CN115066251A - Inhibitor of reduction of expression of CD39 gene - Google Patents
Inhibitor of reduction of expression of CD39 gene Download PDFInfo
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- CN115066251A CN115066251A CN202180013807.7A CN202180013807A CN115066251A CN 115066251 A CN115066251 A CN 115066251A CN 202180013807 A CN202180013807 A CN 202180013807A CN 115066251 A CN115066251 A CN 115066251A
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Abstract
The object is to develop a drug capable of suppressing the reduction in the expression of the CD39 gene involved in the activation of Langerhans cells and regulating the immune response of the skin. It is based on the finding that a composition comprising carboxymethyl- β -glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and camellia extract inhibits the decrease in the expression of CD39 gene caused by testosterone.
Description
Technical Field
The present invention relates to an agent for inhibiting a decrease in expression of CD39 gene. The immune response of the skin can be regulated by the inhibition of the reduction of the expression of the CD39 gene.
Background
Skin is an organ located at the outermost layer of an organism, and is often exposed to stimuli from the outside, such as ultraviolet rays, physical stimuli, chemical stimuli, and biological attacks. The skin is a three-layer structure of epidermis, dermis and subcutaneous tissue. Among them, the outermost epidermis is composed of keratinocytes (keratinocytes), langerhans cells, melanocytes, and the like. The outermost epidermis has the function of protecting the human body from the external environment, such as moisture evaporation, foreign matter invasion, ultraviolet rays, and the like. Keratinocytes subjected to an external stimulus release a stimulus-responsive factor. The surrounding keratinocytes that receive the signal of the released stimulus-responsive factor secrete inflammatory cytokines. The immune cells are guided by the secreted cytokines to cause inflammation at the stimulation site (non-patent document 1). Further, as a result of recent studies, it has become clear that langerhans cells play an important role in skin immune function through antigen processing and antigen presenting ability. When an antigen enters as a foreign substance from the outside, the langerhans cells rapidly come into contact with the antigen and are treated, migrate to lymph nodes to present the antigen to T cells, and cause a series of immune response reactions thereafter. This makes it clear that Langerhans cells have a function of protecting against chemical stimuli and biological attacks. On the other hand, langerhans cells also have the ability to express CD39, which functions as an ATPase, and to decrease the amount of ATP, which is an extracellular stimulus-responsive factor (non-patent document 2). Extracellular ATP has been recognized as one of the signals of the inflammatory process. Therefore, langerhans cells are thought to contribute to sedation of inflammation by decomposing extracellular ATP, and to reduce skin damage caused by uv light or physical stimuli. It has been reported that if the number of langerhans cells decreases due to zinc deficiency, the sedative function of the skin response to external stimuli by CD39 molecules decreases, and the stimulus response becomes excessive, resulting in excessive inflammation (non-patent document 3).
Therefore, enhancement of skin immune function, reduction of inflammation, and reduction of skin damage such as sunburn can be expected by increasing or activating langerhans cells, and therefore, a method of screening a drug using the number of langerhans cells as an index (patent document 1), and development of a drug containing a specific plant extract or a langerhans cell reduction inhibitor (patent document 2) have been carried out. Further, it is disclosed that gene expression of CD39 in langerhans cells is promoted by carboxymethyl- β -glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and rose water (patent document 4).
