KR101840133B1 - Anti-inflamatory composition containing griseusrazin a - Google Patents

Abstract

The present invention relates to an anti-inflammatory composition comprising griseuracin A as an active ingredient, wherein Griseus rasin A, an active ingredient of the composition of the present invention, is a pyrazine derivative compound isolated from a marine organism- Glycus rasin A has an excellent anti-inflammatory effect to inhibit the inflammatory response in mouse-derived macrophages and has been shown to be effective in the treatment of hematoxylin-1 (Heme Oxygenase-1, HO-1 ), As well as natural substances derived from natural materials which are less likely to cause side effects due to their stability, and thus can be usefully used for the treatment, improvement or prevention of inflammation-related inflammatory diseases.

Description

ANTI-INFLAMATORY COMPOSITION CONTAINING GRISEUSRAZIN A ", which contains griseuracin A as an active ingredient,

The present invention relates to a composition having an anti-inflammatory effect or an anti-inflammatory agent, specifically, a anti-inflammatory composition comprising a component derived from a natural substance as an active ingredient.

Inflammation is a localized immune response that minimizes the damage of a cell or tissue when it is damaged or destroyed by various factors, such as harmful substances or organisms from the outside, and restores the damaged area to the original state. And is a useful defense mechanism to remove the products produced by tissue damage. As a result, pain, swelling, redness, fever, or the like may occur as a result of the defensive mechanism, resulting in malfunction. Various factors causing inflammation include physical factors such as trauma, burn, bronze, radioactivity, chemical factors such as acid, and immunological factors due to antibody reaction. In addition, blood vessel and hormone imbalance .

The inflammation normally functions to neutralize or eliminate the causative factor through in vivo inflammatory reaction and regenerate the upper tissue to restore the normal structure and function. However, when the degree of inflammation is over a certain level or becomes chronic, chronic inflammation And the like. In addition to being able to observe inflammatory responses in almost all diseases of clinical diseases, enzymes related to inflammatory reaction play an important role in carcinogenesis.

Recently, it has been known that the progress of the inflammatory reaction in the body is related to COX (cyclooxygenase) enzyme activity. The COX enzyme is a major enzyme involved in the biosynthesis of prostaglandin in vivo (Smith et al., J. Biol. Chem., 271, 33157 (1996)), and two kinds of isozyme enzymes, COX-1 and COX -2 is known to exist. The COX-1 is constantly present in tissues such as the stomach or kidney and is involved in maintaining normal homeostasis, while the COX-2 is involved in mitogen or cytokines in inflammation or other immune responses. Is a transient and rapidly expressed enzyme in the cell.

Another strong inflammatory mediator, nitric oxide (NO), is produced from L-arginine by NO synthase (NOS), and is produced by a variety of substances, such as UV, external stress, endotoxin or cytokines Lt; / RTI > cells. These inflammatory stimuli increase the expression of inducible NOS (iNOS) in the cells, thereby inducing NO production in the cells and activating the macrophages to cause an inflammatory reaction.

Therefore, in order to effectively alleviate inflammation, researches on a substance capable of inhibiting the production of NO are under way. However, some side effects of anti-inflammatory substances developed by these studies are problematic. For example, non-steroidal anti-inflammatory drugs used in the treatment of chronic inflammatory diseases such as acute or rheumatoid arthritis are known to exhibit side effects such as gastrointestinal disorders by inhibiting COX-1 enzyme as well as inhibiting COX-2 enzyme .

On the other hand, cosmetics used in everyday life are products used for protecting skin and cleansing the shine, but when the cosmetic composition is examined, ingredients different from the purpose of skin protection are used as indispensable substances for product formation. For example, surfactants, preservatives, fragrances, sunscreens, pigments, and other ingredients used to impart other benefits or effects. Ingredients that are essential for the manufacture of cosmetics are generally known to cause skin irritation, rashes, swelling, and various other side effects.

Further, when sebum components, sweat components, and fatty acids, higher alcohols, and proteins in cosmetic components, which are discharged from the body, are decomposed into highly toxic substances by skin-derived bacteria existing on the skin, they may cause skin inflammation It is well known that skin inflammation is caused by ultraviolet rays from the sun.

