WO2023047810A1 - 免疫関連細胞の一次繊毛の抑制剤およびその利用 - Google Patents
免疫関連細胞の一次繊毛の抑制剤およびその利用 Download PDFInfo
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- WO2023047810A1 WO2023047810A1 PCT/JP2022/029762 JP2022029762W WO2023047810A1 WO 2023047810 A1 WO2023047810 A1 WO 2023047810A1 JP 2022029762 W JP2022029762 W JP 2022029762W WO 2023047810 A1 WO2023047810 A1 WO 2023047810A1
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- primary cilia
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
Definitions
- the present invention relates to an inhibitor of primary cilia of immune-related cells and its use.
- Inflammation is one of biological reactions caused by chemical and/or physical stimuli. Since inflammation can damage living tissue, anti-inflammatory agents are sometimes applied to inflammation.
- the present inventors have so far found that immune-related cells have organelles called primary cilia, and that the expression of primary cilia is enhanced in skin diseases accompanied by inflammation (for example, see Patent Documents 1 to 3). This indicates that inhibitors of primary cilia of immune-related cells can be used as anti-inflammatory agents.
- An object of one aspect of the present invention is to provide an inhibitor of primary cilia of immune-related cells and a technique for using the same.
- the present inventors found that (i) silymarin, silybin and dehydrosilybin, which are components of the extract of Silybum marianum, and (ii) graviola (Annona muricata)
- the inventors have found that annonacin and quercetin, which are components of the extract of A., have the effect of suppressing the expression of primary cilia of immune-related cells, and completed the present invention. That is, the present invention includes the following configurations.
- An inhibitor of primary cilia of immune-related cells containing at least one selected from the group consisting of A to E below: A: silymarin, B: silybin, C: dehydrosilybin, D: Annonacine, E: Quercetin.
- an inhibitor of primary cilia of immune-related cells it is possible to provide an inhibitor of primary cilia of immune-related cells and a technique for using the same.
- 101 is a graph showing the inhibitory effect of silymarin on primary cilia in immune-related cells
- 102 is a graph showing the inhibitory effect of silybin on primary cilia in immune-related cells
- 201 and 202 are graphs showing the inhibitory effects of 2,3-dehydrosilybin A and 2,3-dehydrosilybin B on primary cilia in immune-related cells, respectively.
- 301, 302 and 303 are graphs showing the inhibitory effects of primary cilia on immune-related cells of cosmetic raw materials containing materials derived from Silybum marianum, respectively.
- 401 and 402 are graphs showing the inhibitory effects of annonacine and quercetin hydrate on primary cilia in immune-related cells, respectively.
- An inhibitor of primary cilia of immune-related cells contains at least one selected from the group consisting of A to E below: A: silymarin, B: silybin, C : dehydrosilybin, D: annonacine, E: quercetin.
- the above-mentioned immune-related cells include immune cells that are mainly responsible for immune reactions and immune function-bearing cells that are indirectly involved in immune cells.
- Immune function-possessing cells have, for example, the function of activating immune cells.
- immune cells include skin dendritic cells (e.g., Langerhans cells, dermal dendritic cells), lymphoid immune cells (e.g., T cells, NK cells, B cells), and monocytic immune cells. (eg, conventional dendritic cells, monocytic dendritic cells (eg, plasmacytoid dendritic cells)).
- immune function-bearing cells include, for example, keratinocytes, fibroblasts, and epithelial cells.
- the immune-related cells may be immune-related cells collected from a living body or established immune-related cells (eg, HaCaT cells).
- Silymarin (CAS No. 65666-07-1) is a mixture of flavonolignans obtained from Silybum marianum. Silymarin contains silybin and dehydrosilybin among the B to E compounds described above.
- silymarin it is possible to use commercially available silymarin, or it is possible to use silymarin obtained from an extract of Silybum marianum.
- the method for obtaining silymarin from the milk thistle extract is not limited.
- milk thistle seeds are first extracted with an organic solvent (eg, ethanol, methanol, acetone, or ethyl acetate) to obtain an extract.
- silymarin can be obtained by removing lipids and highly polar impurities from the extracted extract and then drying the extracted extract by a spray drying method or the like.
- the inhibitor of primary cilia of immune-related cells is a material derived from Silybum marianum (eg, seeds, leaves, stems, buds, flowers of Silybum marianum, or , roots), or pulverized) to inhibit primary cilia of immune-related cells.
- Silybum marianum eg, seeds, leaves, stems, buds, flowers of Silybum marianum, or , roots
- Silybin (CAS No.22888-70-6) is one of the compounds contained in the above-mentioned silymarin.
