JP6629271B2 - Endo180 production promoter - Google Patents

Description

  The present invention relates to an Endo180 production promoter containing a natural product-derived component as an active ingredient.

  In photoaging caused by long-term exposure to ultraviolet light, quantitative and qualitative changes in the dermal collagen fiber structure have been confirmed and are considered to be involved in wrinkle formation. The homeostasis of the collagen fiber structure is maintained by the metabolic balance due to repeated synthesis and degradation of collagen fibers. In the degradation process, the fragmentation of collagen by matrix metalloprotease and the uptake and degradation of the fragmented collagen into fibroblasts are taking place. The involvement of a protein, a collagen receptor “Endo180”, is known (Non-Patent Document 1).

  Endo180, also known as mannose receptor C2 (MRC2), urokinase plasminogen activator receptor-related protein (uPARAP) and CD280, is a recycled endocytotic receptor that binds ligands such as collagen This is then taken up into cells, leading to degradation in endosomes.

  Endo180 has homology to mannose receptor, phospholipase A2, DEC-205 / MR6, etc. which are a member of the macrophage mannose receptor family. Endo180 is unique among the family of mannose receptors in that it targets the recycling endosome from the cell membrane to the late endosome / lysosomal compartment, but not to the late endosome / lysosomal compartment; collagen for cell migration and intracellular degradation It promotes cell uptake and thereby functions in cell motility and extracellular matrix remodeling. In addition, uPARAP forms a triple complex with urokinase-type plasmin activator (uPA) and urokinase-type plasmin activator receptor (uPAR), and is involved in the production of plasmin from plasminogen. Endo180 is localized in pits covered with clathrin on cell surfaces, endosomes, and the like, and is mainly expressed in fibroblasts, endothelial cells, and macrophages. As tissue, it is mainly expressed in lung, blood vessels, bone and skin (see Patent Document 1).

  On the other hand, the dermis of the skin is also a tissue rich in collagen, but there are few reports on the involvement of Endo180 in remodeling of collagen fibers in the dermis. It has been known that Endo180 expression is reduced in fibroblasts in photoaged skin, and fragmented collagen is accumulated in the dermal matrix (Non-patent Document 2). It is known that oxidative stress is induced in fibroblasts by fragmented collagen (Non-Patent Document 3). Furthermore, it is also known that IL-1α produced by keratinocytes is involved in the mechanism of decreasing Endo180 expression by ultraviolet rays (Non-Patent Document 4). For these reasons, Endo180 is thought to be involved in the formation of photoaged skin (eg, wrinkle formation) caused by long-term exposure to ultraviolet light. The mechanism is that when the expression of Endo180 is reduced in fibroblasts, the incorporation of fragmented collagen is suppressed and the regeneration of the normal collagen fiber structure is inhibited, and the accumulation of fragmented collagen around the cells causes It is considered to induce dysfunction of fibroblasts.

  Therefore, for example, if Endo180 expression can be promoted in fibroblasts, it is considered that regeneration of a normal collagen fiber structure can be promoted, and formation of photo-aged skin and wrinkles and the like due to it can be suppressed.

JP, 2012-521217, A

J. Cell Sci., 2009, vol.122, pp.4042-4048 J. Dermatol. Sci., 2013, vol.70, pp.42-48 Am. J. Pathol., 2009, vo.174, pp.101-114 Abstracts of the 40th Cosmetic Science Society of Japan Presentations, 2015, p.16

  An object of the present invention is to find a component having an excellent action of promoting Endo180 production among naturally derived components derived from natural products, and to provide an Endo180 production promoter containing the active ingredient as an active ingredient.

  In order to solve the above-mentioned problems, the Endo180 production promoter of the present invention includes tissou, wisteria tea, gentian, prune, gypsy, starfruit, royal jelly, green tea, wild thyme, horsetail, salamander, golden oak, goldfish, and achillea millefolium Or an extract from one or more natural products selected from the group consisting of:

  According to the present invention, it is selected from the group consisting of diatoms, wisteria tea, gentian, prunes, sagebrush, starfruit, royal jelly, green tea, wild thyme, horsetail, salamander, quince, goldfish, and yarrow derived from natural products. By using an extract from one or two or more natural products as an active ingredient, it is possible to provide an Endo180 production promoter excellent in the effect and high in safety.

Hereinafter, embodiments of the present invention will be described.
The Endo180 production enhancer of the present embodiment is selected from the group consisting of syrup, wisteria tea, gentian, prunes, sagebrush, starfruit, royal jelly, green tea, wild thyme, horsetail, salamander, golden millet, goldfish, and yarrow. The active ingredient is an extract from one or more natural products.

