stem cells and increasing their number. The composition for proliferating mesenchymal stem cells of the present invention can be used for any mesenchymal stem cells existing in body tissues such as bone marrow, peripheral blood, fat, and brain, and preferably for mesenchymal stem cells derived from bone marrow or It can be used for mesenchymal stem cells derived from peripheral blood, especially mesenchymal stem cells derived from bone marrow.
本発明の間葉系幹細胞増殖促進用組成物は、インビトロでの間葉系幹細胞の培養、及びインビボすなわち生体内における間葉系幹細胞の増殖のいずれにおいても利用することができる。本発明の間葉系幹細胞増殖促進用組成物を投与する又は摂取させる対象は、体内における間葉系幹細胞の増殖促進が望まれる哺乳動物であり、例としてマウス、ラット、ハムスター、イヌ、ネコ、ウシ、ブタ、サル、ヒト等を挙げることができるが、ヒトが特に好ましい。 The composition for promoting proliferation of mesenchymal stem cells of the present invention can be used for both in vitro culture of mesenchymal stem cells and in vivo, that is, in vivo proliferation of mesenchymal stem cells. Subjects to whom the composition for promoting mesenchymal stem cell proliferation of the present invention is administered or ingested are mammals in which promotion of proliferation of mesenchymal stem cells in the body is desired, such as mice, rats, hamsters, dogs, cats, Examples include cows, pigs, monkeys, humans, etc., with humans being particularly preferred.
インビトロにおける間葉系幹細胞に対する増殖促進作用は、本発明の間葉系幹細胞増殖促進用組成物の存在下で間葉系幹細胞を培養し、組成物の非存在下で培養した場合と比較して間葉系幹細胞の数がより多いことをもって確認することができる。 The in vitro proliferation-promoting effect on mesenchymal stem cells was determined by culturing mesenchymal stem cells in the presence of the mesenchymal stem cell proliferation-promoting composition of the present invention compared to culturing them in the absence of the composition. This can be confirmed by a higher number of mesenchymal stem cells.
生体内における間葉系幹細胞に対する増殖促進作用は、本発明の間葉系幹細胞増殖促進用組成物を適当な動物、好ましくはマウス、ラットその他の実験動物に投与した又は摂取させたときに、組成物を投与しない又は摂取させない場合と比較して、生体内における間葉系幹細胞の数が、好ましくは骨髄又は末梢血中の間葉系幹細胞の数がより多いことをもって確認することができる。生体内における間葉系幹細胞の数は、モデル動物から採取した骨髄又は末梢血に対して培養等の公知の方法を適用することで測定することができる。 The proliferation-promoting effect on mesenchymal stem cells in vivo can be determined by administering or ingesting the composition for promoting mesenchymal stem cell proliferation of the present invention to a suitable animal, preferably a mouse, rat, or other experimental animal. It can be confirmed that the number of mesenchymal stem cells in the body, preferably in the bone marrow or peripheral blood, is larger than when the substance is not administered or ingested. The number of mesenchymal stem cells in a living body can be measured by applying known methods such as culture to bone marrow or peripheral blood collected from a model animal.
本発明の間葉系幹細胞増殖促進用組成物は、生体内で間葉系幹細胞の増殖を促すことで組織修復、抗炎症、線維化抑制等の機能を発揮し、様々な疾患に対して予防的及び／又は治療的に作用することが期待される。本発明の間葉系幹細胞増殖促進用組成物により予防及び／又は治療され得る疾患としては、例えば、脳梗塞、脊椎損傷、認知症、神経変性疾患等の神経疾患；心筋梗塞等の心血管疾患；関節リウマチ、炎症性腸疾患等の炎症性疾患；糖尿病及びその合併症；腎臓病等を挙げることができる。 The composition for promoting proliferation of mesenchymal stem cells of the present invention exerts functions such as tissue repair, anti-inflammation, and inhibition of fibrosis by promoting proliferation of mesenchymal stem cells in vivo, and prevents various diseases. It is expected to have a therapeutic and/or therapeutic effect. Diseases that can be prevented and/or treated by the composition for promoting proliferation of mesenchymal stem cells of the present invention include, for example, neurological diseases such as cerebral infarction, spinal injury, dementia, and neurodegenerative diseases; cardiovascular diseases such as myocardial infarction. Inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease; Diabetes and its complications; Kidney disease, etc. can be mentioned.
本発明はさらに、β-カロテン含有食品、ルチン含有食品、アントシアニン含有食品及びフラボノール含有食品よりなる群から選択される１又は２以上の食品を有効成分として含有する認知機能改善用組成物を提供する。 The present invention further provides a composition for improving cognitive function containing as an active ingredient one or more foods selected from the group consisting of β-carotene-containing foods, rutin-containing foods, anthocyanin-containing foods, and flavonol-containing foods. .
本発明の認知機能改善用組成物は、哺乳動物に投与する又は摂取させることで、当該動物の認知機能を改善することができる。本発明において認知機能とは、記憶、判断、計算、理解、学習、思考、言語等を含む脳の高次の機能をいい、その改善とは、それらいずれかの機能を維持する又は機能の低下を妨げること、機能低下の進行速度を減少させること、及び低下した機能を回復させることを含むものとして理解される。したがって、本発明の認知機能改善用組成物は、認知機能維持用組成物及び認知機能低下抑制用組成物と表すこともできる。 When the composition for improving cognitive function of the present invention is administered to or ingested by a mammal, the cognitive function of the animal can be improved. In the present invention, cognitive function refers to higher brain functions including memory, judgment, calculation, understanding, learning, thinking, language, etc., and improvement thereof refers to maintaining any of these functions or decreasing the function. It is understood to include inhibiting the development of, reducing the rate of progression of functional decline, and restoring degraded functionality. Therefore, the composition for improving cognitive function of the present invention can also be referred to as a composition for maintaining cognitive function and a composition for suppressing decline in cognitive function.
