WO2007148697A1 - 核内転写因子ap-1の発現抑制剤、それを用いた医薬品および製品 - Google Patents
核内転写因子ap-1の発現抑制剤、それを用いた医薬品および製品 Download PDFInfo
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- A61K36/185—Magnoliopsida (dicotyledons)
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Definitions
- the present invention relates to an expression inhibitor of nuclear transcription factor AP-1, a pharmaceutical and a product using the same.
- Site force-in such as interleukin and TNF (tumor necrosis factor) is involved in the onset of many diseases such as cancer, arteriosclerosis, hypertension and diabetes. Site force-in is secreted by external force stimuli and plays a role in causing various reactions for biological defense.
- TNF tumor necrosis factor
- IL-1 interleukin 1
- IL-1R IL-1 receptor
- IL-RAcP IL-1R-AcP
- MyD88 MyD88
- IRA K force A complex is formed.
- IRAK then departs from the receptor complex within a few minutes and binds to an adapter protein called TRAF6.
- TRAF6 binds to TAK1 and TAB1 and activates as a TABlZTAKl complex.
- TAK1 is one of the kinases belonging to MAP kinase kinase ( ⁇ )
- TAB1 is an activator of TAK1.
- the TABlZTAKl complex phosphorylates and activates both MAP kinase (MAPKK) and NIK (NF- ⁇ B inducing kinase), which activates two downstream kinase cascades.
- MAPKK MAP kinase
- NIK NF- ⁇ B inducing kinase
- One kinase cascade system is a cascade that activates the nuclear transcription factor AP-1 (hereinafter referred to as “AP-1”).
- AP-1 nuclear transcription factor AP-1
- JNK c-JunN-terminal kinase
- p38 both of which are members of MAPKK.
- the other kinase cascade system is a cascade that activates NF- ⁇ B (nuclear factor kappa B).
- NF— ⁇ ⁇ does not bind to DNA and is usually present in the cytoplasm by forming a complex with the I ⁇ in (inhibitor- ⁇ ⁇ ) protein. It is activated by being decomposed and decomposed (separated). This phosphorylation is performed by IKK and NIK.
- an inflammatory reaction is caused, and for example, diseases such as cancer, arteriosclerosis, hypertension or diabetes develop.
- AP-1 has the ability to bind to DNA.
- a specific TRE sequence TGACTCA
- CRE sequence TGACGTCA
- site-in genes such as interleukin 6 (IL-6) and TNF, which have an important role in joint inflammation, and meta-oral protease genes such as collagenase and stromelysin that cause joint destruction
- IL-6 interleukin 6
- TNF tumor necrosis factor 6
- meta-oral protease genes such as collagenase and stromelysin that cause joint destruction
- AP-1 has attracted attention as a drug discovery target for inflammatory diseases of connective tissues such as rheumatoid arthritis.
- Specific examples include substances that suppress the activity of AP-1 by inhibiting the binding of AP-1 to DNA, such as theanine in natural products (Patent Document 1), retinoid compounds (Patent Document 2). ), Oligonucleotides (Patent Document 3) and actinomycete secretions (Patent Document)
- Patent Document 1 Japanese Patent Laid-Open No. 2003-55213
- Patent Document 2 Japanese Patent Publication No. 11-504328
- Patent Document 3 Japanese Patent Laid-Open No. 10-36272
- Patent Document 4 Japanese Patent Laid-Open No. 10-130201
- an object of the present invention is to provide an inhibitor of AP-1, which is excellent in safety and excellent in activity of suppressing AP-1.
- the expression inhibitor of nuclear transcription factor AP-1 of the present invention contains force mamelloside.
- the pharmaceutical product of the present invention is a pharmaceutical product for preventing or treating a disease involving nuclear transcription factor AP-1 or healing a wound, and suppressing the expression of nuclear transcription factor AP-1 of the present invention. Contains agents.
- the product of the present invention is a product for preventing or ameliorating a disease involving nuclear transcription factor AP-1 or promoting wound healing, and suppressing the expression of nuclear transcription factor AP-1 of the present invention. Contains agents.
- the expression suppression method of the present invention is a method of suppressing the expression of nuclear transcription factor AP-1.
- the method of the present invention is a method for preventing or treating a disease involving nuclear transcription factor AP-1 or for healing a wound, which comprises the step of administering force mamelloside.
- the use of the force mamelloside of the present invention is to suppress the expression of nuclear transcription factor AP-1
- the present inventors have made a series of studies on substances that suppress the activity of AP-1, mainly natural products. As a result, the present inventors have found that the expression of the force tameroside force AP-1 contained in the mouth-mouthed mitsule or German chamomile, which is a kind of Asteraceae, is suppressed, and the present invention has been achieved.
- Roman potty or German potion is used, for example, as a food for herbal tea and raw materials for cosmetics, and there is no problem with its safety.
- force mameroside suppresses the expression of AP-1, and thus inhibits the binding of expressed AP-1 to DNA, as in the past, rather than suppressing the activity of AP-1. Effectively suppresses AP-1 activity.
- force mameroside has the activity of suppressing NF- ⁇ B and the activity of suppressing the Maillard reaction as well as the activity of suppressing the expression of AP-1. For this reason, they work synergistically with the AP-1 expression inhibitory activity, and have remarkable effects on various diseases such as inflammatory diseases.