- silybin it is possible to use commercially available silybin, or it is possible to use silybin obtained from an extract of Silybum marianum.
- the method for obtaining silybin from the milk thistle extract is not limited.
- milk thistle seeds are first extracted with an organic solvent (eg, ethanol, methanol, acetone, or ethyl acetate) to obtain an extract.
- Silybin can then be obtained by further purifying the extracted extract by a known purification method (eg, column chromatography, high performance liquid chromatography).
- the inhibitor of primary cilia of immune-related cells is a material derived from Silybum marianum (eg, seeds, leaves, stems, buds, flowers of Silybum marianum, or , roots), or pulverized) to inhibit primary cilia of immune-related cells.
- Dehydrosilybin e.g., 2,3-dehydrosilybin A (CAS No.25166-14-7), 2,3-dehydrosilybin B (CAS No.142796-24-5)
- 2,3-dehydrosilybin A CAS No.25166-14-7
- 2,3-dehydrosilybin B CAS No.142796-24-5
- dehydrosilybin commercially available dehydrosilybin can be used, and dehydrosilybin obtained from milk thistle extract can also be used.
- the method for obtaining dehydrosilybin from the milk thistle extract is not limited.
- milk thistle seeds are first extracted with an organic solvent (eg, ethanol, methanol, acetone, or ethyl acetate) to obtain an extract.
- dehydrosilybin can be obtained by further purifying the extracted extract by a known purification method (eg, column chromatography, high performance liquid chromatography).
- the inhibitor of primary cilia of immune-related cells is a material derived from Silybum marianum (eg, seeds, leaves, stems, buds, flowers of Silybum marianum, or , roots), or pulverized) to inhibit primary cilia of immune-related cells.
- Annonacin (CAS No. 111035-65-5) is one of the compounds obtained from graviola (Annona muricata).
- annonacin commercially available annonacin can be used, and annonacin obtained from graviola extract can also be used.
- the method for obtaining annonacine from the extract of graviola is not limited. For example, first, graviola seeds or leaves are extracted with an organic solvent (eg, ethanol, methanol, acetone, or ethyl acetate) to obtain an extract. Then, annonacin can be obtained by further purifying the extracted extract by a known purification method (eg, column chromatography, high performance liquid chromatography).
- an organic solvent eg, ethanol, methanol, acetone, or ethyl acetate
- an inhibitor of primary cilia of immune-related cells is a material derived from graviola, such as graviola (e.g., seeds, leaves, stems, buds, flowers, or roots of graviola). may be an inhibitor of primary cilia of immune-related cells containing an extract or pulverized product of .
- graviola e.g., seeds, leaves, stems, buds, flowers, or roots of graviola.
- Quercetin (CAS No. 117-39-5) is one of the compounds obtained from graviola (Annona muricata).
- the quercetin may be in the form of hydrate (quercetin hydrate).
- quercetin commercially available quercetin can be used, and quercetin obtained from graviola extract can also be used.
- the method for obtaining quercetin from the graviola extract is not limited. For example, first, graviola seeds or leaves are extracted with an organic solvent (eg, ethanol, methanol, acetone, or ethyl acetate) to obtain an extract. Next, quercetin can be obtained by further purifying the extracted extract by a known purification method (eg, column chromatography, high performance liquid chromatography).
- an inhibitor of primary cilia of immune-related cells is a material derived from graviola, such as graviola (e.g., seeds, leaves, stems, buds, flowers, or roots of graviola). may be an inhibitor of primary cilia of immune-related cells containing an extract or pulverized product of .
- Active ingredients contained in the inhibitor of primary cilia of immune-related cells is not particularly limited, for example, when the inhibitor is 100% by mass, it may be 0.00001% by mass to 100% by mass, may be 0.001% by mass to 100% by mass, may be 0.01% by mass to 100% by mass, may be 0.1% by mass to 100% by mass, and may be 0.001% by mass to 100% by mass. It may be 1% by mass to 95% by mass, may be 0.1% by mass to 90% by mass, may be 0.1% by mass to 80% by mass, and may be 0.1% by mass to 70% by mass.
- % by mass may be 0.1% by mass to 60% by mass, may be 0.1% by mass to 50% by mass, and may be 0.1% by mass to 40% by mass. may be 0.1% by mass to 30% by mass, may be 0.1% by mass to 20% by mass, or may be 0.1% by mass to 10% by mass.