本発明の認知機能改善用組成物を投与する又は摂取させる対象は、認知機能の改善が望まれる哺乳動物であり、例としてマウス、ラット、ハムスター、イヌ、ネコ、ウシ、ブタ、サル、ヒト等を挙げることができるが、ヒトが特に好ましい。認知機能改善作用は、本発明の認知機能改善用組成物を投与した又は摂取させた適当な動物、好ましくマウス、ラットその他のモデル動物を被験体として、認知機能を測定する公知の方法を実施して認知機能を評価し、組成物を投与等しなかったモデル動物の認知機能の評価と比較することで確認することができる。モデル動物の認知機能を測定する公知の方法としては、新奇物体認識試験、Morris水迷路試験、放射状迷路試験等を挙げることができる。 Subjects to whom the composition for improving cognitive function of the present invention is administered or ingested are mammals whose cognitive function is desired to be improved, such as mice, rats, hamsters, dogs, cats, cows, pigs, monkeys, humans, etc. However, humans are particularly preferred. The cognitive function-improving effect can be determined by performing a known method for measuring cognitive function using an appropriate animal, preferably a mouse, rat, or other model animal, to which the composition for improving cognitive function of the present invention has been administered or ingested. This can be confirmed by evaluating the cognitive function of a model animal and comparing it with the evaluation of the cognitive function of a model animal to which the composition was not administered. Known methods for measuring the cognitive function of model animals include novel object recognition tests, Morris water maze tests, radial maze tests, and the like.
本発明の間葉系幹細胞増殖促進用組成物及び認知機能改善用組成物は、β-カロテン含有食品、ルチン含有食品、アントシアニン含有食品及びフラボノール含有食品よりなる群から選択される１又は２以上の食品を有効成分として含有する。 The composition for promoting mesenchymal stem cell proliferation and the composition for improving cognitive function of the present invention contain one or more selected from the group consisting of β-carotene-containing foods, rutin-containing foods, anthocyanin-containing foods, and flavonol-containing foods. Contains food as an active ingredient.
β-カロテンは、植物に存在するカロテノイドの一種で、赤橙色色素の一つとして知られている化合物で、プロビタミンAとも呼ばれる。β-カロテンを多く含有する食用植物としては、例えばニンジン（Daucus carota subsp. Sativus）、シソ、モロヘイヤ、パセリ、バジル、ホウレンソウ、シュンギク、ニラ、カボチャ、コマツナ、チンゲンサイその他の緑黄色野菜を挙げることができ、好ましくはニンジンである。 Beta-carotene is a type of carotenoid found in plants, and is a compound known as one of the red-orange pigments, and is also called provitamin A. Examples of edible plants containing a large amount of β-carotene include carrots (Daucus carota subsp. Sativus), perilla, molokheiya, parsley, basil, spinach, Chinese chrysanthemum, chives, pumpkin, komatsuna, bok choy, and other green and yellow vegetables. , preferably carrots.
ルチンは、植物に存在するフラボノイド配糖体の一種で、ケルセチンとルチノースからなる。ルチンを多く含有する食用植物としては、例えばダッタンソバ(Fagopyrum tataricum)を含むソバ、アスパラガス、柑橘類等を挙げることができ、好ましくはダッタンソバ、特に品種名「満天きらり」（品種登録第23414号）又はその系統品種のダッタンソバである。 Rutin is a type of flavonoid glycoside that exists in plants and consists of quercetin and rutinose. Examples of edible plants containing a large amount of rutin include buckwheat including Fagopyrum tataricum, asparagus, citrus fruits, etc. Preferably, Dattan buckwheat, especially variety name "Manten Kirari" (variety registration No. 23414) or This is the pedigree variety Dattan buckwheat.
アントシアニンは、植物に存在するフラボノイドの一種で、アグリコンであるアントシアニジンに糖鎖、有機酸等が結合した構造を有する。本発明において好ましいアントシアニンは、そのアグリコンがデルフィニジン、シアニジン、ペチュニジン又はペラルゴニジンであるアントシアニンである。デルフィニジン系アントシアニンとしては、例えば、デルフィニジン－３－Ｏ－β－ガラクトピラノシド、デルフィニジン－３－Ｏ－β－（６－トランス－ｐ－クマロイル）ガラクトピラノシド、デルフィニジン－３－Ｏ－β―（６－シス－ｐ－クマロイル）ガラクトピラノシド、デルフィニジン－３－Ｏ－β－グルコピラノシド、デルフィニジン－３－Ｏ－β－（６－トランス－ｐ－クマロイル）グルコピラノシド等が挙げられる。シアニジン系アントシアニンとしては、例えば、シアニジン－３－Ｏ―β―ガラクトピラノシド、シアニジン－３－Ｏ－β－グルコピラノシド、シアニジン－３－Ｏ－β－（６－トランス－ｐ－クマロイル）ガラクトピラノシド、シアニジン－３－Ｏ－β－（６－トランス－ｐ－クマロイル）グルコピラノシド等が挙げられる。 Anthocyanin is a type of flavonoid present in plants, and has a structure in which sugar chains, organic acids, etc. are bound to anthocyanidin, which is an aglycone. Preferred anthocyanins in the present invention are those whose aglycone is delphinidin, cyanidin, petunidin or pelargonidin. Examples of delphinidin-based anthocyanins include delphinidin-3-O-β-galactopyranoside, delphinidin-3-O-β-(6-trans-p-coumaroyl)galactopyranoside, and delphinidin-3-O-β. -(6-cis-p-coumaroyl)galactopyranoside, delphinidin-3-O-β-glucopyranoside, delphinidin-3-O-β-(6-trans-p-coumaroyl)glucopyranoside, and the like. Examples of cyanidin-based anthocyanins include cyanidin-3-O-β-galactopyranoside, cyanidin-3-O-β-glucopyranoside, and cyanidin-3-O-β-(6-trans-p-coumaroyl)galactopyranoside. and cyanidin-3-O-β-(6-trans-p-coumaroyl) glucopyranoside.