- FIG. 1 is a diagram showing an HPLC chromatogram of a Roman mitre extract in one example of the present invention.
- FIG. 2 is a graph showing the effect of suppressing the expression of nuclear treadmill factor AP-1 of force mameroside in the above-mentioned Examples.
- FIG. 3 is a graph showing the NF- ⁇ B expression-inhibiting effect of Roman strength mitre extract and strength tunaloside in the Reference Example.
- FIG. 4 is a diagram showing the relationship between interleukin 1 and nuclear transcription factors AP-1 and NF- ⁇ B.
- FIG. 5 is a diagram showing an HPLC chromatogram in one example of the present invention, (a) is an HPLC chromatogram of a German chamomile extract, and (b) is a Roman force mitre. It is a chromatogram of HPLC of origin force mameroside.
- the suppression of AP-1 expression is at least one of expression suppression at the gene level and expression suppression at the protein level.
- the suppression of expression at the gene level includes suppression of transcription into mRNA.
- the expression suppression at the protein level includes suppression in translation, and when it is modified after translation, it includes suppression of the modification.
- the expression of AP-1 can be suppressed at the gene level or protein level.
- the AP-1 expression inhibitor of the present invention is not limited, but is preferably administered or ingested to, for example, humans and mammals other than humans.
- examples of the force mamelloside include force mamelloside derived from Roman force mitre (Anthemis nob ilis), force mameroside derived from German force fir tree (Matricaia recutita), and the like.
- the force mamelloside derived from the Roman force mitre may be derived from any part of the Roman force miele. Examples include whole Roman honey (whole plants), flowers, stems, leaves, branches, branches and leaves, rhizomes, root barks, roots, seeds, etc. Better ,.
- the force chamomile derived from German chamomile may be derived from any part of the German chamomile. For example, ja One man chamomile (whole plant), flowers, stems, leaves, branches, branches and leaves, rhizome, root bark, roots, seeds, etc. Among these, whole plant and flowers derived force tallows are preferred.
- the expression inhibitor of the present invention only needs to contain force tameloside.
- the form of force tameloside is not limited. That is, the expression-suppressing agent of the present invention may contain, for example, purified force mamelloside, or may contain force mamelloside, for example, by including all or part of Roman force mire or German chamomile. Good. Examples of the former include force mamelloside, which is obtained by extracting Roman force mire or German chamomile force and further purifying it. When purifying the extract, the gull mouth side may be a single purified product or a partially purified product.
- the latter includes, for example, an extract of all or part of a Roman force or German chamomile (for example, an unrefined crude state), or all or part of a Roman force or German force. Crushed material and the like.
- Either the Roman force or German force module may be used, or both of them may be included.
- a synthetic product or a commercially available product may be used as the force mamelloside.
- the force mameloside is apigenin 7-glucoside-6,,-(3 ,, -hydroxy-3 ',, -methyl-glutrate), and is represented by the following chemical formula. . It should be noted that the force mamelloside in the present invention may be a salt of force mameroside (for example, Na salt, K salt, etc.).
- the AP-1 expression inhibitor of the present invention is not limited in its configuration and form as long as it contains forceful tunaloside. That is, the AP-1 expression inhibitor of the present invention is: As described above, force mamelloside alone, Roman force mit or German force fir extract alone, mixture of Roman force mistlet and German chamomile extract, Roman force mitelle or German chamomile alone, Roman force A mixture of a pulverized mitle and a German chamomile pulverized product, or a mixture thereof, or may contain other components.
- the other components are not limited and can be appropriately determined depending on the application of the present invention. Examples thereof include various components and various additives described below.
- the extract of Roman force mire or German chamomile is not limited, and examples thereof include a water extract and a solvent extract as described later.
- a solvent extract for example, an alcohol extract is preferable.
- the alcohol extract include isopropyl alcohol extract, ethanol extract, methanol extract and the like. Among these, an ethanol extract is preferable.
- the content of force tunaloside in the expression inhibitor of the present invention is not limited, and can be appropriately determined depending on, for example, the use of the present invention.
- the content of forceful tameloside is compounded so as to be, for example, 0.001 to 90% by weight, particularly 0.1 to 90% by weight in terms of dry weight. It is preferable.
- the expression inhibitor of the present invention is made into a tablet or capsule shape, for example, 0.1 to 90% by weight can be added per tablet or capsule.
- the expression inhibitor of the present invention in such a form can be commercialized as, for example, a pharmaceutical or a supplement described later.
- the expression inhibitor of the present invention when the expression inhibitor of the present invention is made into a liquid, for example, the content of force mameloside as an active ingredient is dissolved in the liquid so that the concentration is, for example, 0.01 to 1% by weight,
- additives can be added and filled into bottle containers (eg, lOOmL volume).
- the liquid include water alcohol and the like, and examples of the additive include a fragrance, a sweetener, and a preservative.
- the container is preferably, for example, a brown bottle to prevent the contents from being denatured.
- the expression inhibitor of the present invention in such a form can be commercialized as, for example, a health food or drink, a food for specified health use, a dietary supplement or the like.
- the intake and dose of force mamelloside are not limited, but for example, per adult day, 0.01-: LOOOmgZkg is preferred per day, 0.1-: LOOmgZkg is more preferred.