- silymarin, silybin, dehydrosilybin, annonacine, and quercetin are used at concentrations of 48 ⁇ g/mL or higher, 100 ⁇ M or higher, 10 ⁇ M or higher, 0.5 ⁇ M or higher, and 10 ⁇ M or higher, respectively.
- concentrations 48 ⁇ g/mL or higher, 100 ⁇ M or higher, 10 ⁇ M or higher, 0.5 ⁇ M or higher, and 10 ⁇ M or higher, respectively.
- the expression of primary cilia in those cells can be better suppressed.
- the inhibitor of primary cilia of immune-related cells is 30 ⁇ g/mL or more, 48 ⁇ g/mL or more when the inhibitor is administered to a subject. , 75 ⁇ g/mL or higher, 1 mg/mL or higher, or 5 mg/mL or higher concentration (the upper limit of the concentration is not limited, for example, 100 mg/mL or 10 mg/mL) is immune-related It is preferred to contain an amount of the active ingredient that allows it to come into contact with the cells.
- the inhibitor of primary cilia of immune-related cells according to one embodiment of the present invention contains silymarin or silybin at the above concentration. may With this configuration, the expression of primary cilia of immune-related cells can be better suppressed.
- the inhibitor of primary cilia of immune-related cells has a 1 mM or more, or 5 mM or more concentration (the upper limit of the concentration is not limited, for example, 1 M, 100 mM, or 10 mM) active ingredient in an amount that can contact immune-related cells It is preferable to contain.
- the inhibitor of primary cilia of immune-related cells according to one embodiment of the present invention contains silymarin or silybin at the above concentration. may With this configuration, the expression of primary cilia of immune-related cells can be better suppressed.
- the inhibitor of primary cilia of immune-related cells has a , 50 ⁇ M or more, 100 ⁇ M or more, or 500 ⁇ M or more (the upper limit of the concentration is not limited, for example, 1 M, 100 mM, or 10 mM). It is preferable to contain the active ingredient of Of course, the inhibitor of primary cilia of immune-related cells according to one embodiment of the present invention (for example, liquid, gel, cream) may contain dehydrosilybin at the concentration. . With this configuration, the expression of primary cilia of immune-related cells can be better suppressed.
- the inhibitor of primary cilia of immune-related cells is 0.2 ⁇ M or more, 0.5 ⁇ M or more when the inhibitor is administered to a subject. , 1 ⁇ M or more, 5 ⁇ M or more, or 10 ⁇ M or more (the upper limit of the concentration is not limited, for example, 1 M, 100 mM, or 10 mM). It is preferable to contain the active ingredient of Of course, the inhibitor of primary cilia of immune-related cells according to one embodiment of the present invention (for example, liquid, gel, cream) may contain annonasin at the above concentration. With this configuration, the expression of primary cilia of immune-related cells can be better suppressed.
- the inhibitor of primary cilia of immune-related cells has a concentration of 8 ⁇ M or more, 10 ⁇ M or more, 50 ⁇ M or more, 100 ⁇ M or more, or 500 ⁇ M or more concentration (the upper limit of the concentration is not limited, for example, 1 M, 100 mM, or 10 mM) active ingredient in an amount that can contact immune-related cells It is preferable to contain.
- An inhibitor of primary cilia of immune-related cells according to an embodiment of the present invention may contain quercetin at the concentration. With this configuration, the expression of primary cilia of immune-related cells can be better suppressed.
- Dehydrosilybin and annonacine can suppress the expression of primary cilia in immune-related cells more efficiently at lower concentrations than silymarin, silybin, and quercetin. Therefore, inhibitors containing dehydrosilybin and annonacine may be more effective in suppressing the expression of primary cilia in immune-related cells than inhibitors containing silymarin, silybin and quercetin.
- the inhibitor of primary cilia of immune-related cells may contain ingredients other than the active ingredients described above.
- Ingredients other than the active ingredient are not particularly limited. .
- Examples of the buffering agent include phosphoric acid or phosphate, boric acid or borate, citric acid or citrate, acetic acid or acetate, carbonic acid or carbonate, tartaric acid or tartrate, ⁇ -aminocaproic acid, trometamol is mentioned.
- Examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate.
- Examples of the borate include borax, sodium borate, and potassium borate.
- Examples of the citrate include sodium citrate, disodium citrate, and trisodium citrate.
- Examples of the acetate include sodium acetate and potassium acetate.
- Examples of the carbonate include sodium carbonate and sodium hydrogen carbonate.
- Examples of the tartrate include sodium tartrate and potassium tartrate.
- pH adjuster examples include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, and potassium hydroxide.
