WO2024043114A1 - COMPOSITION FOR EXPRESSING INTEGRIN α5 COMPRISING SHELL GINGER LEAF EXTRACT - Google Patents

COMPOSITION FOR EXPRESSING INTEGRIN α5 COMPRISING SHELL GINGER LEAF EXTRACT Download PDF

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Publication number
WO2024043114A1
WO2024043114A1 PCT/JP2023/029212 JP2023029212W WO2024043114A1 WO 2024043114 A1 WO2024043114 A1 WO 2024043114A1 JP 2023029212 W JP2023029212 W JP 2023029212W WO 2024043114 A1 WO2024043114 A1 WO 2024043114A1
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composition
integrin
leaf extract
expression
present
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PCT/JP2023/029212
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French (fr)
Japanese (ja)
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菜緒 染井
健太朗 加治屋
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株式会社 資生堂
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9062—Alpinia, e.g. red ginger or galangal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9794—Liliopsida [monocotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines

Definitions

  • the present invention relates to a composition
  • a composition comprising a moongweed leaf extract for expressing integrin ⁇ 5.
  • Capillaries are thin blood vessels that connect arteries and veins, and serve to supply blood to the cells that make up living organisms. Blood supplied by capillaries allows oxygen and nutrients to be delivered to cells and carbon dioxide and waste products to be collected. It is known that capillaries decrease with age, and the decrease in capillaries affects the aging of various organs. For example, when capillaries decrease, glandular cell activity decreases and mucus secretion decreases. Glandular cells are present in areas such as the skin, eyes, nose, mouth, throat, stomach, intestines, bladder, uterus, vagina, and anus.
  • mucus secretion decreases, resulting in symptoms such as dry eyes, congestion, rhinitis, stomatitis, gingivitis, heavy stomach, gastritis, diarrhea, constipation, cystitis, and vagina depending on the area. It can cause various diseases such as inflammation.
  • the skin is affected by the state of capillaries, and as the number of capillaries decreases, the metabolism of epidermal cells decreases, resulting in less turnover and a decrease in the activity of dermal fibroblasts. This can lead to a decrease in elastic fibers, leading to cosmetic problems such as spots, wrinkles, sagging, and dullness in the skin.
  • deterioration in blood flow due to a decrease in capillary blood vessels affects hair matrix cells, which can lead to hair problems such as dry hair, dandruff, hair loss, and gray hair.
  • capillaries are composed only of the intima.
  • the intima of capillaries is composed of vascular endothelial cells and the basement membrane lining the vascular endothelial cells.
  • Arteries in the skin ascend from the subcutaneous tissue to the dermis, forming a subcutaneous vascular plexus that spreads planarly and in a mesh pattern in the dermal layer.
  • Capillaries branching from the subcutaneous vascular plexus further ascend to form the subpapillary vascular plexus, which spreads out in a planar and mesh-like manner in the subpapillary layer.
  • Capillaries branching from the subpapillary vascular plexus further ascend to form capillary loops in the papillary dermis layer, which is just below the epidermal basement membrane, which is the boundary with the epidermis, and the epidermal cells present in the epidermal basement layer. It can deliver oxygen and nutrients to.
  • Non-Patent Document 1 It is known that vascular endothelial cells, for example, interact with the extracellular matrix via the basement membrane due to the action of integrins expressed in the cell membrane of endothelial cells (Non-Patent Document 1). Furthermore, adhesion molecules such as integrins are also expressed in fibroblasts, and it is known that fibroblasts also interact with the extracellular matrix (Non-Patent Document 2).
  • the present invention provides a composition for promoting expression of integrin ⁇ 5.
  • the present inventors have discovered that moontooth leaf extract promotes the expression of integrin ⁇ 5.
  • the present invention is based on these findings.
  • composition for promoting expression of integrin ⁇ 5 is provided.
  • FIG. 1 shows the results of evaluation of the influence of moongweed leaf extract on the expression level of integrin ⁇ 5 gene in vascular endothelial cells.
  • a composition for promoting the expression of integrin ⁇ 5 is provided, and the composition comprises a moongweed leaf extract.
  • the present invention also provides a method for promoting the expression of integrin ⁇ 5, which comprises administering a therapeutically effective amount of mentis leaf extract to a subject in need thereof.
  • a moontooth leaf extract in the production of a drug aimed at promoting the expression of integrin ⁇ 5.
  • a composition comprising a moongweed leaf extract for promoting the expression of integrin ⁇ 5.
  • a moongweed leaf extract for promoting the expression of integrin ⁇ 5 is provided.
  • the composition for promoting the expression of integrin ⁇ 5 is not particularly limited, but may exhibit effects such as stabilizing, protecting, increasing, and improving the function of capillaries. Therefore, the composition of the present invention can also be used as a drug for stabilizing, protecting, increasing, or improving the function of capillaries.
  • These drugs are not particularly limited, but have skin beautifying effects (for example, maintaining firmness and elasticity of the skin, preventing sunburn and age spots, maintaining transparent skin, etc.) and osteoporosis improving effects.
  • Various effects can be expected, such as improving vascular dementia and neurite outgrowth (for example, see https://www.nature.com/articles/srep42111), and the neurite outgrowth effect can be used to treat Parkinson's disease. It is also expected to be used for prevention and nerve transplantation.
  • Such drugs may be used for therapeutic purposes carried out by doctors, etc., for cosmetic purposes, or as foods such as health functional foods.