- administration or ingestion of the strength tameloside may be performed once a day or divided into several times a day, for example.
- a skin external preparation such as a coating, for example, cream, jewel, ointment, pap, etc. It is preferable that the amount is 0.1% to 1% by weight.
- the expression-suppressing agent of the present invention when used, for example, as a skin external preparation for cosmetics or the like, force tunaloside is added to lotion, milky lotion, cream, powder, etc. to be 0.001 to LO weight%. It is preferable to combine with 0.1 to 1% by weight.
- the raw material for preparing the extract of Roman force mits or German chamomile that is, various parts of Roman force mits or German chamomile is not limited.
- the raw material include whole (whole plant), flowers, stems, leaves, branches, branches and leaves, rhizomes, root barks, roots, seeds, and the like of at least one of Roman potty and German chamomile. Among these, whole grass and flowers are preferable. If available as a dried herb or herbal medicine, it may be used.
- the extract of Roman force mits or German chamomile can be obtained by, for example, directly extracting a solvent from the above-described raw materials (various parts of Roman force mitsle or German chamomile).
- a pressing liquid obtained from a cocoon paste by subjecting the raw material to a pressing treatment is also included.
- what is obtained by adding a solvent to the squeezed solution or residue obtained by the squeezing treatment and extracting it can also be used.
- the extraction solvent used for the extraction of the force buffaloside is not limited, and can be appropriately selected in consideration of, for example, the intended purpose and type of the product to be provided, or the processing performed later.
- the extraction solvent for example, an aqueous solvent, an organic solvent, a mixed solution thereof or the like can be used.
- Specific examples include, for example, water; lower alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, butanol, isobutanol or water-containing lower alcohols; propylene glycol, 1, 3 butylene glycol, 1, 2- Butylene glycol, 1,4-butylene glycol, 1,5 pentanediol, 1,2 pentanediol, 1,3 pentanediol, 1,4 pentanediol, 1,3,5 pentanetriol, glycerin, polyethylene glycol (molecular weight Polyhydric alcohol or hydrous polyhydric alcohol such as acetone, ethyl acetate, jetyl ether, dimethyl ether, ethyl methyl ether, dioxane, acetonitrile, xylene, vinyl And various organic solvents such as benzene, chloroform, carbon tetrachloride, phenol, and toluene.
- acids and alkalis having normality adjusted as appropriate can be mentioned.
- the acid include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, and the like.
- the alkali include sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonia. Etc. can be used.
- any one of these solvents may be used, or two or more of them may be mixed and used.
- the extraction may be performed using a solvent that can be easily removed after the extraction treatment (for example, a highly volatile solvent), and the solvent may be removed and then dissolved in the aqueous solvent.
- the extraction method is not limited, and can be appropriately determined according to, for example, the temperature of the solvent used, the weight ratio of the solvent to the raw material, and the like.
- the extraction time is not limited, and can be arbitrarily set according to, for example, the type of raw material used, the type of solvent used, or a combination thereof.
- the temperature of the solvent can be arbitrarily set, for example, in the range of 4 ° C to 100 ° C, but is preferably around 10 to 80 ° C from the viewpoint of the extraction rate and stability of the components contained in the raw material.
- the weight ratio (A: B) of the solvent (B) to the raw material (A) can be arbitrarily set within a range of, for example, 4: 1 to 1:50, and in particular, 1: 1 to 1:20. A range is preferred.
- the Roman honey beetle extract or German chamomile extract may be subjected to a purification treatment as appropriate after performing the extraction as described above, for example.
- the above-described Roman mitsule extract or German chamomile extract The form is not limited, and examples thereof include liquid, solid, powder, paste, and gel.
- the dosage form of the AP-1 expression inhibitor of the present invention is not limited, and can be arbitrarily set according to the purpose of use, for example. Specific examples include, for example, ampoules, capsules, powders, granules, pills, tablets, solids, liquids, gels, bubbles, emulsions, creams, ointments, sheets, mousses. , Powder dispersion, multilayer, aerosol and the like.
- the AP-1 expression inhibitor of the present invention can be applied to, for example, pharmaceuticals, quasi drugs, and other products.
- the product is not particularly limited, and examples thereof include supplements, foods, drinks, food additives, cosmetic raw materials, and cosmetics.
- the pharmaceutical product of the present invention is a pharmaceutical product for preventing or treating a disease associated with the nuclear transcription factor AP-1 or healing a wound, and comprises the expression inhibitor of AP-1 of the present invention.
- the disease include cancer, cancer metastasis, arteriosclerosis, hypertension, diabetes, skin disease, aggravated hyperproliferative disease, neointimal hyperproliferative disease, non-malignant hyperproliferative disease, autoimmune disease, immune Group, consisting of diseases, arthritis, asthma, allergies, chronic inflammatory diseases, lipid metabolism transport-related diseases, dry eye syndrome, neurodegenerative diseases, Arnno-Ima monomorphic diseases, and Parkinson's disease Includes at least one selected disease.
- the dermatosis includes at least one disease selected from the group force consisting of, for example, rapeseed, Darier's disease, psoriasis, ichthyosis, eczema, sun dermatitis and atopic dermatitis.
