JP2019026564A - Sugar-derived carbonylated protein production inhibitor - Google Patents

Abstract

To provide a novel sugar-derived carbonylated protein production inhibitor.SOLUTION: A sugar-derived carbonylated protein production inhibitor contains isothiocyanate as an active ingredient. Preferably, the sugar-derived carbonylated protein production inhibitor contains, as isothiocyanate, at least one of iberin and sulforaphane.SELECTED DRAWING: None

Description

The present invention relates to a sugar-derived carbonylated protein production inhibitor. The present invention is widely used for functional foods and skin external preparations.

  The living body is constantly exposed to oxidative stress (oxygen in the air, ultraviolet rays, harmful substances in the air, irritants in food, etc.). Although the living body originally has a mechanism for scavenging active oxygen, it is known that oxidation proceeds in vivo due to generation of active oxygen exceeding the scavenging ability and reduction of scavenging ability. Among these, proteins are important molecules that not only determine the structure of a living body but also control biological functions such as enzymes, and therefore, studies on the oxidation of biological proteins are being actively conducted. Moreover, it is thought that the oxidation of a biological protein is concerned in the organ function fall, and the increase of the oxidized protein accompanying aging is known (refer nonpatent literature 1).

  “Oxidation” of biological proteins encompasses various reactions caused by active oxygen, and is defined to include not only proteins but also various reactions involving sugars, lipids, and nucleic acids. On the other hand, protein oxidation in a narrow sense means a direct oxidation reaction of a protein by active oxygen that does not involve sugars, lipids, nucleic acids and the like.

One of the protein modification reactions is a protein carbonylation reaction. There are various reactions in this carbonylation reaction. Among them, there are a carbonylation reaction derived from sugar and a carbonylation reaction derived from lipid peroxide. “Sugar-derived carbonylation reaction” means a protein modification reaction involving oxidation of sugar. That is, the “sugar-derived carbonylation reaction” refers to a reaction in which a substance having an aldehyde group or carbonyl group, such as glyoxal, methylglyoxal, or glycolaldehyde, is produced by oxidative degradation of a sugar such as glucose and modifies the protein. (See Non-Patent Documents 2 and 3). The protein produced by this reaction is called “sugar-derived carbonylated protein”.
There are a wide variety of protein modification reactions involving sugars in addition to this pathway, and many final products have been identified. Among these, carbonylated products have also been identified.

  On the other hand, protein modification reactions involving lipids are called “peroxidized lipid-derived carbonylation reactions”. When lipids are exposed to active oxygen, highly reactive aldehydes (carbonyl compounds) such as acrolein, 4-hydroxy-2-nonenal, and malondialdehyde are generated. That is, a reaction in which these intermediate products modify proteins is referred to as “a carbonylation reaction derived from lipid peroxide”.

  Carbonylation of these biological proteins has been reported to be involved in various diseases and symptoms. Carbonylated proteins are known to be detected in various tissues in the living body. For example, it has been reported that they generally increase with age in the liver and brain (Non-patent Documents 4 and 4). (See Patent Document 5). In addition, in progeria and the like that appear by promoting the aging phenomenon, it has been reported that carbonylated protein increases (see Non-Patent Document 6), and the causal relationship has been studied. The existence of carbonylated protein is also known in the skin, and accumulation in the horny layer of the exposed part and in the dermis of the photoaging site has been reported (see Non-Patent Document 7 and Non-Patent Document 8). Specifically, it has been reported that the carbonylated protein in the exposed stratum corneum brings about a change in physical properties such as a decrease in optical transmittance (see Non-Patent Document 9). Accumulation according to the severity of sexual elastic fibrosis has been reported (see Non-Patent Document 10 and Non-Patent Document 11).

  Thus, carbonylation of proteins occurs non-enzymatically and non-specifically, causing aging in all tissues. It is thought that it causes wrinkles, sagging, dullness in the skin, causes functional deterioration in the internal organs and the brain, and may cause various diseases. From such a background, development of various pharmaceutical or cosmetic agents having an action of suppressing protein carbonylation is desired.

  Since carbonylation of biological proteins occurs non-enzymatically and non-specifically, it causes aging in all tissues. Carbonylation of skin, especially dermal fibroblasts, causes wrinkles, sagging, dullness based on a mechanism different from that caused by melanin, causes functional deterioration in the internal organs and brain, and various diseases. It is thought that it can cause.

In the dermis of skin exposed to ultraviolet rays, it has been confirmed that carbonylation has a significant effect on yellowing, and when examined by age, the amount of carbonylated protein increases in the 40s and beyond. It has become clear (Non-Patent Document 12).

(Non-Patent Document 1 Tahara S et al., Mech Ageing Dev. 2001 Apr 15; 122 (4): 415-26) Glomb MA et al. J Biol Chem. 1995 Apr 28; 270 (17): 10017-26 Thornalley PJ et al. Biochem J. 1999 Nov 15; 344 Pt 1: 109-16 Stadtman E.R. et al., EXS. 1992,62: 64-72 Levine RL et al. Free Radic Biol Med. 2002 May 1; 32 (9): 790-6 Stadtman E.R. et al., J biol Chem. 1987, 262: 5488-5491 Fujita H. et al., Skin Res Tech. 1, 2007, 3: 84-90 Sander, C.S. et al., J Invest Dermatol. 2002,118: 618-25 Iwai I. et al., Int J Cosmet Sci. 2008 30: 41-46 Tanaka, N. et al., Arch Dermatol Res. 2001 293: 363-367 Sander, C.S. et al., J Invest Dermatol. 2002 118: 618-25 Published on August 31, 2010 Shiseido News Release “Shiseido Elucidates New Mechanism of“ Yellow Gusumi ”Skin” Internet https://www.jpo.go.jp/shiryou/kijun/kijun2/pdf/tjkijun_i-3 .pdf

Under such a background, the present inventor found that isothiocyanate has an action of suppressing the production of sugar-derived carbonylated protein, and completed the present invention.
That is, an object of the present invention is to provide a novel sugar-derived carbonylated protein production inhibitor.