In this way, the causes of skin adverse effects in cosmetics are always present and various studies have been conducted to solve them. To date, substances that are used for irritation relief and inflammation relief such as erythema and edema include flutenamic acid, ibuprofen, benzydamine, indomethacin, , Steroids such as prednisolone and dexamethasone, and allantoin, azrene, epsilon-aminocaproic acid, hydrocotisone, licorice acid and its derivatives (? -Glycyrrhetinic acid, glycyrrhetinic acid derivative) It is known to be effective for anti-inflammation.

However, the indomethacin generally used as an anti-inflammatory agent is a substance that can not be used in cosmetics. The amount of hydrocotisin is limited. The licorice acid and its derivatives are difficult to stabilize or have poor solubility, It is difficult to achieve a substantial effect. Thus, known anti-inflammatory agents have problems in terms of skin safety and stability in mixing cosmetics, and their use is limited.

Therefore, it is possible to inhibit the production of NO effectively and without any side-effect or cytotoxic effect with a natural-substance-derived substance, so that the anti-inflammatory effect is excellent, and the inflammation can be suppressed without any side effects. The development of materials that can be used in cosmetics is required.

In recent years, in order to meet the needs of consumers, research and development of cosmetics using natural raw materials have been actively conducted.

10-2015-0135425A 10-1656561B 10-1337045B

 Mosmann T, Journal of immunological methods 65, pp. 55-63 (1983)  Jeong GS et al., Natural Product Sciences, 13, pp. 268-272 (2007)  Royall J and H Ischiropoulos, Archives of biochemistry and biophysics, 302, 348-355 (1993)  Li B et al, European Journal of Pharmacology 614, pp. 58-65 (2009)  Tenhunen R et al, The Journal of Laboratory and Clinical Medicine, 75, pp. 410-421 (1970)

In order to meet such a demand, it is an object of the present invention to provide a anti-inflammatory composition comprising as an active ingredient a natural-derived component having a low possibility of causing a problem related to side effects.

In addition, unlike existing anti-inflammatory substances, it is derived from marine, ie, marine-derived actinomycetes, rather than natural products, specifically land microorganisms or atmospheric microorganisms, and is not only cytotoxic but also has an excellent safety and can effectively inhibit inflammatory cytokines In particular, it is an object of the present invention to provide an anti-inflammatory or cosmetic composition for the treatment, improvement or prevention of an inflammatory disease by inhibiting the production of NO, particularly inhibiting anti-inflammatory activity in inflammation-related macrophages, .

In order to attain the above object, the present invention provides a method for producing an extract from a marine-derived actinomycetes-derived component, specifically, Griseusrazin A, a pharmaceutically acceptable salt thereof, or a combination thereof, ≪ RTI ID = 0.0 > anti-inflammatory < / RTI >

The glycus rasin A may have the structure of formula (1).

[Chemical Formula 1]

In addition, the anti-inflammatory composition may be a composition for treating, preventing or ameliorating an inflammatory disease.

The Griseo's rasin A was able to effectively inhibit the secretion of NO, control various cytokines related to inflammation, and was derived from natural products and had no cytotoxicity, thus showing excellent anti-inflammatory effect .

In this respect, the composition of the present invention may be used as an active ingredient of a pharmaceutical composition for antiinflammation, a pharmaceutical composition for treating or preventing inflammatory diseases, a health functional food composition for preventing or ameliorating inflammatory diseases, or a cosmetic composition for alleviating inflammation .

In this aspect, the present invention provides a pharmaceutical composition for antiinflammation comprising, as an active ingredient, any one selected from the group consisting of Griseusrazin A, a pharmaceutically acceptable salt thereof, and a combination thereof.

The glycus rasin A may have the structure of formula (1).

[Chemical Formula 1]

In addition, Griseusrazin A of the present invention can be provided as an active ingredient of a cosmetic composition or an anti-inflammatory cosmetic composition, that is, an effective ingredient of a cosmetic composition having anti-inflammatory properties, for the purpose of suppressing inflammation.