- tonicity agent examples include ionic tonicity agents (e.g., sodium chloride, potassium chloride, calcium chloride, magnesium chloride), nonionic tonicity agents (e.g., glycerin, propylene glycol, sorbitol, mannitol, ).
- ionic tonicity agents e.g., sodium chloride, potassium chloride, calcium chloride, magnesium chloride
- nonionic tonicity agents e.g., glycerin, propylene glycol, sorbitol, mannitol, ).
- antiseptic examples include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, and chlorobutanol.
- antioxidants examples include ascorbic acid, tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, and sodium sulfite.
- high molecular weight polymer examples include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, and hydroxypropylmethylcellulose phthalate. , carboxymethylethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, atelocollagen.
- excipients examples include lactose, sucrose, D-mannitol, xylitol, sorbitol, erythritol, starch, and crystalline cellulose.
- Examples of the solvent include water, physiological saline, and alcohol.
- antibacterial agent examples include ⁇ -lactam, aminoglycoside, tetracycline, lincomycin, chloramphenicol, macrolide, ketolide, polypeptide, and glycopeptide antibiotics; pyridonecarboxylic acid; (quinolone)-based, new quinolone-based, oxazolidinone-based, and sulfa drug-based synthetic antibacterial agents.
- the amount of components other than the active ingredient contained in the inhibitor of primary cilia of immune-related cells is not particularly limited. % to 99.99999% by mass, may be 0% to 99.9999% by mass, may be 0% to 99.999% by mass, and may be 0% to 99.99% by mass It may be 0% by mass to 99.9% by mass, may be 5% by mass to 99.9% by mass, and may be 10% by mass to 99.9% by mass.
- the weight to weight to 99.9% by mass may be 20% by mass to 99.9% by mass, may be 30% by mass to 99.9% by mass, may be 40% by mass to 99.9% by mass, may be 50% by mass % to 99.9% by mass, 60% to 99.9% by mass, 70% to 99.9% by mass, 80% to 99.9% by mass % by mass, or 90% by mass to 99.9% by mass.
- the dosage form of the inhibitor of primary cilia of immune-related cells is not particularly limited, and examples thereof include external preparations (e.g., liquid preparations, gel preparations, cream preparations, stick preparations, sheet preparations), and tablets. , powders and granules.
- external preparations e.g., liquid preparations, gel preparations, cream preparations, stick preparations, sheet preparations
- tablets e.g., powders and granules.
- Subjects to which the inhibitor of primary cilia of immune-related cells according to one embodiment of the present invention is administered are not particularly limited. Examples include collected tissues, cells collected from these, and established cell lines. Examples of non-human animals include, but are not limited to, monkeys, chimpanzees, cows, pigs, sheep, goats, horses, dogs, cats, rabbits, mice, and rats.
- the administration route of the inhibitor of primary cilia of immune-related cells is not particularly limited, and examples thereof include parenteral administration (eg, transdermal administration) and oral administration.
- the administration interval of the inhibitor of primary cilia of immune-related cells according to one embodiment of the present invention to a subject is not particularly limited, and is, for example, once an hour, once every 1 to 6 hours, 6 to 12 hours. 12 hours to 1 day, 1 to 3 days, 1 to 5 days, 1 to 7 days, 7 to 14 days, 14 days to 21 days, once per month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, once every 6 months, or once per year times.
- An anti-inflammatory (e.g., anti-inflammatory, anti-inflammatory) topical preparation according to an embodiment of the present invention contains an inhibitor of primary cilia of immune-related cells according to an embodiment of the present invention.
- An anti-inflammatory (e.g., prevention of inflammation, treatment of inflammation) topical preparation according to one embodiment of the present invention comprises the inhibitor of primary cilia of immune-related cells according to one embodiment of the present invention, good too.
- Inflammation to which the topical agent is applied is not particularly limited, and includes, for example, inflammation caused by chemical and/or physical irritation, and inflammation associated with inflammatory diseases.
- the inflammatory diseases include atopic dermatitis, psoriasis, eczema, comedones, and contact dermatitis.
- the anti-inflammatory agent for external use can be an anti-inflammatory agent, an anti-inflammatory agent, an anti-inflammatory agent, an anti-inflammatory cosmetic, an anti-inflammatory cosmetic, or an anti-inflammatory cosmetic.
- cosmetics include body lotions, deodorant cosmetics, lotions, milky lotions, skin care creams, tonics, stick cosmetics, lipsticks, facial cleansers, cleansers, sheet cosmetics, and shaving cosmetics. , and hair growth agents.