The technical features of the present invention for solving the above-described problems are as follows.
1. A sugar-derived carbonylated protein production inhibitor containing isothiocyanate as an active ingredient.
2. As the above-mentioned isothiocyanate, at least one of iberine and sulforaphane is used. The sugar-derived carbonylated protein production inhibitor described in 1.

It is a schematic diagram which shows the method of isolating glucosinolate from broccoli seed. It is a diagram showing a chart of ^C 13 -NMR component 1 in FIG. 1. It is a diagram showing a chart of ^C 13 -NMR component 2 in FIG. It is a graph which shows the effect | action which acts on the sugar origin carbonylation protein in a present Example and a comparative example.

The present invention is described in detail below.
In the present specification, “sugar-derived carbonylation” of a protein means a reaction in which a carbonyl compound such as an aldehyde generated by oxidation of a sugar such as glucose modifies the protein nonspecifically and nonenzymatically. . When sugars such as glucose are exposed to active oxygen, aldehydes (carbonyl compounds) such as glyoxal are generated. These intermediate products modify proteins because they are very reactive. Various substances resulting from the modification are called sugar-derived carbonylated proteins (sugar-derived CP). As a reaction pathway known as “sugar-derived carbonylation”, for example, modification of a protein with glyoxal, methylglyoxal, or glycolaldehyde caused by a non-enzymatic reaction of glucose is known (Glomb MA et al. J Biol Chem. 1995; 270 (17): 10017-26, Thornalley PJ et al. Biochem J. 1999 344 Pt 1: 109-16). There are a wide variety of protein modification reactions involving sugars in addition to this pathway, and many final products have been identified. These are called advanced glycation end products (AGEs).

The present invention is characterized by using isothiocyanate as an active ingredient.
The isothiocyanate is a compound represented by the following chemical formula (1).

Examples of the isothiocyanate include Iberine, sulforaphane, phenethyl isothiocyanate, cyberin, alicesin, hesperin, erucin, belteroin and the like. Of these, it is particularly preferable to use Iberine or sulforaphane. This is because it has a superior sugar-derived carbonylated protein production inhibitory action. In addition, these may use only 1 type and may use 2 or more types together.

The method for obtaining the isothiocyanate is not particularly limited, but the glucosinolate is extracted from a plant containing glucosinolate, purified, and an intramolecular reaction is caused by a sulfate ester obtained by cleaving the obtained glucosinolate with an enzyme. Can be obtained.
Examples of plants containing glucosinolate include, but are not limited to, broccoli, cabbage, cauliflower, wasabi and the like.
When broccoli is used as the raw plant, it is preferable to use broccoli seeds. Broccoli seeds are seeds of broccoli (Brassica oleracea var. Italica) belonging to the Brassicaceae genus Brassica, but the production area and cultivation method are not particularly limited. The broccoli seeds may be germinated.

  The method for obtaining glucosinolate from broccoli seeds is not particularly limited, but broccoli seeds are preferably pulverized after drying and, if necessary, degreasing using heat-induced myrosinase inactivation or an organic solvent, etc. . Then, it is desirable to extract, dry and grind to obtain an extract (hereinafter referred to as “broccoli seed extract”), and to isolate and purify glucosinolate from this broccoli seed extract. Moreover, you may sterilize and sieve as needed.

  As an extraction solvent used when obtaining a broccoli seed extract, for example, water, lower monohydric alcohol (methyl alcohol, ethyl alcohol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, etc.), liquid polyvalent Alcohol (glycerin, propylene glycol, 1,3-butylene glycol, etc.), lower ester (ethyl acetate, etc.), hydrocarbon (benzene, hexane, pentane, etc.), ketones (acetone, methyl ethyl ketone, etc.), ethers (diethyl ether, Tetrahydrofuran, dipropyl ether, etc.), acetonitrile and the like, and one or more of them can be used.

  As an example of a preferable extraction method, there is a method in which water-containing ethanol or water-containing methanol having a concentration of 0 to 100% (v / v) is used, extracted at room temperature or heated for 1 to 10 hours, and then filtered. Can be mentioned.

Furthermore, the method for isolating and purifying glucosinolate from the broccoli seed extract is not particularly limited, but if necessary, column chromatography, silica gel chromatography, gel filtration chromatography, ion exchange chromatography, hydrophobic chromatography. Further, it can be purified by combining appropriate separation and purification means such as high performance liquid chromatography. More specifically, the method combining the ion exchange resin and high performance liquid chromatography according to FIG. 1 is most preferable.

The enzyme used for obtaining isothiocyanate from the glucosinolate is not particularly limited as long as it is classified as a β-glycosidase enzyme. For example, myrosinase, 6-phospho-β-glycosidase and the like can be used. It is preferable to use myrosinase. This is because the isothiocyanate can be obtained more easily. Myrosinase is a β-thioglucosidase enzyme involved in the hydrolysis of glucosinolate, a naturally occurring plant metabolite. This enzyme catalyzes the hydrolysis of these S-glucosides to yield D-glucose and aglycone fragments, which are then rearranged to give sulfate and isothiocyanate.

Moreover, the method of obtaining isothiocyanate is not limited to said method, You may use a commercial item.

The isothiocyanate used in the present invention is derived from sugar by blending it into various forms of bases used for usual sugar-derived carbonylated protein production inhibitors and formulating it as an active ingredient in accordance with conventional methods. Although a carbonylated protein production inhibitor can be obtained, a sugar-derived carbonyl protein production inhibitor that further synergistically enhances these effects can be obtained by further combining with other medicinal agents.
The sugar-derived carbonylated protein production inhibitor of the present invention can be used as a material for various foods and drinks. Examples of food and drink include confectionery (gum, candy, caramel, chocolate, cookies, snacks, jelly, gummi, tablet confectionery, etc.), noodles (soba, udon, ramen, etc.), and dairy products (milk, ice cream, yogurt). ), Seasonings (miso, soy sauce, etc.), soups, beverages (juice, coffee, tea, tea, carbonated drinks, sports drinks, etc.), health foods (tablets, capsules, etc.), nutrition Supplementary foods (such as energy drinks), functional foods, and special health foods. The sugar-derived carbonylated protein production inhibitor of the present invention may be appropriately mixed with these foods and drinks.