本発明においては、特にデルフィニジン－３－Ｏ－β－ガラクトピラノシド、シアニジン－３－Ｏ―β―ガラクトピラノシド、デルフィニジン－３－Ｏ－β－グルコピラノシド、シアニジン－３－Ｏ－β－グルコピラノシド、デルフィニジン－３－Ｏ－β－（６－トランス－ｐ－クマロイル）ガラクトピラノシド、デルフィニジン－３－Ｏ－β―（６－シス－ｐ－クマロイル）ガラクトピラノシド等、が好ましい。ペラルゴニジン系アントシアニンとしては、ペタニン、ペチュニジン系アントシアニンとしては、ペラニンが好ましい。 In the present invention, delphinidin-3-O-β-galactopyranoside, cyanidin-3-O-β-galactopyranoside, delphinidin-3-O-β-glucopyranoside, cyanidin-3-O-β- Glucopyranoside, delphinidin-3-O-β-(6-trans-p-coumaroyl)galactopyranoside, delphinidin-3-O-β-(6-cis-p-coumaroyl)galactopyranoside, and the like are preferred. As the pelargonidin-based anthocyanin, petanin is preferred, and as the petunidin-based anthocyanin, peranin is preferred.
デルフィニジン、シアニジン系アントシアニンを多く含有する食用植物としては、例えばカシス、ブルーベリー、ビルベリー、ラズベリー、クランベリー、カシス、アサイー等のベリー類、ハスカップ、ブドウ、ザクロ、ナス、桑の実、黒豆その他の赤紫色又は青紫色の野菜又は果物、及び品種名「茶中間母本農６号」（品種登録第16016号）、品種名「サンルージュ」（品種登録第21262号）等の茶(Camellia sinensis, Camellia taliensis)を挙げることができ、好ましくは品種名「サンルージュ」又はその系統品種の茶である。また、ペチュニジン系アントシアニンであるペタニンやペラルゴニジン系アントシアニンであるペラニンを多く含有する食用植物としては、品種名「インカパープル」（品種登録第8550号）、「キタムラサキ」（品種登録第14041号）、品種名「シャドークイーン」（品種登録第17574号）、品種名「インカレッド」（品種登録第8551号）、品種名「ノーザンルビー」（品種登録第17447号）等のバレイショ(Solanum tuberosum L.）を挙げることができ、好ましくは品種名「シャドークイーン」、品種名「ノーザンルビー」又はそれらの系統品種のバレイショである。 Edible plants that contain large amounts of delphinidin and cyanidin-based anthocyanins include berries such as blackcurrants, blueberries, bilberries, raspberries, cranberries, blackcurrants, acai, haskap, grapes, pomegranates, eggplants, mulberries, black beans, and other reddish-purple plants. or bluish-purple vegetables or fruits, and teas (Camellia sinensis, Camellia taliensis), such as the cultivar name ``Tea Middle Mother Honno 6'' (variety registration No. 16016) and the variety name ``Sun Rouge'' (variety registration No. 21262). ), and tea with the cultivar name "Sun Rouge" or its lineage cultivars is preferable. In addition, edible plants containing a large amount of petanidin-based anthocyanin and peranin, a pelargonidin-based anthocyanin, include variety names such as "Inca Purple" (variety registration No. 8550), "Kitamurasaki" (variety registration No. 14041), Potatoes (Solanum tuberosum L.) such as variety name "Shadow Queen" (variety registration No. 17574), variety name "Inca Red" (variety registration No. 8551), variety name "Northern Ruby" (variety registration No. 17447), etc. Preferred are potatoes with the variety name "Shadow Queen", variety name "Northern Ruby", or their lineage varieties.
フラボノールは、様々な野菜や果実に含まれる3-ヒドロキシフラボン骨格を有するフラボノイドの一種で、フェノール性OHの位置により多数の物質が存在する。本発明において好ましいフラボノールは、ミリセチン（IUPAC;3,3',4',5',5,7-hexahydroxy-2-phenylchromen-4-one）、ケンフェロール（3,4',5,7-tetrahydroxy-2-phenylchromen-4-one）、ケルセチン（3,3',4',5,7-pentahydroxy-2-phenylchromen-4-one）であり、これらのフラボノールを多く含む食用植物として、例えば、茶、クルミ、ブロッコリー、キャベツ、ケール、タマネギ、豆類、ブドウ、ベリー、トマト、イチゴ、リンゴ、柑橘類、ソバ等を挙げることができ、好ましくは茶、特に品種名「サンルージュ」（品種登録第21262号）又はその系統品種の茶である。 Flavonol is a type of flavonoid with a 3-hydroxyflavone skeleton found in various vegetables and fruits, and there are many substances depending on the position of the phenolic OH. Preferred flavonols in the present invention include myricetin (IUPAC; 3,3',4',5',5,7-hexahydroxy-2-phenylchromen-4-one), kaempferol (3,4',5,7-tetrahydroxy -2-phenylchromen-4-one) and quercetin (3,3',4',5,7-pentahydroxy-2-phenylchromen-4-one). , walnuts, broccoli, cabbage, kale, onions, beans, grapes, berries, tomatoes, strawberries, apples, citrus fruits, buckwheat, etc., preferably tea, especially variety name "Sun Rouge" (variety registration No. 21262) ) or its lineage varieties of tea.