In another aspect, the present invention provides a cosmetic composition having anti-inflammatory activity comprising, as an active ingredient, any one selected from the group consisting of Griseusrazin A, a pharmaceutically acceptable salt thereof, and a combination thereof .

The glycus rasin A may have the structure of formula (1).

[Chemical Formula 1]

Further, GRISEUSRAZIN A of the present invention is excellent in anti-inflammatory effect and can be provided as an active ingredient of a composition for the treatment, prevention or amelioration of an inflammatory disease for the purpose of inhibiting inflammation.

In another aspect, the present invention provides a pharmaceutical composition for the treatment or prevention of an inflammatory disease comprising, as an active ingredient, any one selected from the group consisting of Griseusrazin A, a pharmaceutically acceptable salt thereof, Lt; / RTI >

The glycus rasin A may have the structure of formula (1).

 [Chemical Formula 1]

In another aspect, the present invention provides a method for the prevention or amelioration of an inflammatory disease comprising, as an active ingredient, any one selected from the group consisting of Griseusrazin A, a pharmaceutically acceptable salt thereof, To provide a functional food composition.

The glycus rasin A may have the structure of formula (1).

 [Chemical Formula 1]

Hereinafter, the present invention will be described in more detail.

The inventors of the present invention have been studying a substance capable of inhibiting and preventing inflammation of a substance having an anti-inflammatory effect, specifically, a mouse-derived macrophage, in a marine microorganism other than a soiled microorganism or an atmospheric microorganism, Glycus rasin A, isolated from marine actinomycetes-derived fungus, 09-0144, can significantly inhibit inflammation-related cytokines in mouse-derived macrophages and can induce inflammation directly NO and other inflammatory mediators can be effectively inhibited, the present inventors have completed the present invention by confirming that Glycus rasin A has an excellent anti-inflammatory effect.

As used herein, "pharmaceutically acceptable" means that the application (subject) does not have an acceptable or higher toxicity (sufficiently low toxicity) without inhibiting the activity of the active ingredient.

As used herein, the term " pharmaceutically acceptable salt " refers to a salt prepared by a conventional method, including those that can be prepared or applied by methods known to those skilled in the art. Such pharmaceutically acceptable salts include, but are not limited to, salts derived from pharmacological or physiologically acceptable inorganic and organic acids and bases. Examples of the pharmacologically or physiologically acceptable inorganic and organic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, Acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid and the like. In addition, salts derived from the pharmacologically or physiologically acceptable bases may be alkali metals, such as sodium, alkaline noble metals, such as magnesium, ammonium, and the like.

As used herein, unless otherwise specified, the term " active ingredient " refers to a component that alone exhibits the desired activity or that can exhibit activity with a carrier that is itself inactive, and specifically includes a pharmaceutical composition, Refers to a component that provides a therapeutic, ameliorative, or preventive effect of an anti-inflammatory or inflammatory disease in a cosmetic composition.

As used herein, " treatment " means any action that improves or alleviates the symptoms of the disease upon administration of a composition comprising griseuracil A or a pharmaceutically acceptable salt thereof according to the present invention.

As used herein, the term " prophylactic " means any action that inhibits or delays the onset of the disease by administration of a composition comprising griseuracil A or a pharmaceutically acceptable salt thereof according to the present invention.

As used herein, " carrier " means a carrier, excipient, or diluent that does not significantly stimulate the organism and does not interfere with the biological activity and properties of the administered compound.

As used herein, the term 'inflammatory disease' is defined as any state specified by a local or systemic bio-defense response to an external physical or chemical stimulus or an infection of an external infectious agent such as bacteria, fungi, viruses, or allergenic substances. This reaction is an enzyme (e.g., iNOS, COX-2, etc.) activation, inflammation, release of mediators (e.g., release of NO, TNF-α IL-6 , IL-1β PGE 2) associated with various inflammatory mediators and the immune cells , Body fluid infiltration, cell migration, tissue destruction, and is manifested externally by symptoms such as erythema, pain, edema, fever, deterioration or loss of specific function of the body. The inflammatory disease may be acute, chronic, ulcerative, allergic or necrotic, so long as it is included in the definition of inflammatory diseases as above, it may be acute, chronic, ulcerative, allergic, Whether it is necrotic or not.