- the dosage form of the external preparation is not particularly limited, and examples include liquids, gels, creams, sticks, and sheets.
- the degree of gelation of the gel is not particularly limited as it may vary depending on the application.
- the skin to which the external preparation can be applied is not particularly limited, and includes, for example, the head, face, neck, arm, hand, elbow, shin, back, torso, and foot.
- the amount of the inhibitor of primary cilia of immune-related cells contained in the anti-inflammatory topical preparation according to one embodiment of the present invention is not particularly limited. It may be 0.00001% by mass to 100% by mass, may be 0.0001% by mass to 100% by mass, may be 0.001% by mass to 100% by mass, and may be 0.01% by mass ⁇ 100% by mass, may be 0.1% by mass to 100% by mass, may be 0.1% by mass to 95% by mass, and may be 0.1% by mass to 90% by mass may be 0.1% by mass to 80% by mass, may be 0.1% by mass to 70% by mass, may be 0.1% by mass to 60% by mass, It may be 0.1% by mass to 50% by mass, may be 0.1% by mass to 40% by mass, may be 0.1% by mass to 30% by mass, or may be 0.1% by mass It may be up to 20% by mass, or 0.1% by mass to 10% by mass.
- the anti-inflammatory topical preparation according to one embodiment of the present invention may contain components other than the inhibitor of primary cilia of immune-related cells described above.
- the "component other than the inhibitor of primary cilia of immune-related cells” is not particularly limited, and examples thereof include the above [1. inhibitor of primary cilia of immune-related cells].
- the amount of components other than the inhibitor of primary cilia of immune-related cells contained in the anti-inflammatory topical preparation according to one embodiment of the present invention is not particularly limited, and for example, the topical preparation is 100% by mass. In the case, it may be 0% by mass to 99.99999% by mass, may be 0% by mass to 99.9999% by mass, may be 0% by mass to 99.999% by mass, and may be 0% by mass % to 99.99% by mass, 0% to 99.9% by mass, 5% to 99.9% by mass, 10% to 99.9% by mass % by mass, may be 20% by mass to 99.9% by mass, may be 30% by mass to 99.9% by mass, and may be 40% by mass to 99.9% by mass. may be 50% by mass to 99.9% by mass, may be 60% by mass to 99.9% by mass, may be 70% by mass to 99.9% by mass, may be 80% by mass % to 99.9% by mass, or 90% to 99.9% by mass.
- the administration target, administration route, and administration interval of the anti-inflammatory topical preparation according to one embodiment of the present invention are not particularly limited, and the suppression of primary cilia of immune-related cells according to one embodiment of the present invention is described above.
- the administration target, administration route, and administration interval of the agent may be the same.
- One embodiment of the present invention can also be configured as follows.
- An inhibitor of primary cilia of immune-related cells containing at least one selected from the group consisting of A to E below: A: Silymarin, B: Silybin, C: Dehydrosilybin, D: Annonacin, E : Quercetin.
- a subject e.g., human or non-human animal (e.g., monkey, chimpanzee, A method for suppressing primary cilia of immune-related cells, comprising the step of administering to cows, pigs, sheep, goats, horses, dogs, cats, rabbits, mice, and rats: A: Silymarin, B: Silybin, C: dehydrosilybin, D: annonacine, E: quercetin.
- Subject e.g., human or non-human animal (e.g., , monkeys, chimpanzees, cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, mice, and rats). treatment method: A: silymarin, B: silybin, C: dehydrosilybin, D: annonacine, E: quercetin.
- ⁇ 5> Use of at least one selected from the group consisting of A to E below for producing an inhibitor of primary cilia of immune-related cells: A: silymarin, B: silybin, C: dehydrosilybin, D: annonacin, E: quercetin;
- a to E for manufacturing an anti-inflammatory external preparation A: Silymarin, B: Silybin, C: Dehydrosilybin, D: Annonacin, E : Quercetin.
- Neonatal normal human keratinocytes (NHEK, Lonza), one of immune-related cells, were cultured in KGM-Gold medium (Lonza).
- NHEK cells were collected after subculturing, and the NHEK cells were seeded at 1.0 ⁇ 10 5 cells/well on each well of the 8-well chamber slide, and placed under conditions of 37° C. and 5% CO 2 . and incubated overnight.
- IL-13 (manufactured by PeproTech, model number: AF-200-13) was added to each well to a final concentration of 100 ng/mL, and then placed under conditions of 37°C and 5% CO 2 for 48 hours. cultured. This induced the expression of primary cilia in NHEK cells.