  Here, the “extract” in the present embodiment includes an extract obtained by using the natural product as an extraction raw material, a diluent or a concentrate of the extract, a dried product obtained by drying the extract, or Any of a crude product or a purified product of the above is included.

  The extraction raw materials used in the present embodiment include scallop (crude drug name), wisteria tea (scientific name: Ampelopsis grossedentata (Hand.-Mazz.) WTWang, or Ampelopsis cantoniensis (Hook.et Arn.) : Gentiana Lutea L), prune (scientific name: Prunus domestica), guinea pig (scientific name), star fruit (scientific name: Averrhoa carambola), royal jelly, green tea, wild thyme (scientific name: Thymus serphyllum), horsetail (scientific name: Equisetum arvens), There are Sansho (scientific name: Zanthoxylum piperitum De Candolle), Kingpea (scientific name: Osmanthus fragrans var. Aurantiacus), King's cinch (scientific name: Lonicera japonica Thunberg.), And Achillea millefolium (scientific name: Achillea millefolium).

  The Japanese radish (body jujube, crude drug name) is a mature fruit part of a jujube (Rhamnaceae) family jujube (scientific name: Zizyphus jujuba Miller var.inermis Rehder). Jujube is a deciduous small tree that grows naturally in East Asia such as southern Europe and China, and daisies can be easily obtained from these areas. Tissou is known to have relieving, tonic, diuretic and other utilities, and is used for anorexia, diarrhea, palpitations and the like.

  Wisteria tea (Ampelopsis grossedentata (Hand.-Mazz.) W.T.Wang, or Ampelopsis cantoniensis (Hook.et Arn.) Panch.) Is a perennial vine belonging to the grape family. Wisteria tea is native to a wide range of regions from central to southern China and Taiwan, and is readily available from these regions. In China, since ancient times, there have been areas where the leaves of this plant are used as beverages, and the roots or whole plants have been used as folk medicine for the treatment of jaundice hepatitis, colds, sore throat, acute conjunctival inflammation, etc. . The constituent parts that can be used as an extraction raw material include whole tea, flower part, spike part, peel part, fruit part, cone part, seed part, seed coat part, bud part, stem part, leaf part, branch part of wisteria tea , A branch, a rhizome, a root bark, a root, an above-ground part, or a mixture thereof, and a branch and a leaf is preferable.

  Gentian (Gentiana Lutea L) is a perennial herb belonging to the Gentian Gentian family, reaching a height of 1 m or more, and growing in the mountains. Gentians grow naturally at the foot of the Alps in Europe and are readily available from these areas. Examples of the constituent parts that can be used as an extraction raw material include, for example, leaves, branches, stems, fruits, seeds, flowers, rhizomes, roots, and mixtures of these parts. And the rhizome.

  Prunes (Prunus domestica) are plants of the family Rosaceae, grown in Europe and the United States and are readily available from these areas. Examples of constituent parts that can be used as an extraction raw material include leaves, branches, stems, flowers (buds), fruits, flesh, bark, roots, tuberous roots, above-ground parts, and mixtures thereof. Among them, those obtained by treating the pulp portion with an enzyme are preferred.

  Artemisia (herbal medicine) is a leaf part of mugwort (scientific name: Artemisia priceps Pampanini), which is a perennial herb belonging to the Artemisia genus Asteraceae distributed throughout Japan, and can be easily obtained from these regions. Gaiyou has been conventionally used in the field of gynecology for hemostasis, prevention of miscarriage, prevention of cold abdominal pain, and the like.

  Starfruit (Averrhoa carambola, Japanese name: goreng) is an evergreen tree of the genus Agariidae. Starfruits originate in tropical Asia, but are cultivated in tropical and subtropical regions such as southern China, Taiwan, Brazil, Guyana, Trinidad and Tobago, Florida, and Hawaii, as well as throughout Southeast Asia. Available. Starfruits include sweet seeds having a sweet fruit and sour seeds having a sour fruit, and are used for jams, jellies, pickles and the like in addition to raw food. Star fruit leaves have been used as a prophylactic or therapeutic agent for wind flu, acute gastroenteritis, urination disadvantage, postpartum edema and the like. Examples of the constituent parts that can be used as the extraction raw material include, for example, leaves, stems, stems, barks, flowers, fruits, pericarps, roots, and mixtures thereof, and preferably the leaves. .

  Royal jelly is a pharynx of a young worker bee of the European honeybee (Apis melifera L., aka: honeybee) or the European honeybee (scientific name: Apis indeca Radoszkowski) belonging to the honeybee family, honeybees distributed in Europe and Africa. It is a secretion from the gland and is fed to larvae that become queen bees and queen bees that become adults.