- the malignant hyperproliferative disease includes, for example, at least one disease selected from the group consisting of epithelial cancer, breast cancer, prostate cancer, head and neck cancer, and myeloid leukemia.
- the neointimal hyperproliferative disease includes, for example, at least one disease of atherosclerosis and restenosis.
- the non-malignant hyperproliferative disease includes, for example, at least one disease selected from the group consisting of endometrial hyperplasia, benign prostatic hypertrophy and proliferative vitreoretinopathy.
- the autoimmune disease includes, for example, rheumatoid arthritis.
- the immune disease includes, for example, lupus erythematosus.
- the chronic inflammatory disease includes, for example, pulmonary fibrosis.
- the lipid metabolism transport related diseases include, for example, hyperlipidemia.
- the pharmaceutical agent of the present invention may contain, for example, other AP-1 expression inhibitory components, pharmaceutically acceptable additives, and the like.
- specific dosage forms include, for example, tablets, fine granules (including powder), capsules, liquids (including syrup) and the like.
- suitable additives and base materials can be used as appropriate, and they can be produced according to the usual methods described in the Japanese Pharmacopoeia.
- the administration route is not limited, and examples thereof include oral administration and parenteral administration. Examples of the parenteral administration include oral administration, intratracheal administration, rectal administration, subcutaneous administration, intramuscular administration, intravenous administration and the like.
- the parenteral administration includes, for example, application to the skin (transdermal administration).
- the supplement of the present invention is a supplement for preventing or ameliorating a disease involving AP-1 or promoting healing of a wound, and comprises the AP-1 expression inhibitor of the present invention.
- the disease include cancer, cancer metastasis, arteriosclerosis, hypertension, diabetes, skin disease, aggravated hyperproliferative disease, neointimal hyperproliferative disease, non-malignant hyperproliferative disease, autoimmune disease, immune Group, consisting of diseases, arthritis, asthma, allergies, chronic inflammatory diseases, lipid metabolism transport-related diseases, dry eye syndrome, neurodegenerative diseases, Arnno-Ima monomorphic diseases, and Parkinson's disease Includes at least one selected disease.
- the dermatosis includes at least one disease selected from the group force consisting of, for example, rapeseed, Darier's disease, psoriasis, ichthyosis, eczema, sun dermatitis and atopic dermatitis.
- the malignant hyperproliferative disease includes, for example, at least one disease selected from the group consisting of epithelial cancer, breast cancer, prostate cancer, head and neck cancer, and myeloid leukemia.
- the neointimal hyperproliferative disease includes, for example, at least one disease of atherosclerosis and restenosis.
- the non-malignant hyperproliferative disease includes, for example, at least one disease selected from the group consisting of endometrial hyperplasia, benign prostatic hypertrophy and proliferative vitreoretinopathy.
- the autoimmune disease includes, for example, rheumatoid arthritis.
- the immune disease includes, for example, lupus erythematosus.
- the chronic inflammatory disease includes, for example, pulmonary fibrosis.
- the lipid metabolism transport related diseases include, for example, hyperlipidemia.
- the supplement of the present invention may contain various additives, other supplements and the like in addition to the expression inhibitor of the present invention.
- the other components include other AP-1 expression-suppressing components, various vitamins such as vitamin C, amino acids, oligosaccharides, and the like.
- the form of the supplement of the present invention is not particularly limited, and examples thereof include tablets, fine granules (including powder), capsules, liquids (including syrup) and the like.
- the food of the present invention is a food for preventing or ameliorating a disease associated with AP-1 or promoting wound healing, and comprises the expression inhibitor of AP-1 of the present invention.
- the diseases include, for example, cancer, cancer metastasis, arteriosclerosis, hypertension, diabetes, skin diseases, malignant hyperproliferative diseases, neointimal hyperproliferative diseases, non-malignant hyperproliferative diseases, autoimmune diseases, immune diseases, It includes at least one disease selected from the group consisting of arthritis, asthma, allergy, chronic inflammatory disease, lipid metabolism transport-related disease, dry eye syndrome, neurodegenerative disease, Alzheimer's disease and Parkinson's disease.
- the dermatosis includes, for example, at least one disease selected from rapeseed, Darier's disease, psoriasis, ichthyosis, eczema, sun dermatitis (Sunburn) and atopic dermatitis.
- the malignant hyperproliferative disease includes, for example, at least one disease selected from the group consisting of epithelial cancer, breast cancer, prostate cancer, head and neck cancer, and myeloid leukemia.
- the neointimal hyperproliferative disease includes, for example, at least one disease of atherosclerosis and restenosis.
- the non-malignant hyperproliferative disease includes at least one disease selected from the group consisting of endometrial hyperplasia, benign prostatic hypertrophy and proliferative vitreoretinopathy, for example.
- the autoimmune disease includes, for example, rheumatoid arthritis.
- the immune disease includes, for example, lupus erythematosus.
- the chronic inflammatory disease includes, for example, pulmonary fibrosis.
- the lipid metabolism transport related diseases include, for example, hyperlipidemia.
- the food of the present invention may contain other various components in addition to the expression inhibitor of the present invention.
- the other components include other AP-1 expression inhibitory components, various supplements, supplements, and the like.
- the food is, for example, a general food And functional foods.