  These foods and drinks can be blended with various ingredients depending on the type, for example, glucose, fructose, sucrose, maltose, sorbitol, stevioside, corn syrup, lactose, citric acid, tartaric acid, malic acid, succinic acid. Acid, lactic acid, L-ascorbic acid, dl-α-tocopherol, sodium erythorbate, glycerin, propylene glycol, glycerin fatty acid ester, polyglycerin fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, gum arabic, Food materials such as carrageenan, casein, gelatin, pectin, agar, vitamin Bs, nicotinic acid amide, calcium pantothenate, amino acids, calcium salts, pigments, fragrances and preservatives can be used.

As a specific production method, the sugar-derived carbonylated protein production inhibitor is dissolved in, for example, fats and oils, ethanol, glycerin, or a mixture thereof to form a liquid and added to a beverage or added to a solid food. Is possible. The sugar-derived carbonylated protein production inhibitor is spray-dried or freeze-dried together with powdered cellulose, and this can be easily contained in foods and drinks (instant foods, etc.) by making powders, granules, tablets or solutions. If necessary, it can be mixed with a binder such as gum arabic or dextrin to form a powder or granules and added to a beverage or a solid food. Among these, for example, a method of dissolving in oil and fat, ethanol, glycerin or a mixture thereof to form a liquid and adding it to the beverage is most preferable.

As the addition amount in the case of applying the sugar-derived carbonylated protein production inhibitor of the present invention to foods and drinks, since beauty is the main purpose, the total content of active ingredients is 0.1 to 2 wt% with respect to the food and drinks. It is preferable that:

The sugar-derived carbonylated protein production inhibitor of the present invention may be used as a raw material for drugs (including pharmaceuticals and quasi drugs). It can be produced by appropriately blending the sugar-derived carbonylated protein production inhibitor of the present invention with a raw material for a pharmaceutical preparation. Examples of the raw material for preparation that can be incorporated into the sugar-derived carbonylated protein production inhibitor of the present invention include, for example, excipients (glucose, lactose, sucrose, sodium chloride, starch, calcium carbonate, kaolin, crystalline cellulose, cocoa butter, hydrogenated vegetable oil. , Kaolin, talc, etc.), binder (distilled water, physiological saline, ethanol water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrant (sodium alginate, Agar, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, gum arabic powder, gelatin, ethanol, etc.), disintegration inhibitors (sucrose, stearin, cocoa butter, hydrogenated oil, etc.), absorption promotion Agent (quaternary ammonium base, Sodium Lil sulfate), adsorbent (glycerin, starch, lactose, kaolin, bentonite, silicic acid, etc.), lubricants (purified talc, stearates, polyethylene glycol, and the like) and the like.

The administration method of the sugar-derived carbonylated protein production inhibitor of the present invention is generally administered orally in the form of tablets, pills, soft / hard capsules, fine granules, powders, granules, liquids, etc. Can be administered parenterally. When administered as a parenteral agent, it can be administered as a solution or with the addition of a dispersing agent, suspension, stabilizer, etc., by local tissue administration, intradermal, subcutaneous, intramuscular and intravenous injection, etc. it can. Moreover, it is good also as forms, such as a suppository.

The dose may vary depending on the administration method, medical condition, age of the patient, etc., but for adults, it is usually 0.5 to 500 mg as an active ingredient per day, and for children it is usually about 0.5 to 300 mg.
The mixing ratio of the sugar-derived carbonylated protein production inhibitor can be appropriately changed depending on the dosage form, but is usually about 0.3 to 1.5 wt% when administered orally or by mucosal absorption, parenterally. In the case of administration, it should be about 0.01 to 1 wt%. In addition, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient, or it may be necessary to administer beyond the range.

The present invention can be used as an external preparation for skin (including cosmetics, pharmaceuticals and quasi drugs).
Examples of the external preparation for skin to which the sugar-derived carbonylated protein production inhibitor of the present invention can be blended include, for example, emulsion, soap, facial cleanser, bath preparation, cream, emulsion, lotion, eau de cologne, shaving cream, whiskers. Shaving lotion, cosmetic oil, sunscreen lotion, funny powder, foundation, perfume, pack, nail cream, enamel, enamel remover, eyebrow, blusher, eye cream, eye shadow, mascara, eyeliner, lipstick, lip balm, shampoo , Rinse, hair dye, dispersion, cleaning agent and the like.
Examples of the form of a pharmaceutical or quasi-drug that can contain the sugar-derived carbonylated protein production inhibitor of the present invention include ointments, creams, and liquids for external use.

In addition to the sugar-derived carbonylated protein production inhibitor according to the present invention, the external preparation for skin of the above form is a component blended in a skin external preparation such as cosmetics and quasi-drugs as long as the carbonylation inhibitory action is not impaired. , Oils, higher alcohols, fatty acids, UV absorbers, powders, pigments, surfactants, polyhydric alcohols / sugars, polymers, physiologically active ingredients, solvents, antioxidants, fragrances, preservatives, etc. it can.
Examples are listed below, but the present invention is not limited to these examples.