  Green tea is a kind of tea that is a drink made from the sprout leaves of the Camellia plant, tea tree (scientific name: Thea sinensis), and the tea is “fermented tea (tea)” and “semi-fermented” due to differences in manufacturing methods. Tea (oolong tea) and unfermented tea (green tea). In the present embodiment, green tea is used as an extraction raw material.

  Wild thyme (Thymus serphyllum, also known as Cyperaceae) is a plant belonging to the family Lamiaceae belonging to the genus Icystaceae, native to Northwest Asia from Europe, growing in a wide area, and easily available from these areas. can do. Examples of a site that can be used as an extraction material include a leaf, a stem, a flower, an above-ground portion, a mixture thereof, and the like, and preferably an above-ground portion.

  Horsetail (Equisetum arvens) is a plant belonging to the genus Euphorbiaceae, which is widely distributed in the warm zone of the Northern Hemisphere, and can be easily obtained from these areas. Examples of a site that can be used as an extraction material include an underground portion, an above-ground portion, a mixture of these portions, and the like, and preferably an above-ground portion.

  Salamander (Zanthoxylum piperitum De Candolle) is a plant belonging to the genus Citrus genus, distributed in the Japanese archipelago and the Korean peninsula, and can be easily obtained from these areas. Examples of the site that can be used as an extraction material include leaves, stems, flowers, buds, fruits, pericarp, pericarp, aerial parts, and mixtures thereof, but preferably pericarp. is there.

  Olemanthus fragrans var. Aurantiacus (also known as katsura) is an evergreen small tree belonging to the genus Oleaceae, which is native to southern China, is widely cultivated in Japan, and is easily obtained from such areas. be able to. Examples of the constituent parts that can be used as an extraction raw material include, for example, leaves, branches, bark, stems, stems, fruit parts, above-ground parts such as flowers, roots, and mixtures of these parts. Preferably it is a flower part.

  In addition, the term “flower” generally refers to the entirety of organs involved in sexual reproduction of a seed plant, and is composed of flower leaves that are deformations of leaves and flower axes that are deformations of stems. , Petals, stamens, carpels and other organs. The “flora” used as an extraction raw material in the present embodiment includes, in addition to the whole of the organs involved in sexual reproduction of a seed plant, a part thereof, for example, leaves, florets (seals and corolla), corolla, petals. Etc. are also included.

  Kingkinka (Lonicera japonica Thunberg., Also known as honeysuckle) is an evergreen vine that belongs to the honeysuckle family, honeysuckle. It grows naturally throughout Japan and throughout East Asia, and can be easily obtained from these areas. it can. Examples of the site that can be used as an extraction raw material include, but are not limited to, leaves, stems, flowers, buds, fruits, pericarp, pericarp, aerial parts, whole plants, and mixtures thereof, but are preferably used. Is a leaf, stem, flower or bud.

  Achillea millefolium is a perennial plant belonging to the genus Achillea belonging to the genus Asteraceae, which is distributed from Europe to India, Siberia, Himalayas, etc., and can be easily obtained from these regions. Examples of components of St. John's wort that can be used as an extraction raw material include leaves, stems, aboveground parts, roots, flowers, whole plants, and the like, and preferably whole plants.

  The extract from the natural product can be obtained by drying the raw material for extraction, pulverizing the raw material as it is or using a crusher, and subjecting the raw material to extraction with an extraction solvent. Drying may be performed in the sun or using a commonly used dryer. Alternatively, the material may be subjected to a pretreatment such as degreasing with a nonpolar solvent such as hexane, and then used as an extraction raw material. By performing a pretreatment such as degreasing, the extraction raw material can be efficiently extracted with a polar solvent.

  As the extraction solvent, it is preferable to use a polar solvent, for example, water, a hydrophilic organic solvent and the like. These may be used alone or in combination of two or more, and used at room temperature or a temperature lower than the boiling point of the solvent. Is preferred.

  Examples of water that can be used as the extraction solvent include pure water, tap water, well water, spring water, mineral water, hot spring water, spring water, fresh water, and the like, as well as those subjected to various treatments. The treatment applied to water includes, for example, purification, heating, sterilization, filtration, ion exchange, osmotic pressure adjustment, buffering, and the like. Therefore, the water that can be used as the extraction solvent in the present embodiment includes purified water, hot water, ion-exchanged water, physiological saline, phosphate buffer, phosphate buffered saline, and the like.