- the form of the food is not limited, and examples thereof include cereals, potatoes, confectionery, soups, meat, seafood, seaweed, vegetables, fruits, beans, various calories, dried foods, frozen foods, There are salmon products, canned food, bottled food, retort food, etc.
- the beverage of the present invention is a beverage for preventing or ameliorating a disease associated with AP-1 or promoting wound healing, and comprises the expression inhibitor of AP-1 of the present invention.
- the diseases include, for example, cancer, cancer metastasis, arteriosclerosis, hypertension, diabetes, skin diseases, malignant hyperproliferative diseases, neointimal hyperproliferative diseases, non-malignant hyperproliferative diseases, autoimmune diseases, immune diseases, It includes at least one disease selected from the group consisting of arthritis, asthma, allergy, chronic inflammatory disease, lipid metabolism transport-related disease, dry eye syndrome, neurodegenerative disease, Alzheimer's disease and Parkinson's disease.
- the dermatosis includes, for example, at least one disease selected from rapeseed, Darier's disease, psoriasis, ichthyosis, eczema, sun dermatitis (Sunburn) and atopic dermatitis.
- the malignant hyperproliferative disease includes, for example, at least one disease selected from the group consisting of epithelial cancer, breast cancer, prostate cancer, head and neck cancer, and myeloid leukemia.
- the neointimal hyperproliferative disease includes, for example, at least one disease of atherosclerosis and restenosis.
- the non-malignant hyperproliferative disease includes at least one disease selected from the group consisting of endometrial hyperplasia, benign prostatic hypertrophy and proliferative vitreoretinopathy, for example.
- the autoimmune disease includes, for example, rheumatoid arthritis.
- the immune disease includes, for example, lupus erythematosus.
- the chronic inflammatory disease includes, for example, pulmonary fibrosis.
- the lipid metabolism transport related diseases include, for example, hyperlipidemia.
- the beverage of the present invention may contain, for example, other various components in addition to the expression inhibitor of the present invention.
- the other components include other AP-1 expression-suppressing components, various additives, supplements, and the like.
- the beverage includes, for example, both general beverages and functional beverages.
- the form of the beverage is not limited, and examples thereof include soft drinks such as juice, carbonated beverages, coffee, tea, green tea, mineral water, and the like.
- the food additive of the present invention is a food additive for preventing or ameliorating a disease involving AP-1 or promoting healing of a wound, comprising the expression inhibitor of AP-1 of the present invention. .
- the disease examples include cancer, cancer metastasis, arteriosclerosis, hypertension, diabetes, skin disease, malignant hyperproliferative disease, neointimal hyperproliferative disease, non-malignant hyperproliferative disease, autoimmune disease, and immune disease.
- Arthritis, asthma, allergies, chronic inflammatory diseases, lipid metabolism transport-related diseases, dry eye syndrome, neurodegenerative diseases, Arnno-Ima monosexual disease and Parkinson's disease group power At least one disease selected.
- the dermatosis includes at least one disease selected from the group consisting of rapeseed, Darier's disease, psoriasis, ichthyosis, eczema, sun dermatitis and atopic dermatitis.
- the malignant hyperproliferative disease includes, for example, at least one disease selected from the group consisting of epithelial cancer, breast cancer, prostate cancer, head and neck cancer, and myeloid leukemia.
- the neointimal hyperproliferative disease includes, for example, at least one disease of atherosclerosis and restenosis.
- the non-malignant hyperproliferative disease includes, for example, at least one disease selected from the group consisting of endometrial hyperplasia, benign prostatic hypertrophy and proliferative vitreoretinopathy.
- the autoimmune disease includes, for example, rheumatoid arthritis.
- the immune disease includes, for example, lupus erythematosus.
- the chronic inflammatory disease includes, for example, pulmonary fibrosis.
- the lipid metabolism transport-related disease includes, for example, hyperlipidemia.
- the food additive of the present invention may contain, for example, other various components in addition to the expression inhibitor of the present invention.
- the other components include other AP-1 expression suppressing components, various additives, supplements, and the like.
- the form of the food additive of the present invention is not limited, and examples thereof include liquid, powder, flakes, and granules.
- the food additive of the present invention includes a food additive for beverages in addition to food.
- the cosmetic raw material of the present invention is a cosmetic raw material for preventing or ameliorating a disease involving AP-1 or promoting healing of a wound, and contains the AP-1 expression inhibitor of the present invention.
- the disease include skin diseases. Specifically, for example, rapeseed, Darier's disease, psoriasis, ichthyosis, eczema, sun dermatitis (Sunburn) and atopic dermatitis force Force Includes at least one disease selected.
- the cosmetic raw material of the present invention is not limited, but is preferably applied to, for example, humans and mammals other than humans.
- the cosmetic raw material of the present invention may contain, for example, other various components in addition to the expression inhibitor of the present invention.
- the other components include other AP-1 expression-suppressing components and various additives.
- the various additives include various fats and oils, waxes, mineral oils, fatty acids, alcohols, polyhydric alcohols, esters, metal soaps, gums, sugars, water-soluble polymers, interfaces.