Documents of the prior art
Patent document
Patent document 1: japanese laid-open patent publication No. 2000-236775
Patent document 2: japanese laid-open patent publication No. 2000-239144
Patent document 3: japanese patent laid-open publication No. 2004-83541
Patent document 4: japanese Kohyo publication No. 2017-511790
Non-patent document
Non-patent document 1: holzer AM and Granstein RD, "Role of extracellular antisense triphosphate in human skin", J Cutan Med Surg 2004,8(2):90-96
Non-patent document 2: mizumontot N, et al, "CD 39is the dominant Langerhans cell-immobilized ectoTNPDase: regulatory roles in inflammation and immunity responsiveness", Nat. Med.2002,8(4):358-
Non-patent document 3: kawamura T, et al, "Severe demattitis with low of epidermal Langerhans cells in human and mouse zinc definitiency", J Clin Invest 2012,122(2):722-
Non-patent document 4: koivukangas V and Oikarinen, "Suction Heater Model of round Healing" (2003) Methods in Molecular Medicine 78:255-
Disclosure of Invention
Problems to be solved by the invention
The present invention addresses the problem of developing a drug that can suppress a decrease in the expression of the CD39 gene involved in the activation of Langerhans cells and regulate the immune response of the skin.
Means for solving the problems
The present inventors screened using, as an index, the gene expression of CD39 that can use langerhans cells as an index of activation, and found that Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether and carboxymethyl- β -glucan sodium can suppress the decrease in gene expression of CD39 in langerhans cells caused by testosterone application. Furthermore, surprisingly, when Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, carboxymethyl- β -glucan sodium, and camellia extract were used in combination, the effect of the decrease in CD39 gene expression due to testosterone application could be completely suppressed, and instead CD39 gene expression could be increased, thereby completing the present invention described below.
Accordingly, the present invention relates to the following inventions:
[1-1] an inhibitor of a decrease in the expression of the CD39 gene, comprising carboxymethyl- β -glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and a camellia extract.
[1-2] use of 3 components consisting of carboxymethyl-beta-glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and camellia extract, for producing an inhibitor of reduction in expression of CD39 gene.
[1-3] A method for suppressing a decrease in the expression of the CD39 gene, comprising administering to a subject in need of suppressing a decrease in the expression of the CD39 gene a composition comprising 3 components consisting of carboxymethyl- β -glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and a Camellia japonica extract.
[1-4] 3 components consisting of carboxymethyl-beta-glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and a camellia extract, for use in the treatment or prevention of skin inflammation in which expression of the CD39 gene is reduced.
[2] The inhibitor of item 1-1, the use of item 1-2, the method of item 1-3, the 3 components of item 1-4, wherein the reduction of expression of the CD39 gene is caused by an external stimulus.
[3] The inhibitor of items 1-1, the use of items 1-2, the method of items 1-3, the 3 components of items 1-4, wherein the reduction in expression of the CD39 gene is caused by an increase in testosterone.
[4] The inhibitor, use, method, or 3 of any one of items 1-1, 1-2, 1-3, 1-4, 2, and 3 inhibits a decrease in expression of the CD39 gene in langerhans cells of the skin.
[5-1] A sedative agent for skin external irritation response, comprising carboxymethyl-beta-glucan or its salt, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and Camellia japonica extract.
[5-2] use of 3 components consisting of carboxymethyl-beta-glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and camellia extract for producing a sedative agent responsive to external skin irritation.
[5-3] A method for sedation of a cutaneous external stimulus response, comprising administering to a subject in need of sedation of a cutaneous external stimulus response a composition comprising 3 components consisting of carboxymethyl- β -glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and camellia extract.
[5-4] 3 components consisting of carboxymethyl-beta-glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and camellia extract, for use in the treatment or prevention of skin inflammation through the calming of skin external stimulus response.
[6-1] A sedative agent for skin immune response comprising carboxymethyl-beta-glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and Camellia japonica extract.
[6-2] use of 3 components consisting of carboxymethyl-beta-glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and camellia extract for producing a sedative agent for skin immune response.
[6-3] A method for calming skin immune response, comprising administering to a subject to be calmed in need of skin immune response a composition comprising 3 components consisting of carboxymethyl- β -glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and Camellia japonica extract.
[6-4] 3 components consisting of carboxymethyl-beta-glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and a camellia extract, for use in the treatment or prevention of skin inflammation through the calming of skin immune response.