(1) Examples of oil components Ester-based oil phase components: glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, isopropyl myristate, butyl myristate, isopropyl palmitate, ethyl stearate, octyl palmitate, isostearic acid Isocetyl, butyl stearate, butyl myristate, ethyl linoleate, isopropyl linoleate, ethyl oleate, isocetyl myristate, isostearyl myristate, isostearyl palmitate, octyldodecyl myristate, isocetyl isostearate, diethyl sebacate, adipine Diisopropyl acid, isoaralkyl neopentanoate, glyceryl tri (capryl / caprate), trimethylolpropane tri-2-ethylhexanoate, trimethylol triisostearate Propane, pentaerythritol tetra-2-ethylhexanoate, cetyl caprylate, decyl laurate, hexyl laurate, decyl myristate, myristyl myristate, cetyl myristate, stearyl stearate, decyl oleate, cetyl ricinoleate, isolaurate Stearyl, isotridecyl myristate, isocetyl myristate, isostearyl myristate, isocetyl palmitate, isostearyl palmitate, octyl stearate, isocetyl stearate, isodecyl oleate, octyldodecyl linoleate, octyldodecyl isoleate, isopropyl isostearate Cetostearyl 2-ethylhexanoate, stearyl 2-ethylhexanoate, hexyl isostearate, ethyleneglycol dioctanoate , Ethylene glycol dioleate, propylene glycol dicaprate, propylene glycol di (capryl / capric acid), propylene glycol dicaprylate, neopentyl glycol dicaprate, neopentyl glycol dioctanoate, glyceryl tricaprylate, glyceryl triundecylate, triisopalmitine Glyceryl acid, glyceryl triisostearate, octyldodecyl neopentanoate, isostearyl octanoate, octyl isononanoate, hexyl decyl neodecanoate, octyldodecyl neodecanoate, isocetyl isostearate, isostearyl isostearate, octyldecyl isostearate, polyglycerin oleic acid Ester, polyglycerol isostearate, dipropyl carbonate, charcoal Dialkyl (C12-18), triisocetyl citrate, triisoaralkyl citrate, triisooctyl citrate, lauryl lactate, myristyl lactate, cetyl lactate, octyl decyl lactate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, Trioctyl citrate, diisostearyl malate, 2-ethylhexyl hydroxystearate, di-2-ethylhexyl succinate, diisobutyl adipate, diisopropyl sebacate, dioctyl sebacate, cholesteryl stearate, cholesteryl isostearate, cholesteryl hydroxystearate, olein Cholesteryl acid, dihydrocholesteryl oleate, phytosteryl isostearate, phytosteryl oleate, 12-stearoyl hydroxystearate Cetyl, 12-stearoyl-hydroxystearic acid stearyl 12-stearoyl-hydroxystearic acid isostearate, and the like.
Hydrocarbon oil phase components: squalane, liquid paraffin, α-olefin oligomer, isoparaffin, ceresin, paraffin, liquid isoparaffin, polybutene, microcrystalline wax, petrolatum and the like.
Animal and vegetable oils and their hydrogenated oils, and naturally occurring waxes: beef tallow, hydrogenated beef tallow, lard, hydrogenated tallow, horse oil, hydrogenated horse oil, mink oil, orange luffy oil, fish oil, hydrogenated fish oil, egg yolk oil and other animal oils and Its hardened oil, avocado oil, almond oil, olive oil, cacao butter, kiwi seed oil, apricot oil, kukui nut oil, sesame oil, wheat germ oil, rice germ oil, rice bran oil, safflower oil, shea butter, soybean oil, evening primrose oil , Perilla oil, tea seed oil, camellia oil, corn oil, rapeseed oil, hydrogenated rapeseed oil, palm kernel oil, hydrogenated palm kernel oil, palm oil, hydrogenated palm oil, peanut oil, hydrogenated peanut oil, castor oil, hydrogenated castor oil , Vegetable oils such as sunflower oil, grape seed oil, jojoba oil, hardened jojoba oil, macadamia nut oil, medhome oil, cottonseed oil, hardened cottonseed oil, coconut oil, hardened coconut oil and its hardened , Beeswax, high acid value beeswax, lanolin, reduced lanolin, hydrogenated lanolin, liquid lanolin, carnauba wax and montan wax.
Silicone oil phase components: dimethylpolysiloxane, methylphenylpolysiloxane, methylcyclopolysiloxane, octamethylpolysiloxane, decamethylpolysiloxane, dodecamethylcyclosiloxane, methylhydrogenpolysiloxane, polyether-modified organopolysiloxane, dimethyl Siloxane / methylcetyloxysiloxane copolymer, dimethylsiloxane / methylstearoxysiloxane copolymer, alkyl-modified organopolysiloxane, terminal-modified organopolysiloxane, amino-modified silicone oil, amino-modified organopolysiloxane, dimethiconol, silicone gel, acrylic Examples include silicone, trimethylsiloxysilicic acid, and silicone RTV rubber.
Fluorine oil phase components: perfluoropolyether, fluorine-modified organopolysiloxane, fluorinated pitch, fluorocarbon, fluoroalcohol, fluoroalkyl / polyoxyalkylene co-modified organopolysiloxane, and the like.

(2) Examples of higher alcohols Lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, behenyl alcohol, 2-ethylhexanol, hexadecyl alcohol, octyldodecanol and the like can be mentioned.

(3) Examples of fatty acids Caprylic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, arachidonic acid, behenic acid , Erucic acid, 2-ethylhexanoic acid and the like.

(4) Examples of UV absorbers Paraaminobenzoic acid, amyl paraaminobenzoate, ethyldihydroxypropyl paraaminobenzoate, glyceryl paraaminobenzoate, ethyl paraaminobenzoate, octyl paraaminobenzoate, octyldimethyl paraaminobenzoate, ethylene glycol salicylate, salicylic acid Octyl, triethanolamine salicylate, phenyl salicylate, butylphenyl salicylate, benzyl salicylate, homomenthyl salicylate, benzyl cinnamate, octyl paramethoxycinnamate, 2-ethylhexyl paramethoxycinnamate, mono-2-diparamethoxycinnamate Glyceryl ethylhexanoate, isopropyl paramethoxycinnamate, diethanolamine salt of paramethoxyhydrocinnamic acid, diisopropyl diisopropylcinnamic acid Stealth mixture, urocanic acid, ethyl urocanate, hydroxymethoxybenzophenone, hydroxymethoxybenzophenone sulfonic acid and its salts, dihydroxymethoxybenzophenone, dihydroxymethoxybenzophenone sodium disulfonate, dihydroxybenzophenone, dihydroxydimethoxybenzophenone, hydroxyoctoxybenzophenone, tetrahydroxybenzophenone, Butylmethoxydibenzoylmethane, 2,4,6-trianilino-p- (carbo-2-ethylhexyl-1-oxy) -1,3,5-triazine, 2- (2-hydroxy-5-methylphenyl) benzotriazole , Methyl-O-aminobenzoate, 2-ethylhexyl-2-cyano-3, 3-diphenyl acrylate, phenylbenzimidazole sulfate, 3- (4-methylbenzylidene) can Examples include full, isopropyldibenzoylmethane, 4- (3,4-dimethoxyphenylmethylene) -2, 5-dioxo-1-imidazolidinepropionate 2-ethylhexyl, and the like, polymer derivatives, silane derivatives, and the like.