- NHEK cells on the slide were fixed at 4° C. for 20 minutes using 4% paraformaldehyde phosphate buffer (manufactured by Fujifilm, model number: 163-20145).
- the NHEK cells after the fixation treatment were washed with PBS (Phosohate-buffered saline) three times, the NHEK cells were treated with 10% FBS (Fetal Bovine Serum)/0.1% Triton X-100 (manufactured by Sigma, model number : T8787) at room temperature for 30 minutes for blocking.
- PBS Phosohate-buffered saline
- the NHEK cells after blocking treatment were allowed to react with the primary antibody overnight at 4°C.
- the primary cilia marker protein ARL13B was stained to detect primary cilia
- the centrosome marker protein CEP164 was stained to detect centrosomes. Information on the primary antibody used and the dilution factor when using the primary antibody are shown below.
- the NHEK cells after reacting with the primary antibody were washed in phosphate-buffered saline (PBST) containing 0.1% Tween-20 (manufactured by Sigma, model number: P9416), and then the NHEK cells were The plate was allowed to react with the secondary antibody at room temperature for 1 hour while shielding from light.
- PBST phosphate-buffered saline
- Hoechst 33342 (1:1000) (manufactured by Thermo Fisher Scientific, model number: H3570) was used to stain the nuclei of the NHEK cells.
- anti-mouse IgG donkey polyclonal antibody (1:1000) (manufactured by Thermo Fisher Scientific, model number: A-21202) and anti-rabbit IgG donkey polyclonal antibody (1:1000) (manufactured by Thermo Fisher Scientific , model number: A-21207) was used.
- the NHEK cells enclosed between the slide and the cover glass were observed using a confocal laser scanning microscope (manufactured by OLYMPUS, trade name: FV1200 IX83 or FV3000 IX83).
- ⁇ Test 1> Silybin (manufactured by Tokyo Chemical Industry Co., Ltd.), 2,3-dehydrosilybin A (manufactured by Phytolab) or 2,3-dehydrosilybin B (manufactured by Phytolab) at various concentrations (0 ⁇ M, 5 ⁇ M, 10 ⁇ M, 50 ⁇ M, or 100 ⁇ M) Phytolab), or silymarin (Sigma-Aldrich) at various concentrations (0 ⁇ g/mL, 2.4 ⁇ g/mL, 4.8 ⁇ g/mL, 24 ⁇ g/mL, or 48 ⁇ g/mL), and ( ii) NHEK cells were induced to express primary cilia in KGM-Gold medium containing IL-13 (100 ng/mL).
- NHEK cells with primary cilia were immunostained after induction of primary cilia expression, and the presence or absence of ARL13B and CEP164 staining was used as an index to determine the presence of ARL13B and CEP164 staining. Percentage of cells was calculated. 1 and 2 show the test results.
- 101 in FIG. 1 is a graph showing the inhibitory effect of silymarin on primary cilia in immune-related cells.
- 102 in FIG. 1 is a graph showing the inhibitory effect of silybin on primary cilia in immune-related cells.
- silymarin was found to inhibit the expression of primary cilia in NHEK cells in a concentration-dependent manner. More specifically, silymarin was found to more effectively inhibit the expression of primary cilia in HEK cells at concentrations of 48 ⁇ g/mL and above.
- silybin was found to inhibit the expression of primary cilia in NHEK cells in a concentration-dependent manner. More specifically, silybin was found to more effectively inhibit the expression of primary cilia in HEK cells at concentrations of 100 ⁇ M and above.
- 201 and 202 in FIG. 2 are graphs showing the inhibitory effects of 2,3-dehydrosilybin A and 2,3-dehydrosilybin B on primary cilia in immune-related cells, respectively.
- 2,3-dehydrosilybin A was found to inhibit the expression of primary cilia in NHEK cells in a concentration-dependent manner. More specifically, 2,3-dehydrosilybin A was found to more effectively inhibit the expression of primary cilia in HEK cells at concentrations of 10 ⁇ M or higher.
- 2,3-dehydrosilybin B was found to inhibit the expression of primary cilia in NHEK cells in a concentration-dependent manner. More specifically, 2,3-dehydrosilybin B was found to more effectively inhibit the expression of primary cilia in HEK cells at concentrations of 10 ⁇ M or higher.
- Holstein Ingredient name: Ameriox; Display name: lecithin, carnosine, tocopherol, milk thistle fruit extract, glycerin, ethanol, water) and SilstemU (manufactured by H-Holstein; Raw material name: Silstem-U; Display name: glycerin, water , propanediol, marian thistle extract, urticaria leaf extract) are known.