Specifically, the inflammatory diseases include asthma, allergic and non-allergic rhinitis, chronic and acute rhinitis, chronic and acute gastritis or enteritis, ulcerative gastritis, acute and chronic nephritis, acute and chronic hepatitis, Inflammatory bowel syndrome, inflammatory bowel disease, inflammatory pain, epigastric pain, headache, back pain, fibromyalgia, fascia disease, viral infection (eg, C-type infection), bacterial infection, fungal infections, burns, surgical or dental surgery (Including atopic dermatitis), eczema, multiple sclerosis, rheumatoid arthritis, rheumatoid arthritis, ankylosing spondylitis, Hodgkin's disease, pancreatitis, conjunctivitis, iritis, scleritis, And sclerosis.

Hereinafter, the present invention will be described in more detail.

The present invention relates to an anti-inflammatory agent comprising any one selected from the group consisting of Griseusrazin A, a pharmaceutically acceptable salt thereof, and a combination thereof, ≪ / RTI >

[Chemical Formula 1]

The Griseo's rasin A may be a marine-derived microorganism, specifically a marine-derived fungus, more specifically a marine-derived actinomycetes-derived 09-0144 compound.

According to one embodiment of the present invention, Griseo's rasin A can effectively inhibit the secretion of NO that can effectively inhibit inflammation-related inflammation-related cytokines and can directly induce inflammation, (Heme Oxygenase-1, HO-1), which has anti-inflammatory effect and protective effect against neurons.

Therefore, anti-inflammatory compositions containing the griseuracil A as an active ingredient can be used to suppress inflammation or to treat, ameliorate or prevent inflammatory or inflammatory diseases.

The inflammation may include one or more selected from the group consisting of various dermatitis, allergies, systemic lupus erythematosus, retinitis, gastritis, hepatitis, enteritis, pancreatitis, arthritis and nephritis. Allergic rhinitis, allergic rhinitis, anaphylaxis, allergic rhinitis, asthma, allergic conjunctivitis, allergic dermatitis, atopic dermatitis, contact dermatitis, urticaria, , Food allergies and drug allergies.

The anti-inflammatory composition can be used to inhibit inflammation of nerve cells, specifically macrophages, or to treat, ameliorate or prevent inflammation.

Therefore, the anti-inflammatory composition of the present invention can be applied as a pharmaceutical composition for treating or preventing an inflammatory disease, or as a food composition for preventing or ameliorating the inflammatory disease. The food composition may be, for example, a health functional food composition for preventing or ameliorating the inflammatory disease.

In this respect, the pharmaceutical composition for the treatment or prevention of the inflammatory disease or the health functional food composition for the prevention or amelioration of the inflammatory disease comprises Griseusrazin A having the structure represented by the following formula (1) A salt thereof, and a combination thereof.

[Chemical Formula 1]

The above-mentioned health functional foods are used to control the bio-defense rhythm of the food group or the food composition imparted with added value to function and express the function of the relevant food by physical, biochemical and biotechnological techniques, Means a food which is processed and designed so that the body controlling function of the body is sufficiently expressed to the living body. The health functional food may include food-acceptable food supplementary additives, and may further include suitable carriers, excipients and diluents conventionally used in the production of health functional foods.

The health functional food composition for preventing or ameliorating an inflammatory disease according to the present invention may contain 0.001% by weight to 99.9% by weight or 0.01% by weight to 50% by weight or 0.1% by weight to 30% by weight, 0.1% to 15% by weight.

The anti-inflammatory composition containing the griseuracil A as an active ingredient can be directly applied to animals including humans. The animal is a group of organisms corresponding to plants. It mainly consumes organic matter as nutrients, and differentiates digestive organs, excretory or respiratory organs. Preferably, it is a mammal, more preferably a human.

The Griseo's rasin A may be used alone in the anti-inflammatory composition, and may further include other pharmacologically acceptable carriers, excipients, diluents or subcomponents. More particularly, when the composition comprising Griseos lancein A is used as a medicament or is used for medicinal or pharmaceutical purposes, the griseus rasin A may be administered in a conventional manner to a pharmaceutically acceptable carrier or May be mixed with an excipient or diluted with a diluent.