  • integrin is a cell membrane protein that exists in the cell membrane, functions as a cell adhesion molecule, and interacts with the extracellular matrix and basement membrane. Integrins exist as heterodimers in which ⁇ and ⁇ chains associate, and at least 18 types of ⁇ subunits and 8 types of ⁇ subunits have been confirmed.
  • integrin ⁇ 5 is known to mainly associate with integrin ⁇ 1 to form integrin ⁇ 5 ⁇ 1.
  • Integrin ⁇ 5 ⁇ 1 is also called VLA-5, fibronectin receptor.
  • Integrin ⁇ 5 expressed in the cell membrane of vascular endothelial cells binds to fibronectin that constitutes the extracellular matrix (ECM).
  • the integrin ⁇ 5 of the present invention includes those having mutations such as deletions, substitutions, and insertions in part of the amino acid sequence within a range that does not impair its function.
  • a composition for promoting expression of integrin ⁇ 5 is provided.
  • Promotion of expression of integrin ⁇ 5 may be either promotion of expression of integrin ⁇ 5 gene, promotion of expression of integrin ⁇ 5 protein, or both.
  • the composition of the present invention may have the ability to promote expression of the integrin ⁇ 5 gene.
  • Such abilities include, but are not particularly limited to, the ability to promote the initiation of transcription of integrin ⁇ 5 gene mRNA, the ability to promote the expression of integrin ⁇ 5 gene mRNA, and the ability to promote the expression of integrin ⁇ 5 gene mRNA. Examples include the ability to inhibit degradation and the ability to promote translation of the mRNA into protein.
  • the composition of the present invention may have the ability to promote expression or function of integrin ⁇ 5 protein.
  • Such abilities include, but are not particularly limited to, the ability to promote extracellular secretion of integrin ⁇ 5 protein, the ability to promote signal transduction functions, and the like.
  • Alphaa zerumbet in the present invention refers to Alpinia zerumbet, which is a perennial evergreen herb belonging to the Zingiberaceae family and the genus Alpinia.
  • the part used as the raw material for extracting the moon peach leaf extract is the leaf part.
  • the moontooth leaf extract in the present invention is not particularly limited to, but includes, but is not limited to, an extract obtained by using moontooth leaf as an extraction raw material, a diluted or concentrated liquid of the extract, a dried product obtained by drying the extract, Alternatively, it may be either a crudely purified product or a purified product thereof.
  • the method for producing the moongeach leaf extract in the present invention is not particularly limited, and extraction can be performed according to a method commonly used in the technical field.
  • the extraction method is not particularly limited, but includes, for example, a hot water extraction method, an ultrasonic extraction method, a filtration method, a reflux extraction method, a solvent (for example, ethanol) extraction method, and the like. These methods may be performed alone, or two or more methods may be used in combination. Additionally, the extract may be further extracted one or more times in a similar manner to obtain a highly pure extract.
  • the type of extraction solvent used for producing the moongweed leaf extract in the present invention is not particularly limited, and any solvent known in the art may be used.
  • solvents include, but are not limited to, water, alcohols having 1 to 4 carbon atoms, ethyl acetate, acetone, chloroform, etc., and two or more of these may be used in combination. It's okay.
  • the Moon Peach leaf extract in the present invention is commercially available, it may be used as long as it can provide the desired effect of the present invention.
  • the amount of moongweed leaf extract contained in the composition of the present invention can be determined as appropriate depending on the intended use.
  • the cells on which the composition of the present invention acts in order to promote the expression of integrin ⁇ 5 are not particularly limited, but are preferably vascular endothelial cells.
  • vascular endothelial cells are cells that make up the inner lining of blood vessels. Arteries and veins are composed of three layers: intima, media, and adventitia, but capillaries are composed only of the intima, which is composed of vascular endothelial cells. In vascular endothelial cells, endothelial cells are adhered primarily by the action of a cell adhesion molecule called VE-cadherin, and the extracellular matrix and vascular endothelial cells are adhered by the action of integrins.
  • VE-cadherin cell adhesion molecule
  • the vascular endothelial cells in the present invention are not particularly limited, but include, for example, endothelial cells obtained from a living body, subcultured cells thereof, established cell lines, umbilical cord blood vein endothelial cells, and Examples include cells that have been passaged.
  • the vascular endothelial cells in the present invention are not particularly limited, but HUVEC or HMEC-1 may be used.
  • the vascular endothelial cells in the present invention may be cells derived from any animal or plant including fungi, and are preferably animal cells, preferably human cells, although not limited thereto.
  • the composition of the present invention may be either an oral composition or a topical composition, but is preferably a topical composition.
  • known components that are blended into topical compositions can be further blended.
  • Such ingredients include, but are not limited to, emulsifiers, hydrating agents, solvents, emollients, stabilizers, thickeners, preservatives, lubricants, chelating agents, fillers, and excipients. , powders, fragrances, perfumes, absorbents, dyes, opacifying agents, antioxidants, vitamins, amino acids, etc.
  • the topical composition of the present invention may be liquid, semi-solid, or solid, preferably, but not limited to, a solution, suspension, dispersion, emulsion, cream, ointment, or gel. , in the form of a lotion, foam, paste, or spray.
  • composition of the present invention is not particularly limited, it may be a pharmaceutical composition, a cosmetic composition, or a food composition, and is preferably a cosmetic composition.
  • the cosmetic composition in the present invention refers to a composition used for the purpose of applying makeup, and may be either an oral composition or a topical composition.
  • the food composition of the present invention may be a food with health claims such as a food with nutritional function claims, a food for specified health uses, a food with functional claims, etc. It may also be manufactured as a dietary therapy food, a nursing care food, etc.