[7] A method of screening for an inhibitor of reduced CD39 expression comprising:
a step of culturing Langerhans cells in the presence of testosterone and a candidate substance,
A step of measuring the expression of CD39 gene, and
determining the CD39 expression promoting effect of the candidate substance based on the expression level of the CD39 gene.
[8] The method of item 7, wherein the inhibitor of the reduction of CD39 expression is a sedative agent responsive to external skin irritation.
[9] The method of item 7, wherein the inhibitor of the reduction of CD39 expression is a sedative agent for immune response in skin.
ADVANTAGEOUS EFFECTS OF INVENTION
The present invention can exhibit at least 1 or more effects of suppression of reduction in expression of the CD39 gene, increase in expression of the CD39 gene, suppression of skin response by external stimuli, and suppression of skin immune response.
Drawings
FIG. 1 is a bar graph showing that in the case (T) where testosterone was applied to cultured mononuclear cells, a decrease in the expression of the CD39 gene was observed as compared with the control (noT), and on the other hand, in the case (+ GA) where CM-glucan (G) and Polyoxyethylene (POE) 14/polyoxypropylene (POP)7 random copolymer dimethyl ether (A) were previously applied, a decrease in the expression of the CD39 gene was suppressed. FIG. 1 is a bar graph further showing that the expression of CD39 gene was increased in the case of using camellia extract (flower: F, leaf: L) (+ GA + FL) in addition to CM-glucan (G) and Polyoxyethylene (POE) 14/polyoxypropylene (POP)7 random copolymer dimethyl ether (A).
Detailed Description
The present invention relates to an inhibitor of reduction of expression of CD39 gene, a sedative agent for external skin irritation response, and a sedative agent for skin immune response, which comprise 3 components consisting of carboxymethyl- β -glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and camellia extract.
CD39 is a protein also called ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1), and is an enzyme that hydrolyzes ATP/UTP and ADP/UDP to nucleosides such as AMP, respectively. CD39 is a membrane protein having 2 transmembrane domains, and expression was confirmed in T cell subsets, B cells, dendritic cells, and the like, in addition to langerhans cells. CD39 is known to have an extracellular ATP decomposing effect, and by this effect, CD 39-expressing cells have an action of calming inflammation.
ATP degraded by the enzymatic activity of CD39 is used as a medium for energy in cells, but acts as an information transfer substance outside the cells. For example, ATP is known to function as a neurotransmitter in the nervous system. On the other hand, in the skin, ATP is released to the outside of the cell in response to mechanical stimulation, chemical stimulation, ultraviolet stimulation, or cell destruction, and acts on immune cells in the vicinity to promote the production of cytokines and chemokines. Since immune cells are guided by this, extracellular ATP is considered to contribute to immune, allergic, and inflammatory reactions in the skin (non-patent document 1). Therefore, cells expressing CD39 can calm an excessive response to external stimuli and an excessive immune response to the skin, particularly the epidermis, by decomposing extracellular ATP.
In the skin, melanocytes and langerhans cells are examples of cells expressing CD39 (hereinafter, also referred to as CD39 positive cells). Langerhans cells are bone marrow-derived dendritic cells, and are free cells present in the middle to upper stratum of the spinous layer. Langerhans cells are cells that express markers such as CD1a in addition to CD 39. The function of langerhans cells, which are mainly involved in immune response reactions in the skin, includes a function of capturing and recognizing foreign substances invading from the outside and presenting them to T cells, a function of recognizing cancer cells, a function of inducing immune tolerance, a function of decomposing extracellular ATP, and the like. Among the numerous functions possessed by langerhans cells, the function of decomposing extracellular ATP via CD39 makes it possible to calm excessive responses to external stimuli and excessive immune responses in the skin, particularly the epidermis (FRAGRANCE JOURNAL2018-1, 16-20). Testosterone, which is an androgen, is known to be produced in the skin in response to external stimuli (Journal of Steroid Biochemistry & Molecular Biology 137(2013) 107-123). It is reported that The number of Langerhans cells in The skin is decreased by The action of testosterone produced in The skin (The Journal of Investigative Dermatology (1989) vol.92, No.1, 86-89). In addition, testosterone generally exerts an inhibitory effect on the immune system (Cellular Immunology 294(2015) 87-94). On the other hand, the inventors showed that testosterone reduced the expression of CD39 in langerhans cells. This suggests that testosterone is raised by extracellular ATP to cause hyperimmunization. Thus, testosterone causes opposite effects of suppression of immunity and induction of excessive immunity in the skin, disturbing the skin immunity. The inhibitor for reducing the expression of the CD39 gene of the present invention is an agent that inhibits the reduction of the expression of the CD39 gene in cells expressing the CD39 gene, particularly langerhans cells. The reduced expression of the CD39 gene in the present invention may be caused by any of various factors, such as testosterone produced in the skin in response to an external stimulus.