- Activators various vitamins, various amino acids, plant or animal-derived additives, crude drugs, marine components, microbial culture metabolites, a-hydroxy acids, inorganic pigments, UV absorbers, UV blockers, whitening agents, tyrosinase activity Inhibitor, melanin pigment reducing agent, melanin pigment degrading agent, cell activator, astringent, active oxygen remover, antioxidant, lipid peroxide inhibitor, anti-inflammatory agent, antibacterial agent, bactericidal agent, disinfectant, Moisturizer, elastase activity inhibitor, hair agent, antiandrogen agent, peripheral vascular blood flow promoter, stimulant, metabolic activator, antiseborrheic agent, keratolytic agent, oxidizing agent, hair remover, hair swelling agent , Dyes, fragrances, pigments Coloring agents, sweeteners, nutrition enhancers, dairy products, hormones, sequestering agents, pH regulators, chelating agents, preservatives, fungicides, cooling agents, stabilizers
- the cosmetic of the present invention contains the cosmetic raw material of the present invention.
- the cosmetic of the present invention is preferably applied to, for example, humans and mammals other than humans.
- the cosmetic of the present invention may contain, for example, other additives in addition to the cosmetic raw material of the present invention.
- lifted with the above-mentioned cosmetic raw material can be used, for example.
- the form of the cosmetic product of the present invention is not particularly limited.
- basic cosmetics such as lotion, emulsion, cream, ointment, lotion, oil, pack, etc .
- skin such as stone candy, cleansing cream, cleansing growth, face wash
- Cosmetics for hair washing such as shampoo, rinse, treatment, etc .
- Hair conditioners such as hair cream, hair spray, hair tonic, hair jersey, hair lotion, hair oil, hair essence, hair water, hair wax, hair foam; Hair's hair nourishment; 1-component hair dye, 2 agent hair dye, hair color such as hair color; Permanentue hair perfume such as hair straightener and hair cosmetic such as wave retention agent ;
- Make-up cosmetics such as foundation, white powder, white, lipstick, scarlet, eye shadow, eyeliner, mascara, eyebrows, eyelashes, etc .
- cosmetics for finishing such as beauty nails
- cosmetics such as perfumes Composition.
- toothpastes for example, toothpastes; oral compositions such as gargles; external pharmaceutical preparations; ointments; poultices; bath preparations; medicinal oral compositions such as medicated toothpastes and mouth refreshers; medicinal cosmetics; permanent waves Hair solvents such as solvents, hair dyes, hair restorers, hair loss inhibitors, hair removers, etc .; odor and body odor preventives; hygiene products, sanitary cotton, wet-tissues and other external pharmaceutical products.
- the present invention is a method for suppressing the expression of AP-1, which comprises the step of administering the force tunaloside.
- the administration of force mamelloside can suppress the expression of AP-1 in cells.
- the subject to which force mamelloside is administered is not limited and may be, for example, a living body, a cell isolated from a living body, or a cultured cell. Examples of the living body include, but are not limited to, humans and mammals including humans.
- the form of the force mamelloside to be administered is not limited, and may be, for example, purified force mamelloside as described above, and may be an extract or a pulverized product of Roman force or German chamomile. It is done. Specific examples of the form of force mamelloside in the present invention include the same forms as those of the AP-1 expression inhibitor, pharmaceuticals, various products and the like of the present invention described above.
- the administration method is not limited, and examples thereof include oral administration and parenteral administration in the case of a living body.
- parenteral administration include oral administration, intratracheal administration, rectal administration, subcutaneous administration, intramuscular administration, intravenous administration, application to the skin (transdermal administration) and the like.
- a method of culturing by adding strong tunaloside to the medium can be mentioned.
- the present invention is a method for preventing or treating a disease involving AP-1 or healing a wound, which comprises the step of administering force mamelloside.
- the form of the AP-1 expression inhibitor of the present invention is not limited and is the same as described above.
- the AP-1 expression inhibitor is, for example, as described above, an inflammatory improver, a pharmaceutical, a supplement, a food, You may administer as a drink and a food additive.
- the administration method is not limited, and examples thereof include oral administration and parenteral administration.
- Examples of the parenteral administration include oral administration, intratracheal administration, intrarectal administration, subcutaneous administration, intramuscular administration, intravenous administration, and application to the skin (transdermal administration).
- the subject to which the mouth side of the seagull is administered is not limited, and examples thereof include humans and mammalian animals including humans.
- the silica gel-containing concentrated fraction was purified for the first time by the following column chromatography.
- the silica gel-containing concentrated fraction was suspended in black mouth form Z methanol (volume ratio 8Z1), and the pH was adjusted to 4. Then, place the chromatograph tube with a diameter of 5 cm and a height of 20 cm on the About 400 cm 3 of silica gel equilibrated with oral form Z methanol (volume ratio 7/1) was filled, and from above, the suspension of the concentrated fraction containing silica gel was filled from above. .
- elution was performed using about 1200 mL each of Kuroguchi Forms methanol (volume ratio 7Zl, 5/1, 3/1, lZl) and methanol in this order.
- the fraction eluted with chloroform Zmethanol (volume ratio 1Z1) was collected, and the contained solvent was removed under reduced pressure.
- the fraction collected by the first column chromatography was further purified a second time by the following column chromatography matrix.
- the concentrated recovered fraction was dissolved in acetonitrile, water ZTFA (volume ratio 10Z90ZO. 1).