  • Human umbilical vein endothelial cells (HUVEC) were placed in each well of a collagen-coated 6-well plate at 2 ⁇ 10 5 cells/mL in supplemented EBM2 medium (manufactured by Lonza). and incubated at 37° C. for 24 hours in a 5% CO 2 humidified atmosphere. After incubation, the medium was changed to EBM2 medium supplemented with 0.5% FBS and HUVECs were starved for 24 hours. Subsequently, 0.1% of Bulgaria leaf extract (Albanian leaf extract BG, manufactured by Maruzen Pharmaceutical Co., Ltd.) was added, and the mixture was treated for 24 hours.
  • EBM2 medium manufactured by Lonza
  • the measurement was performed using an integrin ⁇ 5 FAM-labeled TaqMan gene expression probe (Hs01547673_m1) together with Taqman RNA-to-CtTM 1-step Kit (manufactured by Thermo Fisher).
  • the PCR reaction conditions were reverse transcription at 48°C for 15 minutes, polymerase activation at 95°C for 10 minutes, and denaturation-annealing-extension at 95°C for 15 seconds and 60°C for 1 minute, repeated 40 times.
  • the gene expression level of integrin ⁇ 5 was standardized using FAM-labeled Gapdh TaqMan Probe (Hs02786624_g1). The obtained results were tested by an unpaired t-test (in the case of P ⁇ 0.05, it is indicated as *).

Abstract

Disclosed is a composition that promotes expression of integrin α5. The composition comprises shell ginger leaf extract.

Description

インテグリンα５を発現させるための、月桃葉エキスを含んでなる組成物A composition comprising a moontooth leaf extract for expressing integrin α5 関連出願の参照References to related applications
　本特許出願は、先に出願された日本国における特許出願である特願２０２２－１３２７３７号（出願日：２０２２年８月２３日）に基づく優先権の主張を伴うものである。この先の特許出願における全開示内容は、引用することにより本明細書の一部とされる。 This patent application is accompanied by a priority claim based on Japanese Patent Application No. 2022-132737 (filing date: August 23, 2022), which is a patent application filed earlier in Japan. The entire disclosure in this earlier patent application is incorporated herein by reference.
　本発明は、インテグリンα５を発現させるための、月桃葉エキスを含んでなる組成物に関する。 The present invention relates to a composition comprising a moongweed leaf extract for expressing integrin α5.
　毛細血管は、動脈と静脈とをつなぐ細い血管であり、生体を構成する細胞に血液を供給する役目を果たす。毛細血管から供給された血液により、細胞に酸素及び栄養素を届け、二酸化炭素及び老廃物を回収することができる。毛細血管は加齢に伴い減少することが知られており、毛細血管の減少は、様々な臓器の加齢に影響する。例えば、毛細血管が減少すると、腺細胞の活性が低下し粘液の分泌が低下する。腺細胞は、皮膚、目、鼻、口、のど、胃、腸、膀胱、子宮、膣、肛門などの部位に存在する。これらの部位における毛細血管が減少することで、粘液の分泌が低下し、部位に応じて、例えばドライアイ、充血、鼻炎、口内炎、歯肉炎、胃もたれ、胃炎、下痢、便秘、膀胱炎、膣炎など様々な疾患の原因になりうる。また、皮膚も毛細血管の状態に影響されることが知られており、毛細血管が減少することで、表皮細胞の新陳代謝が減少し、ターンオーバーが少なくなること、並びに真皮線維芽細胞の活性低下による弾性線維の減少などが生じ、皮膚におけるシミ、シワ、たるみ、くすみなどの美容上の問題を引き起こしうる。また、毛細血管の減少による血流の悪化により、毛母細胞への影響が及び、髪のパサつき、ふけ、抜け毛、白髪などの頭髪の問題も生じうる。 Capillaries are thin blood vessels that connect arteries and veins, and serve to supply blood to the cells that make up living organisms. Blood supplied by capillaries allows oxygen and nutrients to be delivered to cells and carbon dioxide and waste products to be collected. It is known that capillaries decrease with age, and the decrease in capillaries affects the aging of various organs. For example, when capillaries decrease, glandular cell activity decreases and mucus secretion decreases. Glandular cells are present in areas such as the skin, eyes, nose, mouth, throat, stomach, intestines, bladder, uterus, vagina, and anus. As the capillaries in these areas decrease, mucus secretion decreases, resulting in symptoms such as dry eyes, congestion, rhinitis, stomatitis, gingivitis, heavy stomach, gastritis, diarrhea, constipation, cystitis, and vagina depending on the area. It can cause various diseases such as inflammation. It is also known that the skin is affected by the state of capillaries, and as the number of capillaries decreases, the metabolism of epidermal cells decreases, resulting in less turnover and a decrease in the activity of dermal fibroblasts. This can lead to a decrease in elastic fibers, leading to cosmetic problems such as spots, wrinkles, sagging, and dullness in the skin. In addition, deterioration in blood flow due to a decrease in capillary blood vessels affects hair matrix cells, which can lead to hair problems such as dry hair, dandruff, hair loss, and gray hair.