本発明における系統品種とは、当該品種の親品種、並びに当該品種及びその親品種から生じる後代の育種系統や品種を意味する。例えば、サンルージュは茶中間母本農６号の交雑により育種された品種であることから、茶中間母本農６号はサンルージュの系統品種であり、またシャドークイーンはキタムラサキの交雑により育種された品種であることから、キタムラサキはシャドークイーンの系統品種である。 The pedigree cultivar in the present invention refers to the parent cultivar of the cultivar, and the breeding lines and cultivars of progeny generated from the cultivar and the parent cultivar. For example, Sunrouge is a cultivar bred by crossing Chachu Chumamoto No. 6, so Chachu Chubamoto No. 6 is a lineage variety of Sunrouge, and Shadow Queen is bred by crossing Kitamurasaki. Kitamurasaki is a pedigree variety of Shadow Queen.
β-カロテン含有食品、ルチン含有食品、アントシアニン含有食品及びフラボノール含有食品は、それぞれβ-カロテン、ルチン、アントシアニン、フラボノールを多く含有する食用の生物（動物、植物、菌類等）又はその加工物をいい、好ましくは先に挙げた各成分を多く含有する食用植物の中からそれぞれ一種又は二種以上を適宜選択して使用することができる。β-カロテン含有食品、ルチン含有食品、アントシアニン含有食品及びフラボノール含有食品は、本発明の組成物が動物又は植物等の生物そのものとならないかぎり、その形態及び形状を限定することなく本発明の組成物において使用することができる。 β-carotene-containing foods, rutin-containing foods, anthocyanin-containing foods, and flavonol-containing foods refer to edible organisms (animals, plants, fungi, etc.) or processed products thereof that contain large amounts of β-carotene, rutin, anthocyanins, and flavonols, respectively. Preferably, one or more kinds of edible plants containing a large amount of each of the above-mentioned components can be appropriately selected and used. β-carotene-containing foods, rutin-containing foods, anthocyanin-containing foods, and flavonol-containing foods can be used as the compositions of the present invention without any limitations on their form or form, as long as the compositions of the present invention do not consist of living organisms such as animals or plants. It can be used in
上述のように、β-カロテン含有食品、ルチン含有食品、アントシアニン含有食品及びフラボノール含有食品はいずれも各成分を多く含有する食品として間葉系幹細胞増殖促進作用及び認知機能改善作用を示すことから、各食品に多く含まれるβ-カロテン、ルチン、アントシアニン及びフラボノールが前記作用に関与していると考えられる。このように、本発明は、β-カロテン、ルチン、アントシアニン及びフラボノールよりなる群から選択される１又は２以上の物質を有効成分とする間葉系幹細胞増殖促進用組成物又は認知機能改善用組成物も提供する。これらの組成物において、β-カロテン、ルチン、アントシアニン及びフラボノールは、いずれもそれらを含有する植物その他の生物材料から、当業者に知られた方法によって精製又は部分精製して使用することができる。 As mentioned above, β-carotene-containing foods, rutin-containing foods, anthocyanin-containing foods, and flavonol-containing foods all have a mesenchymal stem cell proliferation-promoting effect and a cognitive function-improving effect as foods containing a large amount of each component. β-carotene, rutin, anthocyanin, and flavonol, which are abundantly contained in each food, are thought to be involved in the above-mentioned effects. Thus, the present invention provides a composition for promoting mesenchymal stem cell proliferation or a composition for improving cognitive function, which contains one or more substances selected from the group consisting of β-carotene, rutin, anthocyanin, and flavonol as an active ingredient. We also provide things. In these compositions, β-carotene, rutin, anthocyanin, and flavonol can be used after being purified or partially purified from plants and other biological materials containing them by methods known to those skilled in the art.
本発明の間葉系幹細胞増殖促進用組成物及び認知機能改善用組成物は、飲食品、医薬品又は医薬部外品として提供することができ、したがって飲食品組成物、医薬組成物又は医薬部外品組成物と表すこともできる。また、本発明の組成物は、経口又は経腸摂取用の組成物であってもよい。本発明の組成物の形態に制限はなく、例えば搾汁（ジュース）、ペースト、乾燥粉末、エキス等の形態であり得る。また、本発明の組成物は製剤化されていてもよく、好ましくは錠剤、カプセル剤、散剤、顆粒剤、細粒剤、丸剤、懸濁剤、乳剤、液剤、シロップ剤等の経口剤の形態であり得る。本発明の間葉系幹細胞増殖促進用組成物及び認知機能改善用組成物は、その態様に応じて、それぞれ間葉系幹細胞増殖促進剤及び認知機能改善剤と表すこともできる。 The composition for promoting mesenchymal stem cell proliferation and the composition for improving cognitive function of the present invention can be provided as a food/beverage product, a drug, or a quasi-drug. It can also be expressed as a product composition. Furthermore, the composition of the present invention may be a composition for oral or enteral ingestion. The form of the composition of the present invention is not limited, and may be in the form of, for example, juice, paste, dry powder, extract, or the like. Furthermore, the composition of the present invention may be formulated into a formulation, preferably an oral formulation such as a tablet, capsule, powder, granule, fine granule, pill, suspension, emulsion, liquid, or syrup. It can be a form. The composition for promoting mesenchymal stem cell proliferation and the composition for improving cognitive function of the present invention can also be referred to as a mesenchymal stem cell proliferation promoter and a cognitive function improving agent, respectively, depending on the aspect thereof.