In this case, the content of griseuracil A in the composition may be 0.001 wt% to 99.9 wt%, 0.1 wt% to 99 wt%, or 1 wt% to 50 wt%, but is not limited thereto, And the content of the compound may be appropriately adjusted depending on the method of use.

Examples of the pharmaceutically acceptable carrier, excipient or diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, propylhydroxybenzoate, talc, magnesium stearate and mineral oil , Dextrin, calcium carbonate, propylene glycol, liquid paraffin, and physiological saline. However, the present invention is not limited thereto, and any conventional carrier, excipient or diluent may be used. In addition, the pharmaceutical composition may further comprise at least one selected from the group consisting of conventional fillers, extenders, binders, disintegrants, anticoagulants, lubricants, humectants, pH adjusters, nutrients, vitamins, electrolytes, alginic acid and its salts, pectic acid and its salts, , Fragrances, emulsifiers, preservatives, and the like. The components may be added to the active ingredient griseus rasin A independently or in combination.

In addition, the composition of the present invention may further comprise a substance used as a known substance having a known anti-inflammatory effect, for example, a substance used as a COX-2 inhibitor, an NO inhibitor, or an anti-inflammatory agent.

When the composition is used as a medicine, it can be administered orally or parenterally. In one example, it can be administered through various routes including oral, transdermal, subcutaneous, intravenous or muscular.

In addition, the formulations of the compositions may vary depending on the method of use and may be formulated using methods well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to the mammal . In general, solid dosage forms for oral administration include tablets, pills, soft or hard capsules, pills, powders and granules, which may contain one or more Excipients such as starch, calcium carbonate, sucrose or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, Sweeteners, fragrances, preservatives, and the like.

Forms for parenteral administration include creams, looses, ONITMENTS, PLASTERS, LIQUIDS AND SOULTIONS, AEROSOLS, FRUIDEXTRACTS, (ELIXIR), INFUSIONS, SACHET, PATCH or INJECTIONS.

Furthermore, the compositions of the present invention may be formulated using any suitable method known in the art or using methods disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA .

The dosage of the composition may be determined in consideration of the administration method, the age, sex, the severity of the patient, the condition of the patient, the degree of absorption of the active ingredient in the body, the inactivity and the drug to be used in combination. Kg body weight to 500 mg / kg body weight, 0.1 mg / kg body weight to 400 mg / kg body weight or 1 mg / kg body weight to 300 mg / kg body weight, And may be administered once or several times in divided doses. The dose is not intended to limit the scope of the invention in any way.

The present invention also relates to a pharmaceutical composition comprising an anti-inflammatory composition comprising said griseus rasin A as an active ingredient, or any one selected from the group consisting of griseusrazin A, a pharmaceutically acceptable salt thereof, As an active ingredient, an anti-inflammatory agent or griseuracil A, which is contained as an active ingredient.

The glycus rasin A may have the structure of formula (1).

[Chemical Formula 1]

The pharmaceutical composition for antiinflammation or the composition for treating or preventing inflammatory diseases may further comprise the above-mentioned active ingredient alone or may further include a pharmaceutically acceptable carrier or excipient depending on the formulation, use method and purpose of use. have. When provided as a mixture, the active ingredient may be contained in an amount of 0.1 to 99.9% by weight based on the total amount of the composition for the treatment or prevention of inflammation, or the pharmaceutical composition for antiinflammatory diseases, but it is usually 0.001 to 50% by weight .

The pharmaceutical composition for anti-inflammation or the composition for the treatment or prevention of inflammatory diseases may be used for various acute inflammatory diseases such as rheumatoid arthritis, lupus, various chronic inflammatory diseases such as multiple sclerosis, sepsis, shock, rejection of organ transplantation, , Or for the prevention and treatment of inflammatory bowel disease.

Examples of the carrier or the excipient include water, dextrin, calcium carbonate, lactose, propylene glycol, liquid paraffin, physiological saline, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gelatin, calcium phosphate, But are not limited to, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Two or more carriers or excipients may be used.