　内膜、中膜、外膜といった三層から構成される動脈や静脈とは異なり、毛細血管は、内膜のみで構成される。毛細血管の内膜は、血管内皮細胞および血管内皮細胞を裏打ちする基底膜から構成される。皮膚における動脈は、皮下組織から真皮へと上行し、真皮層において平面的かつ網目状に広がる皮下血管叢を形成する。皮下血管叢から分岐した毛細血管はさらに上行し、乳頭下層でさらに平面的かつ網目状に広がる乳頭下血管叢を形成する。乳頭下血管叢から分岐した毛細血管はさらに上行して、表皮との境界である表皮基底膜の直下である真皮乳頭層において係蹄（ｃａｐｉｌｌａｒｙ　ｌｏｏｐ）を構成し、表皮基底層に存在する表皮細胞にまで酸素及び栄養素を届けることができる。 Unlike arteries and veins, which are composed of three layers: intima, media, and adventitia, capillaries are composed only of the intima. The intima of capillaries is composed of vascular endothelial cells and the basement membrane lining the vascular endothelial cells. Arteries in the skin ascend from the subcutaneous tissue to the dermis, forming a subcutaneous vascular plexus that spreads planarly and in a mesh pattern in the dermal layer. Capillaries branching from the subcutaneous vascular plexus further ascend to form the subpapillary vascular plexus, which spreads out in a planar and mesh-like manner in the subpapillary layer. Capillaries branching from the subpapillary vascular plexus further ascend to form capillary loops in the papillary dermis layer, which is just below the epidermal basement membrane, which is the boundary with the epidermis, and the epidermal cells present in the epidermal basement layer. It can deliver oxygen and nutrients to.
　血管内皮細胞においては、例えば、内皮細胞の細胞膜に発現するインテグリンの働きにより、基底膜を介して細胞外マトリクスと相互作用していることが知られている（非特許文献１）。また、インテグリンなどの接着分子は線維芽細胞においても発現しており、線維芽細胞も細胞外マトリクスと相互作用していることが知られている（非特許文献２）。 It is known that vascular endothelial cells, for example, interact with the extracellular matrix via the basement membrane due to the action of integrins expressed in the cell membrane of endothelial cells (Non-Patent Document 1). Furthermore, adhesion molecules such as integrins are also expressed in fibroblasts, and it is known that fibroblasts also interact with the extracellular matrix (Non-Patent Document 2).
　このインテグリンに関しては、トウキンセンカ、シベリアニンジン、及びニクジュヨウからなる群から選ばれる植物体のエキス、又は酵母エキスが、血管内皮細胞において、その発現を促進させることが知られている（特許文献１）。 Regarding this integrin, it is known that extracts of plants selected from the group consisting of Calendula, Siberian ginseng, and Cinnamon or yeast extract promote its expression in vascular endothelial cells (Patent Document 1) .
国際公開第２０１９／０９８３０２号公報International Publication No. 2019/098302
　本発明は、インテグリンα５の発現を促進させるための組成物を提供する。 The present invention provides a composition for promoting expression of integrin α5.
　本発明者らは、月桃葉エキスがインテグリンα５の発現を促進させることを見出した。本発明はこれらの知見に基づくものである。 The present inventors have discovered that moontooth leaf extract promotes the expression of integrin α5. The present invention is based on these findings.
　本発明によれば、以下の発明が提供される。
（１）インテグリンα５の発現を促進させるための組成物であって、月桃葉エキスを含んでなる、組成物。
（２）血管内皮細胞においてインテグリンα５の発現を促進させるための、（１）に記載の組成物。
（３）局所用組成物である、（１）または（２）に記載の組成物。
（４）溶液、懸濁液、分散液、エマルジョン、クリーム、軟膏、ゲル、ローション、フォーム、ペースト、またはスプレーの形態である、（３）に記載の組成物。
（５）化粧用組成物である、（１）～（４）のいずれかに記載の組成物。
（６）インテグリンα５の発現の促進を目的とする薬剤の製造のための、月桃葉エキスの使用。
（７）血管内皮細胞におけるインテグリンα５の発現の促進を目的とする薬剤の製造のための、（６）に記載の使用。
（８）月桃葉エキスを含んでなる組成物の、インテグリンα５の発現を促進するための使用。
（９）月桃葉エキスを含んでなる組成物の、血管内皮細胞においてインテグリンα５の発現を促進するための、（８）に記載の使用。
（１０）前記組成物が局所用組成物である、（８）または（９）に記載の使用。
（１１）前記組成物が溶液、懸濁液、分散液、エマルジョン、クリーム、軟膏、ゲル、ローション、フォーム、ペースト、またはスプレーの形態である、（１０）に記載の使用。
（１２）前記組成物が化粧用組成物である、（８）～（１１）のいずれかに記載の使用。
（１３）インテグリンα５の発現を促進するための、月桃葉エキス。
（１４）血管内皮細胞においてインテグリンα５の発現を促進するための、（１３）に記載の月桃葉エキス。 According to the present invention, the following inventions are provided.
(1) A composition for promoting the expression of integrin α5, which comprises a moongweed leaf extract.
(2) The composition according to (1) for promoting expression of integrin α5 in vascular endothelial cells.
(3) The composition according to (1) or (2), which is a topical composition.
(4) The composition according to (3), which is in the form of a solution, suspension, dispersion, emulsion, cream, ointment, gel, lotion, foam, paste, or spray.
(5) The composition according to any one of (1) to (4), which is a cosmetic composition.
(6) Use of moongweed leaf extract for the production of a drug aimed at promoting the expression of integrin α5.
(7) The use according to (6) for producing a drug aimed at promoting expression of integrin α5 in vascular endothelial cells.
(8) Use of a composition comprising a moontooth leaf extract for promoting the expression of integrin α5.
(9) The use according to (8) for promoting the expression of integrin α5 in vascular endothelial cells, of a composition comprising a moontooth leaf extract.
(10) The use according to (8) or (9), wherein the composition is a topical composition.