本発明における飲食品組成物は、人の健康に危害を加えるおそれが少なく、通常の社会生活において経口摂取又は経管摂取可能なものであればよく、経口摂取若しくは経管栄養が可能な担体若しくは賦形剤、又は有効成分以外の飲食品を含有することができる。本発明において、飲食品組成物は、飲料（飲料の濃縮原液及び調整用粉末を含む）、調味料を含む一般的な加工食品、サプリメント、健康食品（機能性飲食品）、保健機能食品（特定保健用食品、栄養機能食品、機能性表示食品）を幅広く含むものとして理解される。 The food and drink composition of the present invention may be one that has little risk of harming human health and can be taken orally or tubed in normal social life, and may be a carrier or tube that can be taken orally or tubed. It can contain excipients or foods and drinks other than the active ingredient. In the present invention, the food and drink compositions include beverages (including concentrated beverage concentrates and powders for preparation), general processed foods including seasonings, supplements, health foods (functional foods and drinks), and foods with health claims (specific It is understood to include a wide range of foods (health foods, nutritionally functional foods, and foods with functional claims).
本発明において特に好ましい飲食品組成物は、間葉系幹細胞増殖促進作用、認知機能改善作用又はそれらから科学的に導かれる好ましい作用が表示される保健機能食品（特定保健用食品、機能性表示食品、栄養機能食品）である。 Particularly preferred food and drink compositions in the present invention are foods with health claims (foods for specified health uses, foods with functional claims) that are labeled as having a mesenchymal stem cell proliferation promoting effect, a cognitive function improving effect, or a desirable effect scientifically derived therefrom. , nutritional functional food).
飲食品組成物は、例えば、デキストリン、デンプン等の糖類；ゼラチン、大豆タンパク、トウモロコシタンパク等のタンパク質；アラニン、グルタミン、イソロイシン等のアミノ酸類；セルロース、アラビアゴム等の多糖類；大豆油、中鎖脂肪酸トリグリセリド等の油脂類などの任意の助剤を添加して任意の形状の飲食品組成物として製造することができる。 Food and beverage compositions include, for example, saccharides such as dextrin and starch; proteins such as gelatin, soybean protein, and corn protein; amino acids such as alanine, glutamine, and isoleucine; polysaccharides such as cellulose and gum arabic; soybean oil, medium-chain By adding arbitrary auxiliary agents such as fats and oils such as fatty acid triglycerides, food and drink compositions of arbitrary shapes can be produced.
本発明における医薬組成物及び医薬部外品組成物は、薬学的に許容される担体若しくは添加剤、又は有効成分以外の生理活性物質を含有することができる。薬学的に許容される担体若しくは添加剤は当業者に周知であり、当業者が通常の実施能力の範囲内で、例えば第十七改訂日本薬局方その他の規格書に記載された成分から製剤の形態に応じて適宜選択して使用することができる。また、医薬組成物及び医薬部外品組成物の投与方法は特に限定されず、製剤の形態に応じて適宜決定される。 The pharmaceutical composition and quasi-drug composition of the present invention can contain a pharmaceutically acceptable carrier or additive, or a physiologically active substance other than the active ingredient. Pharmaceutically acceptable carriers or excipients are well known to those skilled in the art and can be used within the ordinary skill of those skilled in the art to prepare formulations from, for example, the ingredients listed in the Japanese Pharmacopoeia, 17th Edition and other specifications. It can be appropriately selected and used depending on the form. Furthermore, the method of administering the pharmaceutical composition and quasi-drug composition is not particularly limited, and is appropriately determined depending on the form of the preparation.
医薬組成物及び医薬部外品組成物における本発明の有効成分以外の生理活性物質としては、好ましくは、認知症その他の神経変性疾患の治療薬、例えばアセチルコリンエステラーゼ阻害作用を示すドネペジルやガランタミン等を挙げることができる。 The physiologically active substance other than the active ingredient of the present invention in the pharmaceutical composition and quasi-drug composition is preferably a therapeutic agent for dementia or other neurodegenerative diseases, such as donepezil or galantamine, which exhibits an acetylcholinesterase inhibitory effect. can be mentioned.
本発明の組成物における各有効成分の含有量及び対象への投与量又は摂取量は、組成物の種類、用法、対象の年齢、投与経路その他の条件などに応じて、体重60kgの成人への1日当たりの投与量又は摂取量が、β-カロテン換算で1mg～100mg、ルチン換算で50mg～1000mg、アントシアニン換算で1mg～500mg、フラボノール換算で2mg～500mgでの範囲内となるように適宜調節すればよい。これらの量は、1日に1回若しくは複数回に分けて、又は間歇的に投与する又は摂取させることができる。 The content of each active ingredient in the composition of the present invention and the amount administered or ingested to a subject will vary depending on the type of composition, usage, age of the subject, route of administration, and other conditions. The daily dose or intake should be adjusted as appropriate so that it is within the range of 1mg to 100mg in terms of β-carotene, 50mg to 1000mg in terms of rutin, 1mg to 500mg in terms of anthocyanin, and 2mg to 500mg in terms of flavonol. Bye. These amounts can be administered or ingested once a day, in divided doses, or intermittently.