When the pharmaceutical composition for antiinflammation or the composition for treating or preventing inflammatory diseases is to be formulated, it is possible to use conventional fillers, extenders, binders, disintegrators, surfactants, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers or preservatives As shown in FIG.

In addition, the pharmaceutical composition for anti-inflammation or the composition for treating or preventing inflammation according to the present invention may further comprise a compound having a known anti-inflammatory activity or a plant extract in addition to the above-mentioned effective ingredient. By weight to 20 parts by weight.

The pharmaceutical composition for antiinflammation or the composition for the treatment or prophylaxis of an inflammatory disease may be in a form suitable for the method of use and may be formulated for administration to the mammal, And may be formulated by employing methods known in the art.

Exemplary formulations include, but are not limited to, excipients, granules, lotions, liniments, rimonadense, powders, syrups, ointments, liquids, aerosols, EXTRACTS, elixirs, ointments, Suspensions, premixes, infusions, eye drops, tablets, suppositories, injections, main tablets, capsules, creams, pills, soft or hard gelatin capsules.

The pharmaceutical compositions for the treatment or prevention of inflammation according to the present invention can be used orally or parenterally and can be administered orally or parenterally in the form of, for example, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, And the dosage thereof is determined in consideration of the administration method, the age, sex, and weight of the recipient, the severity of the disease, and the like. For example, the pharmaceutical composition for antiinflammation of the present invention can be administered at least once at a dose of 0.1 mg / kg (body weight) to 100 mg / kg (body weight) per day based on the active ingredient. However, the above-mentioned dosage is only for illustrative purposes and is not limited to the above range.

The present invention also provides a cosmetic composition comprising as an active ingredient any one selected from the group consisting of Griseusrazin A, a pharmaceutically acceptable salt thereof, and a combination thereof.

The Glycus rasin A is not only cytotoxic since it is derived from a natural substance but also has excellent antiinflammatory and anti-irritant activity because it has excellent anti-inflammatory effect. Therefore, It is possible to effectively control induced inflammation. Accordingly, the anti-inflammatory composition comprising any one selected from the group consisting of Griseusrazin A, a pharmaceutically acceptable salt thereof, and a combination thereof, or a pharmaceutical composition containing the Griseusrazin A ), A pharmaceutically acceptable salt thereof, and a combination thereof may be used as an active ingredient of a cosmetic composition having an inflammation improving and alleviating effect.

The cosmetic composition may be used as a cosmetic composition for basic cosmetics, makeup cosmetics, body cosmetics, hair cosmetics, scalp cosmetics, shaving cosmetics or oral cosmetics.

Examples of the cosmetic cosmetic include a cream, a lotion, a pack, a massage cream, and a milky lotion. Examples of the cosmetic cosmetic include a foundation, a makeup base, a lipstick, an eye shadow, an eyeliner, a mascara, an eyebrow pencil, Examples of the cosmetic material include soap, liquid cleansing agent, bathing agent, sunscreen cream, and sun oil. Examples of the cosmetic for hair include shampoo, rinse, hair treatment, hair mousse, hair liquid, pomade, hair color, hair bleach Examples of the cosmetic composition for scalp include hair tonic or scarf treatment, and examples of the cosmetic composition for shaving include aftershave lotion or shaving cream. Examples of the oral cosmetic composition include Toothpaste or mouth washer.

The cosmetic composition may contain, in addition to the active ingredient, a component incorporated in the cosmetic composition, for example, a moisturizer, an ultraviolet absorber, a vitamin, an animal or plant extract, an extinguishing agent, a whitening agent, a vasodilator, an astringent, Hormones and the like may be further added. In addition, the cosmetic composition may further include a medicament or a mechanism necessary for infiltrating or transferring the active ingredient into the dermal tissue.

The formulation of the cosmetic composition may take any appropriate form depending on the intended use and the properties of the cosmetic composition. Examples of the formulation include an aqueous solution, a solubilization system, an emulsion system, an emulsion system, a gel system, a paste system, an ointment system, A two-layer system or a water-oil-powder three-layer system. Examples of the formulations are merely illustrative, and the formulations and forms of the cosmetic composition of the present invention are not limited by the above examples.