(11) The use according to (10), wherein the composition is in the form of a solution, suspension, dispersion, emulsion, cream, ointment, gel, lotion, foam, paste, or spray.
(12) The use according to any one of (8) to (11), wherein the composition is a cosmetic composition.
(13) Moon peach leaf extract for promoting the expression of integrin α5.
(14) The mentis leaf extract according to (13) for promoting expression of integrin α5 in vascular endothelial cells.
　本発明によれば、インテグリンα５の発現を促進させるための組成物が提供される。 According to the present invention, a composition for promoting expression of integrin α5 is provided.
図１は、月桃葉エキスが血管内皮細胞におけるインテグリンα５遺伝子発現量に与える影響を評価した結果を表す。FIG. 1 shows the results of evaluation of the influence of moongweed leaf extract on the expression level of integrin α5 gene in vascular endothelial cells.
発明の具体的説明Specific description of the invention
　本発明によれば、インテグリンα５の発現を促進させるための組成物が提供され、該組成物は、月桃葉エキスを含んでなる。また、本発明によれば、治療上有効な量の月桃葉エキスを、それを必要とする被験体に投与することを含んでなる、インテグリンα５の発現を促進させるための方法が提供される。さらに、本発明によれば、インテグリンα５の発現の促進を目的とする薬剤の製造における、月桃葉エキスの使用が提供される。さらに、本発明によれば、月桃葉エキスを含んでなる組成物の、インテグリンα５の発現を促進するための使用が提供される。さらに、本発明によれば、インテグリンα５の発現を促進するための、月桃葉エキスが提供される。 According to the present invention, a composition for promoting the expression of integrin α5 is provided, and the composition comprises a moongweed leaf extract. The present invention also provides a method for promoting the expression of integrin α5, which comprises administering a therapeutically effective amount of mentis leaf extract to a subject in need thereof. Further, according to the present invention, there is provided the use of a moontooth leaf extract in the production of a drug aimed at promoting the expression of integrin α5. Further, according to the present invention, there is provided the use of a composition comprising a moongweed leaf extract for promoting the expression of integrin α5. Furthermore, according to the present invention, a moongweed leaf extract for promoting the expression of integrin α5 is provided.
　本発明において、インテグリンα５の発現を促進させるための組成物は、特に限定されるわけではないが、毛細血管の安定化、保護、増加、機能向上等の作用を発揮してもよい。したがって、本発明の組成物は、毛細血管の安定化、保護、増加、または機能向上のための薬剤として用いることもできる。このような薬剤は、特に限定されるわけではないが、美肌効果（例えば、ハリや弾力性がある肌の維持、日焼け・シミの予防、透明感がある肌の維持等）や骨粗鬆症の改善効果、血管性認知症の改善効果、神経突起伸長（例えば、https://www.nature.com/articles/srep42111参照）等の様々な効果が期待でき、神経突起伸長効果を利用してパーキンソン病の予防や神経移植に用いることも期待される。このような薬剤は、医師等により行われる治療目的で用いてもよく、美容目的で用いてもよく、保健機能食品等の食品として用いてもよい。 In the present invention, the composition for promoting the expression of integrin α5 is not particularly limited, but may exhibit effects such as stabilizing, protecting, increasing, and improving the function of capillaries. Therefore, the composition of the present invention can also be used as a drug for stabilizing, protecting, increasing, or improving the function of capillaries. These drugs are not particularly limited, but have skin beautifying effects (for example, maintaining firmness and elasticity of the skin, preventing sunburn and age spots, maintaining transparent skin, etc.) and osteoporosis improving effects. Various effects can be expected, such as improving vascular dementia and neurite outgrowth (for example, see https://www.nature.com/articles/srep42111), and the neurite outgrowth effect can be used to treat Parkinson's disease. It is also expected to be used for prevention and nerve transplantation. Such drugs may be used for therapeutic purposes carried out by doctors, etc., for cosmetic purposes, or as foods such as health functional foods.
　一般に、インテグリンは、細胞膜に存在する細胞膜タンパク質であり、細胞接着分子として機能して、細胞外マトリックスや基底膜と相互作用する。インテグリンは、α鎖とβ鎖が会合するヘテロダイマーで存在し、αサブユニットとして少なくとも１８種類、βサブユニットとして８種類が確認されている。特に、インテグリンα５は、主にインテグリンβ１と会合し、インテグリンα５β１を形成することが知られている。インテグリンα５β１は、ＶＬＡ－５、フィブロネクチン受容体とも呼ばれる。血管内皮細胞の細胞膜に発現されたインテグリンα５は、細胞外マトリクス（ＥＣＭ）を構成するフィブロネクチンと結合する。なお、本発明におけるインテグリンα５には、その機能を損なわない範囲において、アミノ酸配列の一部に欠失、置換、挿入等の変異を有するものも含まれる。 In general, integrin is a cell membrane protein that exists in the cell membrane, functions as a cell adhesion molecule, and interacts with the extracellular matrix and basement membrane. Integrins exist as heterodimers in which α and β chains associate, and at least 18 types of α subunits and 8 types of β subunits have been confirmed. In particular, integrin α5 is known to mainly associate with integrin β1 to form integrin α5β1. Integrin α5β1 is also called VLA-5, fibronectin receptor. Integrin α5 expressed in the cell membrane of vascular endothelial cells binds to fibronectin that constitutes the extracellular matrix (ECM). Incidentally, the integrin α5 of the present invention includes those having mutations such as deletions, substitutions, and insertions in part of the amino acid sequence within a range that does not impair its function.