以下の実施例によって本発明をさらに詳細に説明するが、本発明はこれらの例に限定されるものではない。 The present invention will be explained in more detail with reference to the following examples, but the present invention is not limited to these examples.
実施例１－１．間葉系幹細胞増殖促進作用の評価
ニンジンジュース（商品名「完全生搾りジュース」（ニンジン１００％のストレートジュース）、伊橋産業株式会社、品種名 向陽二号）、三ヶ日産温州みかん６倍濃縮ジュース、緑茶（品種名サンルージュ）、ダッタンソバ（品種名 満天きらり）及びバレイショ（品種名 シャドークイーン）を用意し、それらの乾燥粉末又は蒸熱粉砕物をそれぞれ10%配合したラット用ペレット餌（HOKUDO社AIN-76Aベース）を製造した。各餌の成分分析の結果を表１に示す。
SDラット（雄、33週齢）を、コントロール群、ニンジンジュース摂取群、サンルージュ摂取群、ダッタンソバ摂取群、温州みかん摂取群及びシャドークイーン摂取群（n＝10／群）に分け、上で調製した各ペレット餌を自由摂取させて10週間飼育した。コントロール群には、いずれの農産物も含まない標準ペレット餌を摂取させた。各群におけるペレット餌の摂取量から算出されるヒト60kg体重換算の1日当たりの推定機能性成分の摂取量は、ニンジンのβ-カロテン：7mg、サンルージュのアントシアニン：12mg、サンルージュのフラボノール：40 mg、ダッタンソバのルチン：150mg、シャドークイーンのアントシアニン：50mgであった。 SD rats (male, 33 weeks old) were divided into a control group, a carrot juice intake group, a Sun Rouge intake group, a Dattan buckwheat intake group, a Satsuma mandarin orange intake group, and a Shadow Queen intake group (n = 10/group), and the above preparation was performed. The animals were reared for 10 weeks with ad libitum access to each pelleted diet. The control group received a standard pelleted diet that did not contain any agricultural products. The estimated daily intake of functional components calculated from the pellet feed intake in each group based on a 60 kg human body weight is: carrot β-carotene: 7 mg, Sun Rouge anthocyanin: 12 mg, Sun Rouge flavonol: 40 mg, rutin from Dattan buckwheat: 150 mg, and anthocyanin from Shadow Queen: 50 mg.
飼育終了後、各群のラットから骨髄（大腿骨2本、頸骨2本）及び末梢血を採取し、既報（Kim S. et al., Brain Res. 2006; 1123, 27-33. Ukai R et al., J. Neurotrauma. 2007; 24: 508-520.）の方法に従い、ダルベッコの改変イーグル培地（DMEM）で25mLに希釈し、加熱不活化した10％FBS（末梢血は30％FBS）、2mL L-グルタミン、100U/mLペニシリン、0.1mg/mLストレプトマイシンを添加し、5％CO2雰囲気下37℃で10日間インキュベートした後、細胞数をカウントした。 After the breeding, bone marrow (2 femurs, 2 tibias) and peripheral blood were collected from the rats in each group, as previously reported (Kim S. et al., Brain Res. 2006; 1123, 27-33. Ukai R et al. al., J. Neurotrauma. 2007; 24: 508-520.) diluted to 25 mL with Dulbecco's modified Eagle's medium (DMEM) and heat-inactivated 10% FBS (30% FBS for peripheral blood); After adding 2 mL L-glutamine, 100 U/mL penicillin, 0.1 mg/mL streptomycin and incubating for 10 days at 37 °C in a 5% CO atmosphere, the number of cells was counted.
結果を図１に示す。コントロール群と比較して、ニンジンジュース摂取群、サンルージュ摂取群、ダッタンソバ摂取群及びシャドークイーン摂取群において、ラット体内の骨髄間葉系幹細胞数及び末梢血間葉系幹細胞数がいずれも増加していることが確認された。 The results are shown in Figure 1. Compared to the control group, the number of bone marrow mesenchymal stem cells and peripheral blood mesenchymal stem cells in the rat body increased in the carrot juice intake group, Sun Rouge intake group, Duttan Soba intake group, and Shadow Queen intake group. It was confirmed that there is.
実施例１－２．間葉系幹細胞増殖促進作用の評価
実施例１－１で用意した農産物に加えて、緑茶（品種名べにふうき）及びバレイショ（品種名 いんかのめざめ、ノーザンルビー）を用意し、それらの蒸熱粉砕物をそれぞれ10%配合したラット用ペレット餌（HOKUDO社AIN-76Aベース）を製造した。。
Example 1-2. Evaluation of Mesenchymal Stem Cell Proliferation Effect In addition to the agricultural products prepared in Example 1-1, green tea (variety name: Benifuuki) and potatoes (variety name: Inka no Mezame, Northern Ruby) were prepared, and their steamed and ground products were Pellet food for rats (based on HOKUDO's AIN-76A) containing 10% of each was produced. .