(5) Examples of powders and pigments Red 104, Red 201, Yellow 4, Blue 1, Black 401 and other dyes, Yellow 4 AL lake, Yellow 203 BA lake and other lake dyes, nylon powder , Silk powder, urethane powder, Teflon (registered trademark) powder, silicone powder, polymethyl methacrylate powder, cellulose powder, starch, silicone elastomer spherical powder, polyethylene powder, yellow iron oxide, red iron oxide, black Colored pigments such as iron oxide, chromium oxide, carbon black, ultramarine and bitumen, white pigments such as zinc oxide, titanium oxide and cerium oxide, extender pigments such as talc, mica, sericite, kaolin and barium sulfate plate, titanium mica Pearl pigments such as barium sulfate, calcium carbonate, magnesium carbonate, aluminum silicate, metal salts such as magnesium silicate, Inorganic powders such as Rica and alumina, metal soaps such as aluminum stearate, magnesium stearate, zinc palmitate, zinc myristate, magnesium myristate, zinc laurate, zinc undecylenate, bentonite, smectite, boron nitride, etc. It is done. There are no particular restrictions on the shape of these powders (spherical, rod-like, needle-like, plate-like, irregular shape, flake-like, spindle-like, etc.) and particle diameter. These powders are conventionally known surface treatments such as fluorine compound treatment, silicone treatment, silicone resin treatment, pendant treatment, silane coupling agent treatment, titanium coupling agent treatment, oil agent treatment, N-acylated lysine treatment, The surface treatment may or may not be performed in advance by polyacrylic acid treatment, metal soap treatment, amino acid treatment, lecithin treatment, inorganic compound treatment, plasma treatment, mechanochemical treatment or the like.

(6) Examples of surfactants Anionic surfactants: fatty acid soap, α-acyl sulfonate, alkyl sulfonate, alkyl allyl sulfonate, alkyl naphthalene sulfonate, alkyl sulfate, POE alkyl ether sulfate , Alkylamide sulfate, alkyl phosphate, POE alkyl phosphate, alkylamide phosphate, alkyloylalkyl taurine salt, N-acyl amino acid salt, POE alkyl ether carboxylate, alkyl sulfosuccinate, alkyl sulfoacetic acid Sodium, acylated hydrolyzed collagen peptide salt, perfluoroalkyl phosphate, etc. are mentioned.
Cationic surfactant: alkyltrimethylammonium chloride, stearyltrimethylammonium chloride, stearyltrimethylammonium bromide, cetostearyltrimethylammonium chloride, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, behenyltrimethylammonium bromide, benzalkonium chloride , Behenic acid amidopropyldimethylhydroxypropylammonium chloride, stearic acid diethylaminoethylamide, stearic acid dimethylaminopropylamide, lanolin derivative quaternary ammonium salts, and the like.
Amphoteric surfactants: carboxybetaine type, amide betaine type, sulfobetaine type, hydroxysulfobetaine type, amide sulfobetaine type, phosphobetaine type, aminocarboxylate type, imidazoline derivative type, amidoamine type and the like.
Nonionic surfactant: propylene glycol fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, POE sorbitan fatty acid ester, POE sorbitol fatty acid ester, POE glycerin fatty acid ester, POE alkyl ether, POE fatty acid ester, POE cured castor Oil, POE castor oil, POE / POP copolymerization, POE / POP alkyl ether, polyether-modified silicone lauric acid alkanolamide, alkylamine oxide, hydrogenated soybean phospholipid and the like.
Natural surfactant: lecithin, saponin, sugar surfactant and the like.

(7) Examples of polyhydric alcohols and sugars Ethylene glycol, diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, glycerin, diglycerin, polyglycerin, 3-methyl-1,3-butanediol, 1, 3 -Butylene glycol, sorbitol, mannitol, raffinose, erythritol, glucose, sucrose, fructose, xylitol, lactose, maltose, maltitol, trehalose, alkylated trehalose, mixed isomerized sugar, sulfated trehalose, pullulan and the like. These chemically modified compounds can also be used.