- a carrier suspended in methanol (trade name Cosmosill 40 C18—OPN) was packed in a 3 cm diameter chromatographic tube, and equilibrated with 600 mL of acetonitrile Z water ZTFA (volume ratio 10Z90Z0.1).
- the recovered fraction dissolved in the aforementioned acetonitrile Z water ZTFA was applied to this chromatographic tube.
- the elution was then performed using 180 mL each of aceto-sulyl Z water ZTFA (volume ratio 10Z90Z0.1, 18/82 / 0.1, 25/75 / 0.1) and acetonitrile in this order.
- the fractions that were run and eluted with acetonitrile Z water ZTFA were collected.
- the collected fraction obtained was concentrated under reduced pressure and then freeze-dried.
- the lyophilized product was redissolved with methanol, and then this tartrate was isolated by subjecting this methanol solution to preparative HPLC under the following conditions.
- TFA is trifluoroacetic acid.
- the sample was a methanol solution containing 100 mg / mL equivalent of Roman strength mitre extract solids.
- Figure 1 shows the HPLC chromatogram.
- the peak indicated by the arrows in Fig. 1 is the force tuna side peak.
- the identification of force mamelloside is performed by measuring the nuclear magnetic resonance spectrum (NMR) of the substance isolated by HPLC, and confirming the agreement with the analytical value of literature (Gabriela et al., Phytochemistry, 41: 643-646, 1996). went.
- the NMR data is shown in Table 1 below together with the literature data.
- the refined force mamelloside obtained was 32 mg with respect to 300 mg Roman extract.
- HeLa cells were trypsinized and centrifuged at 4 ° C 1000 rpm for 3 minutes. The collected Hela cells were seeded in a 30 mm petri dish so as to have a density of 2 ⁇ 10 5 cells / well and used as a test plate. Place the assay plate in the presence of 5% CO at 37 ° C for 12 hours. After blast culture, transformation was performed. For the transformation, two types of vectors were introduced into the cells using a transformation reagent (trade name Effectene Transfection Reagent, QIAGEN).
- a transformation reagent trade name Effectene Transfection Reagent, QIAGEN
- the cultured cells were detached from the assay plate using trypsin.
- the detached cells were dispensed into a 96-well plate by 0.2 ⁇ 10 4 cells.
- add the above-mentioned force mamelloside solution so that the final concentration (weight of solid extract) is 10 gZmL, 5.0 gZmL, 2.5 ⁇ g / m 1.0 gZmL.
- TPA (12-O-tetradecanoylphorbol acetate) was added to a final concentration of 4 ⁇ gZmL. Twenty-four hours after the addition, 25 L of the medium was collected.
- the collected medium was evaluated for secreated alkaline phosphatase (SEAP) activity based on the contained nuclear transcription factor AP-1 activity using a kit (trade name: Great EscAPe SEAP kit, CLON TECK). Also. The gene expression was corrected using the measured value of Luciferase activity measured by Luciferase activity measurement kit (HPromega). The results are shown in the graph in Fig. 2.
- the evaluation of the suppression of nuclear transcription factor AP-1 was evaluated by relative value% of secreated alkaline ph osphatase (SEAP) activity (inhibition rate. 0 ).
- the expression of the nuclear transcription factor AP-1 could be suppressed (inhibited) in a concentration-dependent manner by adding force mamelloside.
- the power of the legoside IC the power of the legoside IC
- Fig. 5 shows the chromatograms of these HPLCs.
- (a) is a chromatogram of German chamomile extract
- (b) is a chromatogram of Roman tuna-derived force mamelloside.
- the German chamomile extract had a peak at the same retention time as the Roman mitsule-derived force mamelloside shown in the figure (b). From this result, it was possible to identify that the German chamomile extract contains force tunaloside.
- the forceful melamine is also included in the German force mitsu, so that, as in the case of the mouth-watering mitsule, the force chamomile can be prepared using the German chamomile as a raw material, and the AP-1 expression suppression effect is obtained. It is clear that
- the present reference example is an example in which the inhibition of NF- ⁇ B activity was evaluated using the Roman forcelet extract and force mamelloside obtained in Example 1.
- HeLa cells were trypsinized and centrifuged at 4 ° C, 1000 rpm for 3 minutes. The collected Hela cells were plated to a density of 2 ⁇ 10 5 cells Zwell, and then plated on a 30 mm petri dish to prepare an assay plate. Place the assay plate in the presence of 37 ° C, 5% CO for 12 hours,
- the cells were cultured and then transformed.
- two types of vectors were introduced into the cells using a transformation reagent (trade name Effectene Transfection Reagent, QIAGEN).
- a transformation reagent trade name Effectene Transfection Reagent, QIAGEN.
- the vector trade name pNF— ⁇ —SEAP (CLONTECH) (0.4 / zg) and trade name pLuc—control (CLONTECH) (0.02 / zg) were used.
- the cells into which both vectors are introduced are present for 16 hours at 37 ° C and 5% CO.
- the cultured cells were detached from the assay plate using trypsin.
- the detached cells were dispensed into a 96-well plate by 0.2 ⁇ 10 4 cells.