　本発明によれば、インテグリンα５の発現を促進させるための組成物が提供される。インテグリンα５の発現の促進は、インテグリンα５遺伝子の発現の促進、またはインテグリンα５タンパク質の発現の促進のいずれか、またはこの両方であってもよい。 According to the present invention, a composition for promoting expression of integrin α5 is provided. Promotion of expression of integrin α5 may be either promotion of expression of integrin α5 gene, promotion of expression of integrin α5 protein, or both.
　本発明の一つの実施態様によれば、本発明の組成物は、インテグリンα５遺伝子の発現を促進する能力を有していてもよい。このような能力としては、特に限定されるわけではないが、例えば、インテグリンα５遺伝子のｍＲＮＡへの転写開始を促進する能力、インテグリンα５遺伝子のｍＲＮＡの発現を促進する能力、インテグリンα５遺伝子のｍＲＮＡの分解を阻害する能力、該ｍＲＮＡからタンパク質への翻訳を促進する能力等が挙げられる。 According to one embodiment of the present invention, the composition of the present invention may have the ability to promote expression of the integrin α5 gene. Such abilities include, but are not particularly limited to, the ability to promote the initiation of transcription of integrin α5 gene mRNA, the ability to promote the expression of integrin α5 gene mRNA, and the ability to promote the expression of integrin α5 gene mRNA. Examples include the ability to inhibit degradation and the ability to promote translation of the mRNA into protein.
　本発明の一つの実施態様によれば、本発明の組成物は、インテグリンα５タンパク質の発現または機能を促進する能力を有していてもよい。このような能力としては、特に限定されるわけではないが、例えば、インテグリンα５タンパク質の細胞外分泌を促進する能力、シグナル伝達機能を促進する能力等が挙げられる。 According to one embodiment of the present invention, the composition of the present invention may have the ability to promote expression or function of integrin α5 protein. Such abilities include, but are not particularly limited to, the ability to promote extracellular secretion of integrin α5 protein, the ability to promote signal transduction functions, and the like.
　本発明における「月桃」は、ショウガ科ハナミョウガ属に属する多年生常緑草本である月桃（Ａｌｐｉｎｉａ　ｚｅｒｕｍｂｅｔ）を意味する。本発明における月桃葉エキスの抽出原料として使用する部位は葉部である。本発明における月桃葉エキスは、特に限定されるわけではないが、月桃葉を抽出原料として得られる抽出液、当該抽出液の希釈液若しくは濃縮液、当該抽出液を乾燥して得られる乾燥物、またはこれらの粗精製物若しくは精製物のいずれであってもよい。 "Alpinia zerumbet" in the present invention refers to Alpinia zerumbet, which is a perennial evergreen herb belonging to the Zingiberaceae family and the genus Alpinia. In the present invention, the part used as the raw material for extracting the moon peach leaf extract is the leaf part. The moontooth leaf extract in the present invention is not particularly limited to, but includes, but is not limited to, an extract obtained by using moontooth leaf as an extraction raw material, a diluted or concentrated liquid of the extract, a dried product obtained by drying the extract, Alternatively, it may be either a crudely purified product or a purified product thereof.
　本発明における月桃葉エキスの製造方法は、特に制限されず、当技術分野において通常使用される方法に応じて抽出することができる。前記抽出方法としては、特に限定されるわけではないが、例えば、熱水抽出法、超音波抽出法、ろ過法、還流抽出法、溶媒（例えばエタノール）抽出法等が挙げられる。これらは単独で実行、または２種以上の方法を併用して行ってもよい。また、高純度のエキスを得るためにエキスを同様の方法で１回以上ずつさらに抽出してもよい。 The method for producing the moongeach leaf extract in the present invention is not particularly limited, and extraction can be performed according to a method commonly used in the technical field. The extraction method is not particularly limited, but includes, for example, a hot water extraction method, an ultrasonic extraction method, a filtration method, a reflux extraction method, a solvent (for example, ethanol) extraction method, and the like. These methods may be performed alone, or two or more methods may be used in combination. Additionally, the extract may be further extracted one or more times in a similar manner to obtain a highly pure extract.
　本発明における月桃葉エキスの製造のために使用される抽出溶媒の種類は特に制限されず、当技術分野において公知となっている任意の溶媒を使用してもよい。そのような溶媒の例としては、特に限定されるわけではないが、例えば、水、炭素数１～４のアルコール、酢酸エチル、アセトン、クロロホルム等が挙げられ、これらは２つ以上組み合わせて使用してもよい。 The type of extraction solvent used for producing the moongweed leaf extract in the present invention is not particularly limited, and any solvent known in the art may be used. Examples of such solvents include, but are not limited to, water, alcohols having 1 to 4 carbon atoms, ethyl acetate, acetone, chloroform, etc., and two or more of these may be used in combination. It's okay.
　本発明における月桃葉エキスが商業的に販売されている場合、本発明の目的効果を有するエキスが得られるのであれば、それを使用してもよい。 If the Moon Peach leaf extract in the present invention is commercially available, it may be used as long as it can provide the desired effect of the present invention.
　本発明の組成物に含まれる月桃葉エキスの配合量は、用途に応じて適宜決定できる。 The amount of moongweed leaf extract contained in the composition of the present invention can be determined as appropriate depending on the intended use.
　インテグリンα５の発現を促進させるために、本発明の組成物が作用する細胞は、特に限定されるわけではないが、好ましくは血管内皮細胞である。 The cells on which the composition of the present invention acts in order to promote the expression of integrin α5 are not particularly limited, but are preferably vascular endothelial cells.