SDラット（雄、33週齢）を、10群（n＝10／群）に分け、8群に上で又は実施例１－１で調製した8種のペレット餌のいずれかを自由摂取させて10週間飼育した。残りの2群には標準ペレット餌を摂取させ、1群にβ-カロテンを0.1μg/0.5ml を連日腹腔内に注射で投与し（協和発酵バイオ株式会社：デュナリエラカロチン製剤水溶性バイオカロチン02（デュナリエラ由来β-カロチン2%含有乳化液を、生食で薄めたもの。）、1群はコントロール群とした。 SD rats (male, 33 weeks old) were divided into 10 groups (n = 10/group), and 8 groups were given ad libitum access to either of the 8 types of pelleted food prepared above or in Example 1-1. The animals were kept for 10 weeks. The remaining two groups were fed a standard pelleted diet, and one group was given daily intraperitoneal injections of 0.1 μg/0.5 ml of β-carotene (Kyowa Hakko Bio Co., Ltd.: Dunaliella Carotene Preparation Water-Soluble Bio-Carotene 02). (An emulsion containing 2% β-carotene derived from Dunaliella was diluted with saline.) Group 1 was a control group.
飼育終了後、実施例１－１と同様にして、各群のラットの骨髄間葉系幹細胞の数をカウントした。結果を図２に示す。コントロール群と比較して、β-カロテン投与群、ニンジンジュース摂取群、サンルージュ摂取群、ノーザンルビー摂取群、シャドークイーン摂取群及びダッタンソバ摂取群において、ラット体内の骨髄間葉系幹細胞数が増加していることが確認された。 After the breeding was completed, the number of bone marrow mesenchymal stem cells of rats in each group was counted in the same manner as in Example 1-1. The results are shown in Figure 2. Compared to the control group, the number of bone marrow mesenchymal stem cells in the rat body increased in the β-carotene administration group, carrot juice intake group, Sun Rouge intake group, Northern Ruby intake group, Shadow Queen intake group, and Duttan Buckwheat intake group. It was confirmed that
実施例２－１．認知機能改善作用の評価
（１）新奇物体認識試験
高血圧に加えて認知機能低下を呈するSHRラットを認知症モデル動物として用いた。SHRラット（雄、20週齢、三協ラボサービス（株）より購入）をコントロール群及びニンジンジュース摂取群（n＝7／群）に分け、コントロール群には標準ペレット餌を、ニンジンジュース摂取群には試験飼育開始から14日間（20週齢から22週齢まで）は標準ペレット餌を、その後（23週齢から）は水の代わりにニンジンジュース（商品名「とくべつなプレミアムにんじんジュース」（ニンジン100%のストレートジュース、品種名 あけみ五寸）、株式会社一粒万倍）を自由摂取させて５週間飼育した。
Example 2-1. Evaluation of cognitive function improvement effect (1) Novel object recognition test SHR rats, which exhibit cognitive decline in addition to hypertension, were used as dementia model animals. SHR rats (male, 20 weeks old, purchased from Sankyo Labo Service Co., Ltd.) were divided into a control group and a carrot juice intake group (n = 7/group).The control group received standard pellet food and the carrot juice intake group. For the first 14 days (from 20 to 22 weeks of age) from the start of test breeding, standard pellet food was fed, and after that (from 23 weeks of age), carrot juice (trade name: ``Tokubetsu Premium Carrot Juice'' (carrot) was used instead of water). The animals were reared for 5 weeks with free access to 100% straight juice (breed name: Akemi Gosun), Ichigrain Manbai Co., Ltd.).
両群のラットに対して、試験飼育開始時及び試験飼育期間中１週毎に新奇物体認識試験を行い、認知機能の変化を経時的に調べた。新奇物体認識試験の内容は次の通りである。まず、オープンフィールドに全く同一の物体（プラスチック玩具；縦2cm、横3cm、高さ5cm程度）を2つ入れ、ラットに10分間自由に探索させた。24時間後、同様に10分間自由探索させてラットを訓化させ、4時間後にオープンフィールド内の物体のうち1つを新奇物体に変更し、本試験として5分間自由に探索させた。2つの物体の総探索時間に対する新奇物体の探索時間の割合（新奇/新奇+既存物体探索時間）を求め、50%以上を正常な認知機能とした。物体の位置は訓化試験、本試験共に全く同じ位置に設置した。 A novel object recognition test was performed on both groups of rats at the start of the test breeding and every week during the test breeding period, and changes in cognitive function were examined over time. The contents of the novel object recognition test are as follows. First, two identical objects (plastic toys; approximately 2 cm long, 3 cm wide, and 5 cm high) were placed in an open field, and rats were allowed to freely explore them for 10 minutes. After 24 hours, the rats were similarly trained by freely exploring for 10 minutes, and after 4 hours, one of the objects in the open field was changed to a novel object, and the rats were allowed to freely explore for 5 minutes as the main test. The ratio of the search time for the novel object to the total search time for the two objects (novel/novel + existing object search time) was calculated, and 50% or more was considered normal cognitive function. The object was placed in exactly the same position for both the training test and the main test.
（２）モリス水迷路試験
（１）と同様に水又はニンジンジュースで５週間飼育した認知症モデルラットに対してモリス水迷路試験を５日間行い、認知機能の変化を調べた。モリス水迷路試験は、円形のプールに水をはり、ラットが避難できる足場を水面下1cm程度の場所に作り、ラットが避難場所に到達するまでの時間を測定することで行った。初日のみ60秒間自由に探索させ、2日目から到達時間を記録した。
(2) Morris water maze test The Morris water maze test was performed for 5 days on dementia model rats that had been fed water or carrot juice for 5 weeks in the same manner as in (1) to examine changes in cognitive function. The Morris water maze test was performed by filling a circular pool with water, creating a platform approximately 1 cm below the water surface for the rat to take shelter in, and measuring the time it took for the rat to reach the shelter. On the first day, the subjects were allowed to explore freely for 60 seconds, and from the second day onwards, the arrival time was recorded.