Therefore, the inhibitor of the reduction in expression of CD39 gene of the present invention can also be referred to as a CD39 gene expression promoter. Inhibitors of the reduction of expression of the CD39 gene may also be useful as sedatives in response to external stimuli. By the external stimulus-responsive sedative agent of the present invention, the response in the skin, particularly the epidermis, by the external stimulus is calmed. Examples of external stimuli to the skin include ultraviolet light, mechanical stimuli, thermal stimuli, cold stimuli, chemical stimuli, and biological attacks. When the skin is subjected to these external stimuli, the epidermal keratinocytes release stimuli-responsive factors, in particular ATP, to the outside of the cells, and as described above, extracellular ATP acts as a signal-transmitting substance and causes immune, allergic, and inflammatory reactions. Examples of the mechanical stimulation include scratching, rubbing, and mosquito biting, and for example, scratch, laceration, wound, redness, and swelling occur. As a result of the thermal stimulation and the cold stimulation, scald, cold injury (しもやけ), chap, cold injury ( ), chilblain, and the like occur. Sunburn, heat injury, and the like occur as a result of ultraviolet stimulation. The chemical irritation is induced by a chemical substance which is irritating to the skin, for example, an acid, an alkali, an organic solvent, or the like, and as a result, eczema, macula, dermatitis, or the like occurs. Examples of the biological attack include bacterial infection. An excessive immune response is generated by the decrease in the expression of CD39 gene caused by external stimuli. Excessive immune responses are also associated with skin aging. Therefore, an inhibitor of the reduction in expression of the CD39 gene may also be referred to as an inhibitor of skin aging.
The skin external stimulus response sedative agents of the present invention are capable of relieving or alleviating the skin, particularly the epidermis, responses caused by these external stimuli, such as inflammation, or itching, redness, pain, warmth, swelling, etc. caused by inflammation, and as a result, are capable of alleviating, alleviating or treating the above-listed symptoms. Accordingly, the external skin stimulus-responsive sedative agent of the present invention may be an agent for alleviating, treating, or preventing the above-mentioned symptoms. Further, since the skin external stimulus response sedative agent of the present invention can calm the immune response in the skin as a result of calming the skin external stimulus response, the skin external stimulus response sedative agent may be a skin immune response sedative agent.
On the other hand, the external skin stimulus response sedative agent of the present invention is not intended to directly inhibit the cascade of stimulus responses in the skin, but is intended to indirectly alleviate the stimulus responses via promotion of the expression of CD39 gene having ATPase function. Therefore, the external stimulus response sedative agent is an agent that enhances a function that the skin normally has, such as sedation against an excessive response to an external stimulus, and may be referred to as a stimulus response sedative function enhancer. The external stimulus response sedative function-enhancing agent can be used not only directly at the site where inflammation occurs but also at ordinary times when inflammation does not occur, and can function to suppress the inflammatory response such as itching, redness, pain, heat sensation, swelling, and rash in the presence of an external stimulus. Therefore, the external stimulus-responsive sedative agent may be incorporated into a pharmaceutical product, but is preferably incorporated into a cosmetic intended for daily use, and is used prophylactically against an external stimulus. When the external skin stimulus response sedative agent of the present invention is incorporated in a pharmaceutical product, the anti-inflammatory action of the sedative agent can be exerted or enhanced in an auxiliary manner by incorporating the sedative agent together with another agent having an anti-inflammatory action.