　一般に、血管内皮細胞は、血管の内膜を構成する細胞である。動脈や静脈は内膜、中膜、外膜の三層から構成されるが、毛細血管は、血管内皮細胞から構成される内膜のみで構成される。血管内皮細胞においては、主にＶＥ－カドヘリンという細胞接着分子の働きにより内皮細胞間が接着されており、また、インテグリンの働きにより、細胞外マトリクスと血管内皮細胞が接着されている。本発明における血管内皮細胞としては、特に限定されるわけではないが、例えば、生体から取得された内皮細胞、およびその継代された細胞、株化された細胞、臍帯血静脈内皮細胞、およびその継代された細胞等が挙げられる。本発明における血管内皮細胞としては、特に限定されるわけではないが、ＨＵＶＥＣまたはＨＭＥＣ－１を用いてもよい。 In general, vascular endothelial cells are cells that make up the inner lining of blood vessels. Arteries and veins are composed of three layers: intima, media, and adventitia, but capillaries are composed only of the intima, which is composed of vascular endothelial cells. In vascular endothelial cells, endothelial cells are adhered primarily by the action of a cell adhesion molecule called VE-cadherin, and the extracellular matrix and vascular endothelial cells are adhered by the action of integrins. The vascular endothelial cells in the present invention are not particularly limited, but include, for example, endothelial cells obtained from a living body, subcultured cells thereof, established cell lines, umbilical cord blood vein endothelial cells, and Examples include cells that have been passaged. The vascular endothelial cells in the present invention are not particularly limited, but HUVEC or HMEC-1 may be used.
　本発明における血管内皮細胞は、菌類を含め、いかなる動植物に由来する細胞であってもよく、限定されるわけではないが、好ましくは動物細胞であり、好ましくはヒト細胞である。 The vascular endothelial cells in the present invention may be cells derived from any animal or plant including fungi, and are preferably animal cells, preferably human cells, although not limited thereto.
　本発明の組成物は、経口用組成物、局所用組成物のいずれであってもよいが、好ましくは局所用組成物である。本発明の組成物を局所用組成物とする場合、局所用組成物に配合される公知の成分（添加剤）をさらに配合することができる。このような成分としては、限定されるわけではないが、例えば、乳化剤、水和剤、溶媒、エモリエント、安定剤、増粘剤、保存剤、滑沢剤、キレート剤、充填剤、賦形剤、粉末、芳香剤、香料、吸収剤、染料、乳白剤、抗酸化剤、ビタミン、アミノ酸等が挙げられる。 The composition of the present invention may be either an oral composition or a topical composition, but is preferably a topical composition. When the composition of the present invention is used as a topical composition, known components (additives) that are blended into topical compositions can be further blended. Such ingredients include, but are not limited to, emulsifiers, hydrating agents, solvents, emollients, stabilizers, thickeners, preservatives, lubricants, chelating agents, fillers, and excipients. , powders, fragrances, perfumes, absorbents, dyes, opacifying agents, antioxidants, vitamins, amino acids, etc.
　本発明における局所用組成物は、液体、半固体、固体のいずれであってもよく、限定されるわけではないが、好ましくは、溶液、懸濁液、分散液、エマルジョン、クリーム、軟膏、ゲル、ローション、フォーム、ペースト、またはスプレーの形態である。 The topical composition of the present invention may be liquid, semi-solid, or solid, preferably, but not limited to, a solution, suspension, dispersion, emulsion, cream, ointment, or gel. , in the form of a lotion, foam, paste, or spray.
　本発明の組成物は、特に限定されるわけではないが、医薬組成物、化粧用組成物、食品組成物のいずれかとしてもよく、好ましくは化粧用組成物である。本発明における化粧用組成物とは、化粧をすることを目的に使用される組成物のことを意味し、経口用組成物、局所用組成物のいずれであってもよい。 Although the composition of the present invention is not particularly limited, it may be a pharmaceutical composition, a cosmetic composition, or a food composition, and is preferably a cosmetic composition. The cosmetic composition in the present invention refers to a composition used for the purpose of applying makeup, and may be either an oral composition or a topical composition.
　本発明における食品組成物は、栄養機能食品、特定保健用食品、機能性表示食品等の保健機能食品であってもよく、また治療食（すなわち、治療の目的を果たすもの、または、医師が食事箋を出し、それに従い栄養士等が作成した献立に基づいて調理されたもの）、食事療法食、介護食等として、製造されてもよい。 The food composition of the present invention may be a food with health claims such as a food with nutritional function claims, a food for specified health uses, a food with functional claims, etc. It may also be manufactured as a dietary therapy food, a nursing care food, etc.
　以下の例に基づいて本発明を具体的に説明するが、本発明はこれらの例に限定されるものではない。含有量は特記しない限り、質量％で示す。 The present invention will be specifically explained based on the following examples, but the present invention is not limited to these examples. The content is expressed in mass % unless otherwise specified.