結果を図３に示す。図中の上のグラフの縦軸は総探索時間に占める新奇物体に対する探索時間の割合（％）を、横軸は試験飼育開始後の飼育時間（週）を表す。また下のグラフの縦軸は遊泳時間（秒）を、横軸はモリス水迷路試験開始後の学習時間（日）を表す。いずれの試験においても、コントロール群における認知機能低下の進行と比較して、ニンジンジュース摂取群において、認知機能の改善が確認された。 The results are shown in Figure 3. The vertical axis of the upper graph in the figure represents the proportion (%) of exploration time for novel objects in the total exploration time, and the horizontal axis represents the rearing time (weeks) after the start of test rearing. The vertical axis of the graph below represents swimming time (seconds), and the horizontal axis represents learning time (days) after the start of the Morris water maze test. In both studies, improvement in cognitive function was confirmed in the carrot juice intake group compared to progression of cognitive function decline in the control group.
（３）間葉系幹細胞数の測定
（１）と同様に標準ペレット餌又はニンジンジュース配合ペレット餌で５週間飼育した認知症モデルラットを用いて、実施例１－１に記載された方法に従って骨髄間葉系幹細胞数及び末梢血間葉系幹細胞数を測定した。結果を図４に示す。コントロール群と比較して、ニンジンジュース摂取群において、ラット体内の骨髄間葉系幹細胞数及び末梢血間葉系幹細胞数がいずれも増加していることが確認された。
(3) Measurement of the number of mesenchymal stem cells Using dementia model rats that had been fed standard pellet food or carrot juice-containing pellet food for 5 weeks in the same manner as in (1), bone marrow was measured according to the method described in Example 1-1. The number of mesenchymal stem cells and peripheral blood mesenchymal stem cells were measured. The results are shown in Figure 4. It was confirmed that both the number of bone marrow mesenchymal stem cells in the rat body and the number of peripheral blood mesenchymal stem cells increased in the carrot juice intake group compared to the control group.
実施例２－２．認知機能改善作用の評価
認知症モデルラットであるSHRラット（雄、20週齢、三協ラボサービス（株）より購入）をコントロール群、ニンジンジュース摂取群、サンルージュ摂取群、ダッタンソバ摂取群及びシャドークイーン摂取群（n＝7／群）に分け、コントロール群には標準ペレット餌を自由摂取させて５週間飼育した。残りの群には試験飼育開始から14日間（20週齢から22週齢まで）は標準ペレット餌を、その後（23週齢から）は実施例１－１又は１－２で製造したニンジンジュース配合ペレット餌、サンルージュ配合ペレット餌、ダッタンソバ配合ペレット餌又はシャドークイーン配合ペレット餌を自由摂取させて５週間飼育した。その後、各群のラットに対して、実施例２－１と同様にして新奇物体認識試験を行った。
Example 2-2. Evaluation of cognitive function improvement effect Dementia model rats, SHR rats (male, 20 weeks old, purchased from Sankyo Labo Service Co., Ltd.) were used as a control group, a carrot juice intake group, a Sun Rouge intake group, a Duttan buckwheat intake group, and a shadow intake group. The animals were divided into queen feeding groups (n=7/group), and the control group was reared for 5 weeks with standard pelleted food available ad libitum. The remaining groups received standard pelleted food for 14 days from the start of test rearing (from 20 weeks of age to 22 weeks of age), and after that (from 23 weeks of age), they received the carrot juice mixture prepared in Example 1-1 or 1-2. The animals were reared for 5 weeks with ad libitum access to pelleted food, pelleted food containing Sunrouge, pelleted food containing Duttan buckwheat, or pelleted food containing Shadow Queen. Thereafter, a novel object recognition test was performed on each group of rats in the same manner as in Example 2-1.
また、上記と同じ条件で飼育した認知症モデルラットを用いて、実施例２－１と同様にしてモリス水迷路試験を行った。 In addition, a Morris water maze test was conducted in the same manner as in Example 2-1 using dementia model rats raised under the same conditions as above.
両試験の結果を図５に示す。モリス水迷路試験の結果は、学習開始後５日目のものである。ニンジンジュース摂取群、サンルージュ摂取群、ダッタンソバ摂取群及びシャドークイーン摂取群のいずれにおいても、コントロール群と比較した認知機能の改善が確認された。 The results of both tests are shown in Figure 5. The results of the Morris water maze test are from the fifth day after the start of learning. Improvement in cognitive function was confirmed in all of the carrot juice intake group, Sun Rouge intake group, Duttan Soba intake group, and Shadow Queen intake group compared to the control group.
さらに、上記と同じ条件で飼育した認知症モデルラットを用いて、実施例１－１に記載された方法に従って骨髄間葉系幹細胞数及び末梢血間葉系幹細胞数を測定した。結果を図６に示す。ニンジンジュース摂取群、サンルージュ摂取群、ダッタンソバ摂取群及びシャドークイーン摂取群のいずれにおいても、コントロール群と比較して骨髄間葉系幹細胞数及び末梢血間葉系幹細胞数が増加していることが確認された。 Furthermore, using dementia model rats raised under the same conditions as above, the number of bone marrow mesenchymal stem cells and peripheral blood mesenchymal stem cells were measured according to the method described in Example 1-1. The results are shown in FIG. The number of bone marrow mesenchymal stem cells and peripheral blood mesenchymal stem cells increased in the carrot juice intake group, Sun Rouge intake group, Duttan Soba intake group, and Shadow Queen intake group compared to the control group. confirmed.
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