The skin immune response sedative agent of the present invention is an agent for calming the immune response in the skin, and is particularly useful for calming the immune response, particularly excessive inflammation, caused by decrease in langerhans cells and increase in extracellular ATP. Examples of excessive inflammation include chronic dermatitis, for example, atopic dermatitis, psoriasis, erythroderma, etc., acute dermatitis, for example, contact dermatitis such as macula, etc., seborrheic dermatitis, sunburn dermatitis, etc. By using a drug, quasi-drug or cosmetic containing the skin immune response sedative agent of the present invention, excessive reactions such as redness and itching occurring when the skin is subjected to various external stimuli are less likely to occur, and the drug, quasi-drug or cosmetic is useful for the treatment or prevention of the onset of inflammatory skin diseases. Particularly, in skin diseases such as atopic dermatitis, symptoms of the affected part accompanied by itching are worsened, and it is useful for treatment that excessive inflammatory reaction is not easily generated.
Carboxymethyl (CM)/ss-glucan for use in the present invention is usually water-soluble ss-glucan obtained by carboxymethylating insoluble ss-glucan. Carboxymethyl- β -glucan can be produced on the basis of β -glucan derived from any plant, fungus, or bacterium, or by synthesis. The natural beta-glucan can be produced by, for example, mushrooms such as agaricus, ganoderma lucidum, schizophyllum, or yeast. The weight average molecular weight of carboxymethyl- β -glucan is, for example, 1,000 to 5,000,000 daltons depending on the source thereof, and in the case of carboxymethyl- β -glucan using yeast as a raw material, the upper limit is 5,000,000 daltons, more preferably 3,000,000 daltons, further preferably 2,000,000 daltons, and the lower limit is 10,000 daltons, more preferably 100,000 daltons, further preferably 500,000 daltons. The carboxymethyl- β -glucan may be in the form of any salt, and may be, for example, a sodium salt, a potassium salt, an ammonium salt, a triethanolamine salt, or the like. As commercially available carboxymethyl- β -glucan, CM-glucan (Mibelle Biochemistry) or the like as carboxymethyl- β -glucan sodium can be used, but is not limited thereto. The amount of the surfactant to be added may vary depending on the form of the cosmetic or pharmaceutical preparation to be added, and is, for example, 0.0001% by mass or more, preferably 0.0002% by mass or more, and more preferably 0.002% by mass or more, from the viewpoint of exerting sufficient efficacy. On the other hand, from the viewpoint of solubility, the amount is 0.5% by mass or less, more preferably 0.1% by mass or less, and still more preferably 0.01% by mass or less.