ヒト臍帯静脈内皮細胞（ＨＵＶＥＣ）の培養
　ヒト臍帯静脈内皮細胞（ＨＵＶＥＣ）を、コラーゲンコートした６ｗｅｌｌプレートの各ウェルに、サプリメントを添加したＥＢＭ２培地（Ｌｏｎｚａ社製）中で２×１０５ｃｅｌｌｓ／ｍＬとなるように調製し、５％ＣＯ２加湿雰囲気下において、３７℃で２４時間インキュベートした。インキュベート後、培地を、０．５％ＦＢＳを添加したＥＢＭ２培地に変更し、ＨＵＶＥＣを２４時間飢餓状態にした。続いて、月桃葉エキス（月桃葉抽出液ＢＧ、丸善製薬社製）を０．１％添加し、２４時間処理した。 Culture of human umbilical vein endothelial cells (HUVEC) Human umbilical vein endothelial cells (HUVEC) were placed in each well of a collagen-coated 6-well plate at 2×10 5 cells/mL in supplemented EBM2 medium (manufactured by Lonza). and incubated at 37° C. for 24 hours in a 5% CO 2 humidified atmosphere. After incubation, the medium was changed to EBM2 medium supplemented with 0.5% FBS and HUVECs were starved for 24 hours. Subsequently, 0.1% of Albania leaf extract (Albanian leaf extract BG, manufactured by Maruzen Pharmaceutical Co., Ltd.) was added, and the mixture was treated for 24 hours.
月桃葉エキス（月桃葉抽出液ＢＧ）がＨＵＶＥＣにおけるインテグリンα５遺伝子の発現に与える影響の評価
　月桃葉エキス（月桃葉抽出液ＢＧ）処理後、培地を取り除き、ＨＵＶＥＣからＲＮｅａｓｙ　ｍｉｎｉ　ｋｉｔ　（ＱＩＡＧＥＮ社製）を用いてＲＮＡを抽出し、精製した。ＬｉｇｈｔＣｙｃｌｅｒ　４８０（Ｒｏｃｈｅ　Ａｐｐｌｉｅｄ　Ｓｃｉｅｎｃｅ社製）を用いた定量的リアルタイムＲＴ－ＰＣＲにより、ＨＵＶＥＣ内のインテグリンα５のｍＲＮＡの発現量を測定した。測定は、インテグリンα５のＦＡＭ標識　ＴａｑＭａｎ　ｇｅｎｅ　ｅｘｐｒｅｓｓｉｏｎ　ｐｒｏｂｅ（Ｈｓ０１５４７６７３＿ｍ１）をＴａｑｍａｎ　ＲＮＡ－ｔｏ－ＣｔＴＭ　１－ｓｔｅｐ　Ｋｉｔ（Ｔｈｅｒｍｏ　Ｆｉｓｈｅｒ社製）と共に用いて行った。ＰＣＲの反応条件は、逆転写４８℃で１５分、ポリメラーゼ活性化９５℃で１０分、変性―アニール―伸長を９５℃で１５秒と６０℃で１分を繰り返し回数４０回とした。インテグリンα５の遺伝子発現量は、ＦＡＭ標識　Ｇａｐｄｈ　ＴａｑＭａｎ　Ｐｒｏｂｅ（Ｈｓ０２７８６６２４＿ｇ１）を用いて標準化した。得られた結果に対して、対応のないｔ検定による検定（Ｐ＜０．０５の場合、＊と記載）を行った。 Evaluation of the effect of Aspensifolia leaf extract (Ascilifolia extract BG) on the expression of integrin α5 gene in HUVEC After treatment with Ascisolica leaf extract (Ascipias leaf extract BG), remove the medium and remove the medium from HUVEC using the RNeasy mini kit (manufactured by QIAGEN) RNA was extracted and purified using The expression level of integrin α5 mRNA in HUVEC was measured by quantitative real-time RT-PCR using LightCycler 480 (manufactured by Roche Applied Science). The measurement was performed using an integrin α5 FAM-labeled TaqMan gene expression probe (Hs01547673_m1) together with Taqman RNA-to-CtTM 1-step Kit (manufactured by Thermo Fisher). The PCR reaction conditions were reverse transcription at 48°C for 15 minutes, polymerase activation at 95°C for 10 minutes, and denaturation-annealing-extension at 95°C for 15 seconds and 60°C for 1 minute, repeated 40 times. The gene expression level of integrin α5 was standardized using FAM-labeled Gapdh TaqMan Probe (Hs02786624_g1). The obtained results were tested by an unpaired t-test (in the case of P<0.05, it is indicated as *).
　結果を図１に示す。図１の結果から、月桃葉エキス（月桃葉抽出液ＢＧ）がＨＵＶＥＣにおけるインテグリンα５の遺伝子の発現量を有意に増加させることが示された。 The results are shown in Figure 1. The results shown in FIG. 1 showed that Alpinia leaf extract (Alpinia leaf extract BG) significantly increased the expression level of the integrin α5 gene in HUVEC.

Claims (5)

  1. 　インテグリンα５の発現を促進させるための組成物であって、月桃葉エキスを含んでなる組成物。 A composition for promoting the expression of integrin α5, the composition comprising a moontooth leaf extract.
  2. 　血管内皮細胞においてインテグリンα５の発現を促進させるための、請求項１に記載の組成物。 The composition according to claim 1, for promoting the expression of integrin α5 in vascular endothelial cells.
  3. 　局所用組成物である、請求項１または２に記載の組成物。 The composition according to claim 1 or 2, which is a topical composition.
  4. 　溶液、懸濁液、分散液、エマルジョン、クリーム、軟膏、ゲル、ローション、フォーム、ペースト、またはスプレーの形態である、請求項３に記載の組成物。 4. The composition of claim 3 in the form of a solution, suspension, dispersion, emulsion, cream, ointment, gel, lotion, foam, paste, or spray.
  5. 　化粧用組成物である、請求項１または２に記載の組成物。 The composition according to claim 1 or 2, which is a cosmetic composition.
PCT/JP2023/029212 2022-08-23 2023-08-10 COMPOSITION FOR EXPRESSING INTEGRIN α5 COMPRISING SHELL GINGER LEAF EXTRACT WO2024043114A1 (en)

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