(8) Examples of polymers Acrylic ester / methacrylic acid ester copolymer (plus size, manufactured by Kyoyo Chemical), vinyl acetate / crotonic acid copolymer (resin 28-1310, manufactured by NSC), vinyl acetate / croton Acid / vinyl neodecanate copolymer (28-2930, manufactured by NSC), methyl vinyl ether maleic acid half ester (Gantrez ES, manufactured by ISP), T-butyl acrylate / ethyl acrylate / methacrylic acid copolymer (rubymer) , BASF), vinyl pyrrolidone / vinyl acetate / vinyl propionate copolymer (Rubicol VAP, BASF), vinyl acetate / crotonic acid copolymer (Rubiset CA, BASF), vinyl acetate / croton Acid / vinyl pyrrolidone copolymer (Rubiset CAP, manufactured by BASF), vinyl pyrrolidone / acrylate copolymer (Rubiflex, BA SF), acrylate / acrylamide copolymer (Ultrahold, BASF), vinyl acetate / butyl maleate / isobornyl acrylate copolymer (Advantage, ISP), carboxy vinyl polymer (Carbopol, ), Anionic polymer compounds such as acrylic acid / alkyl methacrylate copolymers (pemulene), and acetic acid amphoteric compounds of dialkylaminoethyl methacrylate polymers (Yukaformer, manufactured by Ryo Chemicals), octyl acrylamide / hydroxy acrylate Amphoteric polymer compounds such as propyl / butylaminoethyl methacrylate copolymer (AMPHOMER, NSC), quaternized vinyl pyrrolidone / dimethylaminoethyl methacrylate (GAFQUAT, ISP), methylvinylimidazolium chloride / vinyl Pyrrolidone copolymerization Polymer (ruby coat, manufactured by BASF), polyvinylpyrrolidone (rubiscol K, manufactured by BASF), vinylpyrrolidone / vinyl acetate copolymer (rubiscol VA, manufactured by BASF), vinylpyrrolidone / dimethyl Nonionic polymer compounds such as aminoethyl methacrylate copolymer (copolymer 937, manufactured by ISP) and vinylcaprolactam / vinyl pyrrolidone / dimethylaminoethyl methacrylate copolymer (copolymer VC713, manufactured by ISP) are available. Cellulose or derivatives thereof, keratin and collagen or derivatives thereof, calcium alginate, pullulan, agar, gelatin, tamarind seed polysaccharide, xanthan gum, carrageenan, high methoxyl pectin, low methoxyl pectin, guar gum, gum arabic, crystalline cellulose, arabino Naturally derived polymer compounds such as galactan, gum karaya, gum tragacanth, alginic acid, albumin, casein, curdlan, gellan gum and dextran can also be suitably used.

(9) Examples of physiologically active ingredients Examples of physiologically active ingredients include substances that impart some physiological activity to the skin when applied to the skin. For example, whitening ingredients, immunostimulants, anti-aging agents, UV protection agents, slimming agents, tanning agents, antioxidants, hair growth agents, hair restorers, moisturizers, blood circulation promoters, antibacterial agents, bactericides, desiccants, A cooling sensation agent, a warming sensation agent, vitamins, an amino acid, a wound healing promoter, an irritation relaxation agent, an analgesic agent, a cell activator, an enzyme component, etc. are mentioned. Examples of these suitable ingredients include, for example, ashitaba extract, avocado extract, amateur extract, altea extract, arnica extract, aloe extract, apricot extract, apricot kernel extract, ginkgo biloba extract, fennel extract, turmeric extract, oolong tea extract, ages Extract, Echinacea leaf extract, Ogon extract, Oat extract, Oen extract, Barley extract, Hypericum extract, Oyster extract, Dutch mustard extract, Orange extract, Seawater dried product, Seaweed extract, Hydrolyzed elastin, Hydrolyzed wheat powder, Hydrolyzed silk , Chamomile extract, carrot extract, cormorant extract, licorice extract, calcade extract, oyster extract, kina extract, cucumber
-Extract, Guanosine, Gardenia extract, Kumazasa extract, Clara extract, Walnut extract, Grapefruit extract, Clematis extract, Chlorella extract, Mulberry extract, Gentian extract, Tea extract, Yeast extract, Burdock extract, Rice bran extract, Rice germ oil, Comfrey Extract, Collagen, Cowberry extract, Saishin extract, Psycho extract, Saitai extract, Salvia extract, Salmon extract, Sasa extract, Hawthorn extract, Salamander extract, Shiitake extract, Giant extract, Shikon extract, Perilla extract, Linden extract, Shimotake extract, Peonies extract , Ginger root extract, birch extract, Japanese horse chestnut extract, horseshoe extract, hawthorn extract, elderberry extract, yarrow extract , Mint extract, sage extract, mallow extract, nematode extract, assembly extract, soybean extract, taisu extract, thyme extract, tea extract, clove extract, chigaya extract, chimpi extract, suzuki extract, eucalyptus extract, tonin extract, spruce extract, dokudami extract , Tomato extract, natto extract, carrot extract, garlic extract, wild rose extract, hibiscus extract, bacmond extract, parsley extract, honey, clam extract, parietaria extract, toad extract, bisabolol, loquat extract, dandelion extract, burdock extract Butcher Bloom Extract, Grape Extract, Propolis, Loofah Extract, Safflower Extract, Peppermint Extract, Bodaige Extract, Button Button Kiss, Hop extract, Pine extract, Maronnier extract, Citrus extract, Mukuroji extract, Melissa extract, Peach extract, Cornflower extract, Eucalyptus extract, Yukinoshita extract, Yakuinin extract, Artemisia extract, Lavender extract, Apple extract, Lettuce extract, Lemon extract, Forsythia extract , Rose extract, rosemary extract, roman chamomile extract, royal jelly extract and the like.
Biopolymers such as deoxyribonucleic acid, mucopolysaccharide, sodium hyaluronate, sodium chondroitin sulfate, collagen, elastin, chitin, chitosan, hydrolyzed eggshell membranes, amino acids, hydrolyzed peptides, sodium lactate, urea, sodium pyrrolidonecarboxylate , Moisturizing ingredients such as betaine, whey, trimethylglycine, oily ingredients such as sphingolipid, ceramide, phytosphingosine, cholesterol, cholesterol derivatives, phospholipids, ε-aminocaproic acid, glycyrrhizic acid, β-glycyrrhetinic acid, lysozyme chloride, guaiazulene, Immunostimulants such as hydrocortisone, vitamin A, vitamin B2, vitamin B6, vitamin C, vitamin D, vitamin E, calcium pantothenate, biotin, nicotinamide, vitamin C ester Vitamins, active ingredients such as allantoin, diisopropylamine dichloroacetate, 4-aminomethylcyclohexanecarboxylic acid, antioxidants such as tocopherol, carotenoid, flavonoid, tannin, lignan, saponin, α-hydroxy acid, β-hydroxy acid, etc. Cell activators, blood circulation promoters such as γ-oryzanol and vitamin E derivatives, wound healing agents such as retinol and retinol derivatives, arbutin, kojic acid, placenta extract, sulfur, ellagic acid, linoleic acid, tranexamic acid, glutathione, etc. Whitening agent, cephalanthin, licorice extract, red pepper tincture, hinokitiol, garlic iodide extract, pyridoxine hydrochloride, DL-α-tocopherol, DL-α-tocopherol acetate, nicotinic acid, nicotinic acid derivative, calcium pantothenate, D-pan Tothenyl alcohol, acetyl pantothenyl ethyl ether, biotin, allantoin, isopropylmethylphenol, estradiol, ethinyl estradiol, capronium chloride, benzalkonium chloride, diphenhydramine hydrochloride, takanal, camphor, salicylic acid, nonyl acid vanillylamide, nonanoic acid vanillylamide, pyroctone Olamine, glyceryl pentadecanoate, L-menthol, mononitroguaiacol, resorcin, γ-aminobutyric acid, benzethonium chloride, mexiletine hydrochloride, auxin, female hormone, cantalis tincture, cyclosporine, zinc pyrithione, hydrocortisone, minoxidil, monostearic acid Polyoxyethylene sorbitan, peppermint oil, Sasanishiki extract, placenta, yuzu seed extract, bull Berry extract, lingonberry extract, C. tubulosa extract, black rice extract, green coffee bean extract, resveratrol, kiwi seed extract, strawberry seed extract, and the like hair tonic such as cherry extract.