The average number of addition mols of the polyoxypropylene (POP) group used in the Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether used in the present invention is 2 to 50, the average number of addition mols of the Polyoxyethylene (POE) group is 8 to 100, and the ratio [ POE/(POE + POP) ] of the average number of addition mols of the Polyoxyethylene (POE) group to the total number of addition mols of the Polyoxyethylene (POE) group and the polyoxypropylene (POP) group is preferably 0.5 or more. Here, POE and POP are abbreviated as polyoxyethylene and polyoxypropylene, respectively, and hereinafter, these are sometimes abbreviated as follows. The molar ratio of polyoxyethylene to polyoxypropylene used in the Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether is in the range of 1:5 to 5:1, preferably 1:3 to 3:1, and more preferably 1:2 to 2:1, from the viewpoint of obtaining a polymer that exhibits a desired effect. For example, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether having a POE: POP ratio of 2:1 may be used. The polyoxypropylene/polyoxyethylene random copolymer dialkyl ether can be produced by a known method (patent document 3). For example, it is obtained by subjecting a compound having a hydroxyl group to addition polymerization of ethylene oxide and propylene oxide, followed by ether reaction with an alkyl halide in the presence of a base catalyst. The amount of the surfactant to be added may vary depending on the form of the cosmetic or pharmaceutical preparation to be added, and is, for example, 0.01% by mass or more, preferably 0.05% by mass or more, and more preferably 0.1% by mass or more, from the viewpoint of exerting sufficient efficacy. On the other hand, from the viewpoint of solubility, it is used at 3 mass% or less, more preferably at 1 mass% or less, and still more preferably at 0.5 mass% or less. Further, although it is known that the polyoxyethylene/polyoxypropylene random copolymer dialkyl ether used in the present invention exerts a moisturizing effect or the like by itself or in combination with other components, the effect of the polyoxyethylene/polyoxypropylene random copolymer dialkyl ether on CD39 gene expression is not known.
The camellia extract used in the present invention refers to an extract obtained from a plant body of camellia genus of the family theaceae. Examples of plants of genus Camellia of family Theaceae include Camellia japonica (Camellia japonica), related species thereof, such as Thamnolia vermicularis (Camellia russiana), Camellia sinensis (Camellia sasanqua), and hybrid species thereof. Camellia japonica is native to Japan, and can be extracted from plant bodies thereof, such as flowers, fruits, leaves, branches, trees, and seeds. As the extraction solvent, an organic solvent or an aqueous solvent can be used, and as an example, an alcohol such as butylene glycol, propylene glycol, ethanol, or glycerin, an ether such as diethylene glycol monoethyl ether, an ester such as ethyl acetate or butyl acetate, water, or any mixture thereof can be used. For example, the camellia extract can be obtained by extracting camellia flower with 50% aqueous solution of butanediol. The Camellia japonica leaf extract can be obtained by extracting Camellia japonica leaf with 50% aqueous solution of butanediol. The amount to be blended is, for example, 0.0001% (v/v) or more, preferably 0.0002% (v/v) or more, and more preferably 0.0005% (v/v) or more, from the viewpoint of exerting sufficient efficacy. On the other hand, from the viewpoint of stability and safety, it is used at 5% (v/v) or less, more preferably at 3% (v/v) or less, and still more preferably at 1% (v/v) or less.
The blending ratio of carboxymethyl- β -glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and camellia extract used in the present invention is 1:1 to 100, preferably 1:1 to 20, and more preferably 1:10:10, when the blending amount of a 2% aqueous solution of carboxymethyl- β -glucan or a salt thereof is 1. The carboxymethyl- β -glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and 3 components of the camellia extract used in the present invention may be combined in 1 preparation, or may be combined in a plurality of preparations and administered one by one.
The inhibitor of the reduction in the expression of the CD39 gene, the external stimulus response sedative agent, and the skin immune response sedative agent of the present invention may be incorporated into cosmetics, pharmaceuticals, or quasi drugs, respectively. These agents may be administered orally, or parenterally, for example transdermally. In the case of transdermal administration, it can be made into skin external preparation. The skin external preparation is not particularly limited as long as it can be applied to the skin, and any form of solution, emulsion, solid, semisolid, powder dispersion, water-oil two-layer separation, water-oil-powder three-layer separation, ointment, gel, aerosol, mousse, stick, and the like can be used. In the case of preparing a dosage form of the skin external preparation, a base and an excipient which are generally used in the skin external preparation, for example, a preservative, an emulsifier, a pH adjuster, and the like may be used, and further, an anti-inflammatory component, for example, a steroid, an antihistamine, and the like may be further added. When added to a cosmetic, the cosmetic composition may be added to a cosmetic for face or body such as a lotion, a milky lotion, a beauty lotion, a cream, a lotion (lotion), a pack (pack), essence, or a gel, a color cosmetic such as a foundation, a cream, or a concealer, or a bath agent. By using the cosmetic containing the ingredients of the present invention, inflammatory reactions can be alleviated or prevented, and thus a healthy skin which is less likely to develop redness, itching, or rash can be maintained.