  Examples of the hydrophilic organic solvent that can be used as the extraction solvent include lower aliphatic alcohols having 1 to 5 carbon atoms such as methanol, ethanol, propyl alcohol, and isopropyl alcohol; lower aliphatic ketones such as acetone and methyl ethyl ketone; 1,3-butylene Examples thereof include polyhydric alcohols having 2 to 5 carbon atoms such as glycol, propylene glycol, and glycerin.

  When a mixture of two or more polar solvents is used as the extraction solvent, the mixing ratio can be appropriately adjusted. For example, when a mixed solution of water and a lower aliphatic alcohol is used as an extraction solvent, the mixing ratio of water and the lower aliphatic alcohol is preferably 9: 1 to 1: 9 (volume ratio), More preferably, the ratio is 7: 3 to 2: 8 (volume ratio). When a mixed solution of water and lower aliphatic ketone is used, the mixing ratio of water and lower aliphatic ketone is preferably 9: 1 to 2: 8 (volume ratio), When a mixed solution with a polyhydric alcohol is used, the mixing ratio between water and the polyhydric alcohol is preferably from 8: 2 to 1: 9 (volume ratio).

  The extraction treatment is not particularly limited as long as the soluble component contained in the extraction raw material can be eluted into the extraction solvent, and can be performed according to a conventional method. For example, the extraction raw material is immersed in 5 to 15 times (mass ratio) the extraction raw material of the extraction raw material, the soluble component is extracted at room temperature or under reflux, and then filtered to remove the extraction residue. A liquid can be obtained. When the solvent is distilled off from the obtained extract, a paste-like concentrate is obtained, and when this concentrate is further dried, a dry product is obtained.

  The extracts obtained from diatoms, wisteria tea, gentian, prune, gypsy, starfruit, royal jelly, green tea, wild thyme, horsetail, salamander, quince, goldfish, and yarrow are as described above. Since it has a production promoting action, it can be used as an active ingredient of an Endo180 production promoter. The Endo180 production promoter of the present embodiment can be used for a wide range of uses for foods and drinks, such as pharmaceuticals, quasi-drugs, and cosmetics.

  The Endo180 production promoter of the present embodiment may be an extract from daisies, wisteria tea, gentian, prunes, sagebrush, starfruit, royal jelly, green tea, wild thyme, horsetail, salamander, golden millet, goldfish, or yarrow. It may be composed of a mixture alone, or may be an extract from daisies, wisteria tea, gentian, prunes, sagebrush, starfruit, royal jelly, green tea, wild thyme, horsetail, salamander, quince, goldfish, or yarrow, or a mixture thereof. May be formulated.

  The Endo180 production promoter of the present embodiment may be any of powder, granule, tablet, liquid, etc., according to a conventional method, using a pharmaceutically acceptable carrier such as dextrin and cyclodextrin and other auxiliaries. It can be formulated into a dosage form. At this time, as an auxiliary agent, for example, an excipient, a binder, a disintegrant, a lubricant, a stabilizer, a flavor / odorant, and the like can be used. The Endo180 production promoter can be used by being blended with other compositions (for example, skin cosmetics, foods and drinks, etc.), and can also be used as ointments, liquids for external use, patches and the like.

  When the Endo180 production enhancer of the present embodiment is formulated, extraction from diatom, wisteria tea, gentian, prune, gypsy, star fruit, royal jelly, green tea, wild thyme, horsetail, salamander, golden oak, goldfish, or yarrow The content of the substance or a mixture thereof is not particularly limited, and can be appropriately set according to the purpose.

  In addition, the Endo180 production promoter of the present embodiment may include, as necessary, other natural extracts having an Endo180 production promoting effect, such as diatomaceae, wisteria tea, gentian, prunes, syrup, starfruit, royal jelly, green tea, and wild tea. It can be used as an active ingredient by blending it with an extract from thyme, horsetail, salmon, quince, goldfish, or yarrow, or a mixture thereof.

  Examples of the method of administering the Endo180 production promoter of the present embodiment to a patient include transdermal administration and oral administration. Depending on the type of the disease, a method suitable for prevention / treatment may be appropriately selected. . In addition, the dose of the Endo180 production promoter of the present embodiment may be appropriately increased or decreased depending on the type of disease, severity, individual differences among patients, administration method, administration period, and the like.