- the roman force extract is added so that the final concentration (extract solid weight) is 100 / zg / mL, 50 gZmL, 25 gZmL, or To the final concentration of 100 gZmL, 50 gZmL, and 25 gZmL, the above-mentioned force mamelloside solution was added, and TNF (tumor necrosis factor) -alpha was added to a final concentration of 40 ngZmL. Twenty-four hours after the addition, 25 L of the medium was collected.
- the collected medium was evaluated for secreated alkaline phosphatase (SEAP) activity based on the contained NF- ⁇ — activity using a kit (trade name: Great EscAPe SEAP kit, CLONTECK).
- SEAP secreated alkaline phosphatase
- the gene expression was corrected using the measured value of Luciferase activity measured by Luciferase activity measurement kit (Promega). The results are shown in the graph of Fig. 3.
- the inhibition of NF- ⁇ B expression was evaluated based on the se created alkaline phosphatase (SEAP) activity when the Luciferase activity at each concentration of the test substance (Roman strength mitre extract or strength tunaloside solution) was 100%. It was expressed as a relative value% (inhibition rate%).
- the IC for force tameroside was 80 ⁇ gZmL.
- the expression inhibitor of the nuclear transcription factor AP-1 of the present invention is characterized by containing force teloside, is excellent in safety, and has no problem even if taken for a long time.
- the expression inhibitor of the present invention exhibits an excellent inhibitory activity on the expression of nuclear transcription factor AP-1. Therefore, the expression inhibitor of nuclear transcription factor AP-1 of the present invention can be applied to various agents such as pharmaceuticals, quasi drugs, supplements, foods, beverages, food additives, etc. Wide without being restricted.
Abstract
Description
Claims
Priority Applications (4)
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JP2007548640A JP4836961B2 (ja) | 2006-06-22 | 2007-06-19 | 核内転写因子ap−1の発現抑制剤、それを用いた医薬品および製品 |
US12/161,229 US20100240603A1 (en) | 2006-06-22 | 2007-06-19 | Expression inhibitor of nuclear transcription factor ap-1 and pharmaceuticals and products using the same |
EP07767198A EP2033650A4 (en) | 2006-06-22 | 2007-06-19 | INHIBITOR OF EXPRESSION OF AP-1 NUCLEAR TRANSCRIPTION FACTOR, AND PHARMACEUTICAL OR OTHER PRODUCTS USING THE INHIBITOR |
CN2007800230904A CN101472597B (zh) | 2006-06-22 | 2007-06-19 | 核转录因子ap-1的表达抑制剂及使用其的药品和制品 |
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JP2006-172997 | 2006-06-22 |
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US (1) | US20100240603A1 (ja) |
EP (1) | EP2033650A4 (ja) |
JP (1) | JP4836961B2 (ja) |
CN (1) | CN101472597B (ja) |
WO (1) | WO2007148697A1 (ja) |
Cited By (5)
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WO2008114536A1 (ja) * | 2007-03-20 | 2008-09-25 | Arkray, Inc. | デヒドロエピアンドロステロン産生促進剤およびその用途 |
WO2009141541A2 (fr) * | 2008-04-22 | 2009-11-26 | Centre National De La Recherche Scientifique | Nouvelles compositions inhibant la melanogenese et leurs utilisations |
CH698908A1 (de) * | 2008-05-16 | 2009-11-30 | Veritron Ltd | Pflanzenextrakt und seine therapeutische verwendung. |
ITCS20080019A1 (it) * | 2008-10-09 | 2010-04-10 | Univ Calabria | Molecola naturale estratta da un agrume, processo di estrazione e uso farmaceutico |
US10414787B2 (en) | 2013-03-14 | 2019-09-17 | Mars, Incorporated | Flavor composition containing HMG glucosides |
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CN111773215A (zh) * | 2020-07-30 | 2020-10-16 | 曾辉 | 一种治疗aml的药物及应用 |
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JP2011518214A (ja) * | 2008-04-22 | 2011-06-23 | サントル・ナショナル・ドゥ・ラ・ルシェルシュ・シャンティフィク | メラニン形成を阻害するためのKif13A阻害剤およびAP−1阻害剤の使用 |
US8669238B2 (en) | 2008-04-22 | 2014-03-11 | Institut Curie | Use of Kif13A and AP-1 inhibitors for inhibiting melanogenesis |
CN102014859B (zh) * | 2008-04-22 | 2015-05-20 | 法国国家科学研究中心 | 抑制黑素生成的新组合物及其应用 |
CH698908A1 (de) * | 2008-05-16 | 2009-11-30 | Veritron Ltd | Pflanzenextrakt und seine therapeutische verwendung. |
ITCS20080019A1 (it) * | 2008-10-09 | 2010-04-10 | Univ Calabria | Molecola naturale estratta da un agrume, processo di estrazione e uso farmaceutico |
US10414787B2 (en) | 2013-03-14 | 2019-09-17 | Mars, Incorporated | Flavor composition containing HMG glucosides |
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CN101472597B (zh) | 2012-10-03 |
EP2033650A1 (en) | 2009-03-11 |
CN101472597A (zh) | 2009-07-01 |
JP4836961B2 (ja) | 2011-12-14 |
EP2033650A4 (en) | 2009-10-21 |
US20100240603A1 (en) | 2010-09-23 |
JPWO2007148697A1 (ja) | 2009-11-19 |
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