The present invention further relates to a cosmetic method, an external stimulus response calming method, a healthy muscle maintaining method, and an inflammation treatment method, comprising administering the inhibitor of the reduction in expression of CD39 gene of the present invention, an external stimulus response sedative agent, and a skin immune response sedative agent, i.e., 3 components consisting of carboxymethyl- β -glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and camellia extract. In these methods, the 3 components of the present invention may be applied by using an external preparation for skin or a cosmetic preparation containing all the components, or by continuously using an external preparation for skin or a cosmetic preparation containing individual components.
In other embodiments of the invention, the invention also relates to methods of screening for inhibitors of the reduction of expression of the CD39 gene. The screening method comprises the following steps:
a step of culturing CD39 positive cells in the presence of testosterone and a candidate substance,
A step of measuring the expression of CD39 gene, and
determining the inhibitory effect of the candidate substance on the reduction of the expression of the CD39 gene based on the expression level of the CD39 gene.
Testosterone may be added by addition to a culture of CD39 positive cells cultured in the presence of a candidate substance or medium replacement. Testosterone induces a decrease in the expression of the CD39 gene in CD 39-positive cells, and thus the inhibitory effect of a candidate substance on the decrease in the expression of the CD39 gene can be determined by measuring the expression level of the CD39 gene. The amount of the expressed CD39 gene can be measured by a known method for measuring the amount of mRNA, or the amount of the expressed protein can be measured by a known method. The inhibitory effect on the reduction of expression of the CD39 gene may also be referred to as an expression promoting effect of the CD39 gene. The inhibitor of the thus-selected reduction in expression of the CD39 gene may also be referred to as a sedative agent for a skin external stimulus response or a sedative agent for a skin immune response. As CD39 positive cells, Langerhans cells or Langerhans cell substitutes, such as THP-1 cells, can be used.
All documents mentioned in this specification are incorporated in their entirety into this specification by reference.
The examples of the present invention described below are for illustrative purposes only and do not limit the technical scope of the present invention. The technical scope of the present invention is limited only by the description of the patent claims. Modifications of the present invention, such as addition, deletion, and replacement of constituent elements of the present invention, may be made without departing from the spirit of the present invention.
Examples
Will 10 5 Each of the THP-1 (human monocyte cell line, Virginia USA) cells was seeded in each well of a 12-well plate in 2ml of RPMI1640 medium (Nacalai Tesque, Japan) supplemented with 10% fetal calf serum (FCS; Santa Ana, CA), non-essential amino acids, and essential amino acids (Nacalai Tesque, Japan), followed by culture for 24 hours. mu.L of Phosphate Buffered Saline (PBS) or 10. mu.L of the test substance diluted with PBS was added to the medium. After 1 hour incubation at 37 deg.C, 10. mu.L of EtOH or testosterone dissolved in 10. mu.L of ethanol (TST: SIGMA, St. Louise, Mo.) was added. The final concentrations of each test substance were as follows:
group a (not): PBS only, EtOH
Group B (T): 1ng/ml Testosterone (TST)
Group C (+ GA): 0.01% carboxymethyl beta-glucan (CM-Gulucan, Mibelle Biochemistry), 1ng/mL TST, and 0.1% Polyoxyethylene (POE) 14/polyoxypropylene (POP)7 random copolymer dimethyl ether
Group D (+ GA + FL 0.001): 0.01% carboxymethyl β -glucan (CM-Gulucan, Mibelle Biochemistry Co., Ltd.) and 1ng/mL TST, 0.1% Polyoxyethylene (POE) 14/polyoxypropylene (POP)7 random copolymer dimethyl ether, 0.001% camellia extract (Toyao Kabushiki Kaisha), and 0.001% camellia extract (Toyao Kabushiki Kaisha))
Group E (+ GA + FL 0.01): 0.01% carboxymethyl beta-glucan and 1ng/mL TST, 0.1% Polyoxyethylene (POE) 14/polyoxypropylene (POP)7 random copolymer dimethyl ether, 0.01% camellia extract and 0.01% camellia leaf extract
Further, after 24 hours of culture, RNA was extracted using RNeasy micro plus kit (Qiagen, Netherlands). cDNA was synthesized using the GoScript reverse transcriptase transfer kit (Promega, Japan). RT-PCR was performed using a GoTaq qPCR master mix (Promega, Japan) and a LyteCycler 480II (Roche, Switzerland). The primers used were as follows:
TABLE 1
Expression values for CD39 were normalized to ribosomal protein S9(rpS9) and statistically significant differences were determined by ANOVA and post hoc Tukey test. The results are shown in FIG. 1.