- NHEK cells in KGM-Gold medium containing (i) cosmetic ingredients at various concentrations (0%, 0.1%, or 1%) and (ii) IL-13 (100 ng/mL). induced the expression of primary cilia.
- NHEK cells with primary cilia were immunostained after induction of primary cilia expression, and the presence or absence of ARL13B and CEP164 staining was used as an index to determine the presence of ARL13B and CEP164 staining. Percentage of cells was calculated.
- FIG. 3 shows the test results.
- FIG. 3 are graphs showing the inhibitory effect of primary cilia on immune-related cells of cosmetic raw materials containing organic milk thistle extract, Ameliox, and SilstemU, respectively.
- ⁇ Test 3> (i) annonacin (Cayman Chemical) or quercetin hydrate (Tokyo Chemical Industry Co., Ltd.) at various concentrations (0 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 10 ⁇ M, or 100 ⁇ M), and (ii) NHEK cells were induced to express primary cilia in KGM-Gold medium containing IL-13 (100 ng/mL).
- NHEK cells with primary cilia were immunostained after induction of primary cilia expression, and the presence or absence of ARL13B and CEP164 staining was used as an index to determine the presence of ARL13B and CEP164 staining. Percentage of cells was calculated.
- FIG. 4 shows the test results.
- FIG. 4 are graphs showing the inhibitory effects of annonacine and quercetin (quercetin hydrate) on primary cilia in immune-related cells, respectively.
- annonacine was found to inhibit the expression of primary cilia in NHEK cells in a concentration-dependent manner. More specifically, annonacine was found to more effectively inhibit the expression of primary cilia in HEK cells at concentrations of 0.5 ⁇ M or higher.
- quercetin (quercetin hydrate) inhibits the expression of primary cilia in NHEK cells in a concentration-dependent manner. More specifically, it was revealed that quercetin (quercetin hydrate) more effectively inhibits the expression of primary cilia in HEK cells at a concentration of 10 ⁇ M or higher.
- immune-related cells have organelles called primary cilia, and that the expression of primary cilia is enhanced in skin diseases associated with inflammation.
- the inhibitor of primary cilia of immune-related cells of the present invention has the effect of inhibiting the expression of primary cilia in immune-related cells. This suggests that the agent for suppressing primary cilia of immune-related cells of the present invention also has the effect of suppressing inflammation.
- the present invention can be used as an inhibitor of primary cilia of immune-related cells, and more specifically, an anti-inflammatory agent for external use (e.g., anti-inflammatory agent, anti-inflammatory agent, anti-inflammatory agent, anti-inflammatory (cosmetics, anti-inflammatory cosmetics, anti-inflammatory cosmetics).
- an anti-inflammatory agent for external use e.g., anti-inflammatory agent, anti-inflammatory agent, anti-inflammatory agent, anti-inflammatory (cosmetics, anti-inflammatory cosmetics, anti-inflammatory cosmetics).