  The Endo180 production promoter of the present embodiment is an active ingredient extracted from daisies, wisteria tea, gentian, prune, gypsy, star fruit, royal jelly, green tea, wild thyme, horsetail, salamander, golden oak, goldfish, or yarrow. Promotes the production of Endo180 in fibroblasts through the action of the product to promote Endo180 production, thereby promoting the uptake of fragmented collagen by endocytosis, thereby promoting the regeneration of normal collagen fiber structures, the formation of wrinkles, etc. Such a skin photoaging phenomenon can be prevented, treated or ameliorated. In addition, the Endo180 production promoter of the present embodiment promotes regeneration of a normal collagen fiber structure, thereby reducing the effects of arthritis such as rheumatoid arthritis, osteoarthritis, purulent arthritis, gouty arthritis, traumatic arthritis, and osteoarthritis. It can be used for applications such as prevention, treatment or improvement. However, the Endo180 production promoter of the present embodiment can be used for all purposes that are significant in exhibiting the above-mentioned effects in addition to these uses.

  In addition, the Endo180 production promoter of the present embodiment has an excellent Endo180 production promoting action, and thus is suitable for, for example, blending into a skin external preparation or a food or drink. In this case, the extract from tissou, wisteria tea, gentian, prunes, gypsy, star fruit, royal jelly, green tea, wild thyme, horsetail, salamander, goldfish, goldfish, or yarrow, or a mixture of these materials are used. Endo180 formulated from an extract from syrup, wisteria tea, gentian, prune, sagebrush, star fruit, royal jelly, green tea, wild thyme, horsetail, salamander, goldpea, goldfish, or yarrow, or a mixture thereof You may mix a production promoter.

  Here, the topical skin preparation is not limited in its category, and includes a wide range of skin cosmetics, quasi-drugs, and pharmaceuticals used transdermally.Specifically, for example, ointments, Examples include creams, emulsions, lotions, serums, lotions, gels, beauty oils, packs, foundations, lip balms, bath salts, hair tonics, hair lotions, shampoos, rinses, soaps, body shampoos, and the like.

  Foods and drinks are those that are not likely to cause harm to human health and are ingested in normal social life by oral or gastrointestinal administration. It is not limited to. Therefore, “foods and drinks” in the present embodiment include general foods, health foods (functional foods and drinks), health foods (foods for specified health use, nutritional foods), quasi-drugs, and pharmaceuticals Etc. are widely included.

  In addition, the Endo180 production promoter of the present embodiment has an excellent Endo180 production promoting action, and thus can be suitably used as a reagent for studying the mechanism of these actions.

  Although the Endo180 production promoter of the present embodiment is suitably applied to humans, animals other than humans (for example, mice, rats, hamsters, dogs) can be used as long as the respective effects are exhibited. , Cats, cattle, pigs, monkeys, etc.).

  Hereinafter, the present invention will be described specifically with reference to test examples, but the present invention is not limited to the following examples. In the following test examples, the products shown in Table 1 (samples 1 to 14, all of which were freeze-dried) were used as test samples.

[Test Example 1] Endo180 production promoting action test Endo180 production promoting action was tested on the above natural product-derived components (Samples 1 to 14) as follows.

Human normal skin fibroblasts (NB1RGB) were cultured using Dulbecco MEM containing 10% FBS, and then the cells were collected by trypsinization. The collected cells were diluted with the above medium to a cell density of 1.0 × 10 ⁵ cells / mL, and then seeded in a 96-well microplate at 100 μL / well and cultured overnight.

  After completion of the culture, the medium was removed, and a test sample (samples 1 to 14; see Table 2 below for the sample concentration) dissolved in Dulbecco's MEM containing no FBS was added to each well in an amount of 200 μL, followed by culturing for one day. In addition, it culture | cultivated similarly using Dulbecco MEM without FBS which does not add a sample as a control. After the completion of the culture, the amount of Endo180 present on the cell surface of each well was measured by ELISA. From the measurement results, the Endo180 production promotion rate (%) was calculated by the following equation.

Endo180 production promotion rate (%) = A / B × 100
Each term in the formula represents the following.
A: Endo180 production amount with addition of test sample B: Endo180 production amount without addition of sample Table 2 shows the results.

  As shown in Table 2, syrup extract (sample 1), wisteria tea extract (sample 2), gentian extract (sample 3), prune extract (sample 4), gypsy extract (sample 5), starfruit Extract (sample 6), royal jelly extract (sample 7), green tea extract (sample 8), wild thyme extract (sample 9), horsetail extract (sample 10), salamander extract (sample 11), primrose It was confirmed that the extract (Sample 12), the goldfish extract (Sample 13), and the Achillea millefolium extract (Sample 14) all had an excellent Endo180 production promoting action.

  The Endo180 production promoter of the present invention can greatly contribute to prevention, treatment or improvement of skin photoaging symptoms such as wrinkle formation; prevention, treatment or improvement of various arthritis.

Claims (1)

An Endo180 production promoter comprising an extract from wisteria tea as an active ingredient.