Sequence listing
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<120> inhibitor of reduction of expression of CD39 Gene
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<150> JP 2020-143559
<151> 2020-08-27
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Claims (9)
- An inhibitor of reduction in expression of the CD39 gene, comprising carboxymethyl- β -glucan or a salt thereof, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and camellia extract.
- 2. The inhibitor according to claim 1, wherein the decrease in the expression of CD39 gene is caused by an external stimulus.
- 3. The inhibitor according to claim 1, wherein the decrease in the expression of CD39 gene is caused by an increase in testosterone.
- 4. The inhibitor according to any one of claims 1 to 3, which inhibits the reduction of the expression of CD39 gene in Langerhans cells of the skin.
- 5. A sedative agent for skin external irritation response comprises carboxymethyl-beta-glucan or its salt, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and Camellia japonica extract.
- 6. A sedative agent for skin immune response comprises carboxymethyl-beta-glucan or its salt, Polyoxyethylene (POE)/polyoxypropylene (POP) random copolymer dimethyl ether, and Camellia japonica extract.
- A method of screening for an inhibitor of reduced CD39 expression comprising:a step of culturing Langerhans cells in the presence of testosterone and a candidate substance,A step of measuring the expression of CD39 gene, anddetermining the CD39 expression promoting effect of the candidate substance based on the expression level of the CD39 gene.
- 8. The method of claim 7, wherein the inhibitor of reduced expression of CD39 is a sedative agent responsive to external skin irritation.
- 9. The method of claim 7, wherein the inhibitor of reduced expression of CD39 is a skin immune response sedative agent.
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| JP2020143559 | 2020-08-27 | ||
| JP2020-143559 | 2020-08-27 | ||
| PCT/JP2021/031403 WO2022045261A1 (en) | 2020-08-27 | 2021-08-26 | Inhibitor of downregulation of cd39 gene |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009155317A (en) * | 2007-12-27 | 2009-07-16 | Bhn Kk | Anti-inflammatory agent and skin external medicine |
| CN104039337A (en) * | 2014-03-12 | 2014-09-10 | 株式会社资生堂 | Sedative for skin to respond to external stimuli and method used for tranquilizing respond |
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| JP2000236775A (en) * | 1999-02-23 | 2000-09-05 | Shiseido Co Ltd | Control of immune response in sensitized animal |
| JP2015134737A (en) * | 2014-01-18 | 2015-07-27 | 共栄化学工業株式会社 | External preparation for skin |
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2021
- 2021-08-26 WO PCT/JP2021/031403 patent/WO2022045261A1/en active Application Filing
- 2021-08-26 JP JP2022540597A patent/JPWO2022045261A1/ja active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009155317A (en) * | 2007-12-27 | 2009-07-16 | Bhn Kk | Anti-inflammatory agent and skin external medicine |
| CN104039337A (en) * | 2014-03-12 | 2014-09-10 | 株式会社资生堂 | Sedative for skin to respond to external stimuli and method used for tranquilizing respond |
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