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Abstract
Description
A:シリマリン、
B:シリビン、
C:デヒドロシリビン、
D:アンノナシン、
E:ケルセチン。
本発明の一実施形態に係る免疫関連細胞の一次繊毛の抑制剤は、以下のA~Eからなる群より選択される少なくとも1つを含有するものである:A:シリマリン、B:シリビン、C:デヒドロシリビン、D:アンノナシン、E:ケルセチン。
本発明の一実施形態に係る抗炎症用(例えば、炎症予防用、炎症治療用)の外用剤は、本発明の一実施形態に係る免疫関連細胞の一次繊毛の抑制剤を含有するものである。本発明の一実施形態に係る抗炎症用(例えば、炎症予防用、炎症治療用)の外用剤は、本発明の一実施形態に係る免疫関連細胞の一次繊毛の抑制剤からなるものであってもよい。
本発明の一実施形態は、以下のように構成することもできる。
免疫関連細胞の1つであるNeonatal normal human keratinocyte(NHEK、Lonza社)を、KGM-Gold培地(Lonza社製)中で培養した。
8wellのチャンバースライド(Thermo Fisher Scientific社製、型番:154534)の各well内に、KGM-Gold培地を加えた。
スライド上のNHEK細胞に対して、4%パラホルムアルデヒドリン酸緩衝液(富士フイルム社製、型番:163-20145)を用いて、4℃の条件下にて20分間の固定処理を行った。
[一次繊毛を有する細胞(%)]=[顕微鏡の観察画像中の一次繊毛を有する細胞の数]/[顕微鏡の観察画像中の全細胞の数]×100 ・・・式(I)。
(i)様々な濃度(0μM、5μM、10μM、50μM、または、100μM)のシリビン(東京化成工業社製)、2,3-デヒドロシリビンA(Phytolab社製)若しくは2,3-デヒドロシリビンB(Phytolab社製)、または、様々な濃度(0μg/mL、2.4μg/mL、4.8μg/mL、24μg/mL、または、48μg/mL)のシリマリン(Sigma-Aldrich社製)、および、(ii)IL-13(100ng/mL)、を含有するKGM-Gold培地中で、NHEK細胞に対して一次繊毛の発現を誘導した。
マリアアザミの抽出エキスを含有する化粧品原料として、オーガニックマリアアザミエキス(香栄工業株式会社製;原料名:オーガニックマリアアザミエキスBG-50;表示名称:オオアザミ種子エキス)、Ameliox(エイチ・ホルスタイン社製;原料名:アメリオックス;表示名称:レシチン、カルノシン、トコフェロール、オオアザミ果実エキス、グリセリン、エタノール、水)、および、SilstemU(エイチ・ホルスタイン社製;原料名:Silstem-U;表示名称:グリセリン、水、プロパンジオール、マリアアザミエキス、ウワウルシ葉エキス)が知られている。
(i)様々な濃度(0μM、0.5μM、1μM、10μM、または、100μM)の、アンノナシン(Cayman Chemical社製)、または、ケルセチン水和物(東京化成工業社製)、および、(ii)IL-13(100ng/mL)、を含有するKGM-Gold培地中で、NHEK細胞に対して一次繊毛の発現を誘導した。
Claims (2)
- 以下のA~Eからなる群より選択される少なくとも1つを含有する、免疫関連細胞の一次繊毛の抑制剤:
A:シリマリン、
B:シリビン、
C:デヒドロシリビン、
D:アンノナシン、
E:ケルセチン。 - 請求項1に記載の抑制剤を含有する、抗炎症用の外用剤。
Priority Applications (3)
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KR20050054268A (ko) * | 2003-12-04 | 2005-06-10 | 한국생명공학연구원 | 실리마린을 유효성분으로 함유하는 면역질환인 패혈증또는 염증 질환의 예방 및 치료용 조성물 |
JP2007119431A (ja) * | 2005-10-31 | 2007-05-17 | Ichimaru Pharcos Co Ltd | ペルオキシソーム増殖剤応答性受容体活性化剤 |
JP2012158528A (ja) * | 2011-01-31 | 2012-08-23 | Nisshin Pharma Inc | IgEおよびIL−4産生抑制組成物 |
JP2018510220A (ja) * | 2015-03-19 | 2018-04-12 | サイデックス・ファーマシューティカルズ・インコーポレイテッド | シリマリンおよびスルホアルキルエーテルシクロデキストリンを含有する組成物ならびにそれを使用する方法 |
WO2019172419A1 (ja) * | 2018-03-09 | 2019-09-12 | 株式会社マンダム | 免疫関連疾患の指標の検出方法 |
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JP7540882B2 (ja) | 2019-11-11 | 2024-08-27 | 株式会社マンダム | 免疫関連細胞の一次繊毛の調整方法および調整剤、並びに、試験試料の評価方法 |
JP2021075516A (ja) | 2019-11-11 | 2021-05-20 | 株式会社マンダム | 免疫関連細胞の一次繊毛の調整方法および調整剤、試験試料の評価方法、並びに、その利用 |
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KR20050054268A (ko) * | 2003-12-04 | 2005-06-10 | 한국생명공학연구원 | 실리마린을 유효성분으로 함유하는 면역질환인 패혈증또는 염증 질환의 예방 및 치료용 조성물 |
JP2007119431A (ja) * | 2005-10-31 | 2007-05-17 | Ichimaru Pharcos Co Ltd | ペルオキシソーム増殖剤応答性受容体活性化剤 |
JP2012158528A (ja) * | 2011-01-31 | 2012-08-23 | Nisshin Pharma Inc | IgEおよびIL−4産生抑制組成物 |
JP2018510220A (ja) * | 2015-03-19 | 2018-04-12 | サイデックス・ファーマシューティカルズ・インコーポレイテッド | シリマリンおよびスルホアルキルエーテルシクロデキストリンを含有する組成物ならびにそれを使用する方法 |
WO2019172419A1 (ja) * | 2018-03-09 | 2019-09-12 | 株式会社マンダム | 免疫関連疾患の指標の検出方法 |
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