(10) Examples of antioxidants Sodium bisulfite, sodium sulfite, erythorbic acid, sodium erythorbate, dilauryl thiodipropionate, tocopherol, tolyl biguanide, nordihydroguaiaretic acid, parahydroxyanisole, butylhydroxyanisole, dibutylhydroxy Examples include plant extracts having an antioxidant effect such as toluene, ascorbyl stearate, ascorbyl palmitate, octyl gallate, propyl gallate, carotenoid, flavonoid, tannin, lignan, saponin, apple extract and clove extract.

(11) Examples of solvents Purified water, ethanol, lower alcohol, ethers, LPG, fluorocarbon, N-methylpyrrolidone, fluoroalcohol, volatile linear silicone, next-generation chlorofluorocarbon and the like.

Hereinafter, the present invention will be described based on examples.
Example Production of test sample (compound) As examples, commercially available products of iberin (IB) and sulforaphane (SFN) were used. Further, glucoiberin (GI) and glucoraphanin (GR) used as comparative examples were isolated and purified by the following method.
That is, each component (components 1 to 9) was isolated and purified based on the scheme of FIG. Then, to measure these components at ^C 13 NMR. The results are shown in FIGS.
From these NMR spectra, it was confirmed that component 1 was glucoiverin (FIG. 2) and component 2 was glucoraphanin (FIG. 3).

Test example
Mix BSA (10 mg / mL), 500 mM fructose and various concentrations of glucoiverine (GI), glucoraphanin (GR), iveraline (IB), sulforaphane (SFN) or aminoguanidine hydrochloride (AG), 37 Incubated for 1 week at ° C. As a negative target, 4 ° C preserved material was used. 2 mM HCl solution containing 10 mM DNPH (0.4 mL) was added to the reaction solution (0.1 mL) and allowed to react at room temperature for 1 hour with occasional stirring. After adding 20% trichloroacetic acid (0.5 mL) and allowing to stand on ice for 5 minutes, the mixture was centrifuged at 4 ° C. for 10 minutes to precipitate the protein. The precipitate was washed three times with a mixed solution (1 mL) of ethyl acetate: ethanol (1: 1). The precipitate was dissolved by adding a 20 mM potassium dihydrogen phosphate solution (0.25 mL) containing 6M guanidine. Thereafter, absorbance at 400 nm was measured to measure carbonylated protein. The result is shown in FIG.

Results and Effects of Examples From FIG. 4, the reaction solution to which GI and GR, which are glucosinolates, were added, did not exhibit the action of inhibiting the generation of saccharide-derived carbonylated protein, but IB (10, 30, 100, which is an isothiocyanate). (μg / mL) suppressed sugar-derived carbonylated protein production by 22%, 43%, and 68%, respectively. SFN (30, 100 μg / mL) inhibited the production of sugar-derived carbonylated proteins by 71% and 80%, respectively. The glucosinolates GI and GR did not suppress the production of sugar-derived carbonylated proteins, but the isothiocyanates IB and SFN suppressed the production of sugar-derived carbonylated proteins. It is considered that isothiocyanate is effective in suppressing production. From this, it was confirmed that isothiocyanate has a carbonylated protein inhibitory action produced by a saccharification reaction and is useful as a sugar-derived carbonylated protein production inhibitor.

Although the compounding example of the sugar origin carbonylation protein production inhibitor (Iverin) of the present invention is given below, the following compounding example does not limit the present invention. Moreover, although Iberine was used as a compounding example below, other isothiocyanates (for example, sulforaphane) may be used.
Formulation Example 1: Chewing gum
Sugar 52.0wt%
Gum base 20.0
Glucose 10.0
Minamata 16.0
Fragrance 0.5
Cherry blossom extract 0.5
Glucosylceramide 0.5
Iberine 0.5
100.0wt%

Formulation Example 2: Gummy
Reduced water tank 38.0wt%
Granulated sugar 20.0
Glucose 20.0
Gelatin 4.7
Water 9.68
Kiwi juice 4.0
Kiwi flavor 0.6
Dye 0.02
Cherry blossom extract 1.0
Glucosylceramide 1.0
Iberine 1.0
100.0wt%

Formulation Example 3: Candy
50.0 wt% sugar
Minamata 33.0
Water 14.2
Organic acid 2.0
Fragrance 0.2
Cherry blossom extract 0.1
Glucosylceramide 0.1
Iberine 0.4
100.0wt%

Formulation Example 4: Yogurt (hard / soft)
Milk 41.5wt%
Nonfat dry milk 5.8
Sugar 8.0
Agar 0.15
Gelatin 0.1
Lactic acid bacteria 0.005
Cherry blossom extract 0.1
Glucosylceramide 0.1
Iberine 0.4
Perfume
Water residue
100.0wt%

Formulation Example 5: Soft drink
Fructose glucose liquid sugar 30.0wt%
Emulsifier 0.5
Strawberry seed extract 0.05
Glucosylceramide 0.05
Iberine 0.05
Perfume
Purified water residue
100.0wt%

Formulation Example 6: Soft capsule
Rice germ oil 86.0wt%
Cherry blossom extract 0.5
Glucosylceramide 0.5
Emulsifier 12.0
Iberine 1.0
100.0wt%

Formulation Example 7: Tablet
Lactose 53.0wt%
Crystalline cellulose 30.0
Starch degradation product 10.0
Cherry blossom extract 0.5
Glucosylceramide 0.5
Glycerin fatty acid ester 5.0
Iberine 1.0
100.0wt%

Formulation Example 8: Oral granules (pharmaceuticals)
Iberine 1.0wt%
Strawberry seed extract 0.5
Glucosylceramide 0.5
Lactose 30.0
Cornstarch 60.0
Crystalline cellulose 7.0
Polyvinylpyrrolidone 1.0
100.0wt%

Formulation Example 9: Tablet
75.4 wt% sugar
Glucose 19.0
Sucrose fatty acid ester 0.2
Strawberry seed extract 0.5
Glucosylceramide 0.5
Iberine 0.5
Purified water 3.9
100.0wt%

Formulation Example 15: Cat food
Corn 33.0wt%
Flour 35.0
Meat meal 15.0
Beef tallow 8.9
Salt 1.0
Skipjack extract 4.0
Strawberry seed extract 0.5
Glucosylceramide 0.5
Iberine 1.0
Taurine 0.1
Vitamins 0.5
Minerals 0.5
100.0wt%

Formulation Example 16: Dog food
Corn 34.0wt%
Meat (chicken) 15.0
Defatted soybean 10.0
Flour 24.0
Mosses 5.0
Cherry blossom extract 0.5
Glucosylceramide 0.5
Iberine 1.0
Animal fats and oils 8.9
Oligosaccharide 0.1
Vitamin 0.5
Mineral 0.5
100.0wt%
Formulation Example 1: Cosmetic cream
Squalane 21.0wt%
Beeswax 5.0
Refined jojoba oil 5.0
Glycerin 5.0
Glycerol monostearate 2.0
Polyoxyethylene (20) sorbitan-
Monostearate 2.0
Strawberry seed extract 0.1
Glucosylceramide 0.1
Iberine 1.0
Preservative appropriate amount
Perfume
Purified water residue
100.0wt%

Formulation Example 2: Lotion
Ethanol 5.0wt%
Glycerin 2.0
1,3-butylene glycol 2.0
Polyethylene oleyl ether 0.5
Sodium citrate 0.1
Citric acid 0.1
Strawberry seed extract 0.1
Glucosylceramide 0.1
Iberine 0.1
Purified water residue
100.0wt%

Formulation Example 3: Body Gel
Macadamia nut oil 2.0wt%
Octyldodecyl myristate 10.0
Methylphenylpolysiloxane 5.0
Behenyl alcohol 3.0
Stearic acid 3.0
Batyl alcohol 1.0
Glyceryl monostearate 1.0
Tetraoleic acid polyoxyethylene sorbit 2.0
Hydrogenated soybean phospholipid 1.0
Ceramide 0.1
Retinol palmitate 0.1
Preservative appropriate amount
Centella extract 1.0
Strawberry seed extract 0.1
Glucosylceramide 0.1
Iberine 1.0
1,3-butylene glycol 5.0
Purified water residue
100.0wt%

Formulation Example 4: Latex
Squalane 4.0wt%
Vaseline 2.5
Cetanol 2.0
Glycerin 2.0
Lipophilic glyceryl monostearate 1.0
Stearic acid 1.0
L-Arginine 1.0
Strawberry seed extract 0.1
Glucosylceramide 0.1
Iberine 0.5
Potassium hydroxide 0.1
Perfume
Purified water residue
100.0wt%

Formulation Example 5: Bath agent (liquid)
Propylene glycol 50.0wt%
Ethanol 20.0
Sodium sulfate 5.0
Strawberry seed extract 0.1
Glucosylceramide 0.1
Iberine 0.5
Lanolin 0.5
Avocado oil 0.5
Dye 1.5
Fragrance 22.0
100.0wt%
Formulation Example 6: Shampoo Polyoxyethylene alkyl ether sodium sulfate
(E.O2 mol) 15.0
Palm oil aliphatic diethanolamide 5.0
Glycerin 3.0
Strawberry seed extract 0.1
Glucosylceramide 0.1
Iberine 0.4
Ethanol 5.0
Perfume and preservatives
Ion exchange water
Total 100wt%

Formulation Example 7: Hair Cream
Liquid paraffin 20.0wt%
Solid paraffin 3.0
Polyoxyethylene cetyl ether
(E.O15 mol) 2.0
Sorbitan sesquioleate 1.0
Strawberry seed extract 0.1
Glucosylceramide 0.1
Iberine 0.2
Ethanol 10.0
Potassium hydroxide 0.1
Glycerin 3.0
Perfume and preservatives
Total 100wt%

Formulation Example 8: Ointment
White beeswax 5.0wt%
Purified lanolin 5.0
Strawberry seed extract 0.1
Glucosylceramide 0.1
Iberine 1.0
Fragrance 0.1
Vaseline residue
Total 100wt%

As described above, the present invention can provide a novel pharmaceutical or cosmetic agent containing various active ingredients having an action of suppressing the production of sugar-derived carbonylated proteins.
In addition, by causing the sugar-derived carbonylated protein production inhibitor to act on the dermis, yellowing of the dermis can be effectively prevented.

Claims (2)

A sugar-derived carbonylated protein production inhibitor containing isothiocyanate as an active ingredient. The sugar-derived carbonylated protein production inhibitor according to claim 1, wherein the isothiocyanate is at least one of iberine and sulforaphane.