The active ingredient may be contained in an amount of 0.001 to 50% by weight, preferably 0.01 to 20% by weight, based on the total weight of the cosmetic composition, , And the content of the active ingredient contained in the present invention is not limited by the above content.

The Glycus rasin A of the present invention is a natural product derived from marine actinomycetes and has no cytotoxicity and can effectively inhibit the production of inflammation-related cytokines and NO in mouse-derived macrophages, 1 expression can be remarkably elevated, and it has been experimentally confirmed that the anti-inflammatory composition and the anti-inflammatory composition are excellent in the effect of improving, treating or preventing the anti-inflammatory composition through anti-inflammatory and macrophage-protecting ability.

The Glycus rasin A of the present invention was confirmed to be effective against inflammation by confirming the effect on the amount of NO associated with inflammation and the transcription of various cytokines as a natural material-derived substance. Furthermore, it was confirmed through macrophage that the cell protective and inflammation inhibitory effect was enhanced by the increase of HO-1 expression, which is a cytoprotective effect. Accordingly, the anti-inflammatory composition containing Griseuracil A as an active ingredient is essential for the manufacture of cosmetics in relation to anti-inflammatory or anti-inflammatory pharmaceutical compositions and specific formulations for treating inflammation-related diseases by inhibiting inflammation Or a cosmetic composition having a feature capable of effectively inhibiting inflammation of the skin due to the external environment, and the like. Therefore, the present invention can be widely used in the medical industry related to the treatment of diseases related to inflammation and in the field of the cosmetic industry related to control of skin inflammation.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a diagram showing a method of separating Griseurzacin A from marine actinomycetes 09-0144, a marine-derived fungus, according to an embodiment of the present invention.
FIG. 2 is a data on the substance isolated from marine actinomycetes 09-0144 according to an embodiment of the present invention, and FIG. 2a shows ¹ H-NMR (A) analysis of the substance isolated from strain 09-0144 As a result, FIG. 2B shows the results of ¹³ C-NMR (B) analysis of the substance isolated from strain 09-0144.
FIG. 3 is a diagram showing the structure of the substance, that is, the structure of Glycus rasin A, which is confirmed by analysis of a substance isolated from strain 09-0144 according to an embodiment of the present invention.
FIG. 4 shows the effect of inhibiting NO production (FIG. 4A), inhibiting PGE ₂ production (FIG. 4B), iNOS protein expression level (FIG. 4C) and COX-2 protein (4d). In the graphs of FIGS. 4a to 4d and the graphs of FIGS. 4c and 4d, the abscissa indicates the amount of addition, '+' means the treatment of the substance, '-' means that the material has not been treated.
FIG. 5 shows the effect of inhibiting the expression of TNF-a (FIG. 5A), IL-1b (FIG. 5B) and IL-6 (FIG. 5C), the inflammatory cytokines of griseus rasin, In FIG. 5, the vertical axis represents the expression level and the mRNA expression level of the IL-6 (FIG. 5D), IL-1b And the abscissa indicates the addition amount, '+' means the treatment of the substance, and '-' means the treatment of the substance.
FIG. 6 is a graph showing the anti-inflammatory effect of Griseo's rasin A according to an embodiment of the present invention. In the nuclear fraction of Griseo's rasin A, the transcriptional inhibitory effect (FIG. 6A) of p65 and p50, (Fig. 6 (b)). In the photograph of Fig. 6 (a) and the graph of Fig. 6 (b), the abscissa indicates the amount of addition, and the '+''Means the treatment of the substance, and' - 'means the treatment of the substance.
FIG. 7 is a graph showing the degree of m-RNA production (FIG. 7A) and the degree of protein expression (FIG. 7A) of hreeoxirase A-1 (Heme Oxygenase-1, HO- 7b), a photograph (FIG. 7c) and a graph (FIG. 7d and FIG. 7e) showing the nuclear and cytoplasmic contents of the nuclear transfer of Nrf2 into the nucleus, which is a transcription factor involved in the expression of cytoplasmic and HO-1 proteins , The abscissa of the photograph of FIG. 7 means the elapsed time after the addition of Griseurzac A.
Figure 8 according to one embodiment of the present invention, so the three-house l hematin oxidase of A -1 (Heme Oxygenase-1, HO-1) NO generation inhibiting effect by promoting the expression (Fig. 8a), PGE ₂ produced 8b), TNF-a (FIG. 8c), IL-1b (FIG. 8d), IL-6 (FIG. 8e) and iNOS and COX- In the graph and the photograph of FIG. 8, '+' means that the material is treated, and '-' means that the material is not treated.

Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily carry out the present invention. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

Example  One. Gryceus Rajin  Separation of A

Separation of Griseusrazin A from marine bacterium marine bacterium 09-0144 was carried out in the same manner as described in Fig.

First, 100% ethyl acetate was added to the cultured marine organism-derived fungus 09-0144, and the mixture was sonicated for 6 hours and then left at 10-20 ° C for 24 hours to obtain 100% ethyl acetate extract 379.4 mg. The 100% ethyl acetate extract was subjected to reversed-phase C ₁₈ column chromatography using a step gradient elution method (20%, 40%, 60%, 80%, 100% (methanol: water, v / v) Fractions were obtained.

The anti-inflammatory effect of each fraction was confirmed. The third fraction, which was found to have the highest anti-inflammatory effect, was subjected to reversed phase HPLC for 60 minutes under the solvent gradient condition of 55% to 100% MeOH in H ₂ O (0.1% formic acid) 2.3 mg of a single compound was isolated.

NMR analysis was performed to identify the structure of the separated Griseos rasin A. The structure was identified by confirming ¹ H-NMR analysis (FIG. 2A) and ¹³ C-NMR analysis (FIG. 2B) The above results were analyzed and it was confirmed that the structure-identified compound was Griseus rasin A, which is a compound having the formula shown in FIG. 3, that is, the formula 1.

The isolated compound, Griseuracin A, was stored at -20 ° C until used in the experiment.

Example  2. Mouse-derived macrophages RAW264 . ≪ RTI ID = 0.0 > NO , PGE2 , iNOS and COX -2 Protein Expression Inhibitory Effect

To examine the production of NO and PGE ₂ and the inhibition of protein expression of iNOS and COX-2, which are inflammatory mediators in RAW264.7 cells, mouse-derived macrophages of Griseo's rasin A isolated in Example 1, Kim et al ., < / RTI > European Journal of Pharmacology, 721, pp. 267-276 (2013)). The results are shown in FIG.

Specifically, the mouse-derived macrophages RAW264.7 cells of the above Example 1 were distributed in a 60 mm dish at a concentration of 3 × 10 ⁶ cells / ml and cultured for 12 hours. Then, A was added at a concentration of 5, 10, 20 and 40 μM, pretreated for 3 hours, treated with lipopolysaccharide (LPS) at a concentration of 1 μg / ml and cultured for 24 hours to induce an inflammatory reaction. Lt; RTI ID = 0.0 > 5% < / RTI > carbon dioxide incubator. After the above cultivation, RIPA (89900, Thermo) buffer was added and the supernatant was separated by centrifugation at 4 DEG C and 14,000 X g for 25 minutes. Protein quantification in the supernatant was performed using a BSA protein kit (Pierce Biotechnology).

Expression of anti-inflammatory proteins was confirmed by western blot analysis. Specifically, the supernatant was subjected to electrophoresis for 2 hours using 7.5% or 12% SDS-polyacrylamide gel, and then immobilized on the polyacrylamide gel using a nitrocellulose membrane (NC membrane) Lt; / RTI > The transferred nitrocellulose membrane was terminated in a blocking buffer (0.1% Tween 20 in Tris-buffered saline) containing 5% nonfat milk for 1 hour. After the reaction was stopped, the membrane was washed with PBST (PBS, 0.1% Tween 20) three times, once every 10 minutes, and then iNOS (SC-650, Santacruz biotechnology, USA), COX-2 (SC- Biotechnology, USA) was diluted 1: 1000 and reacted for 1 hour. After the reaction, the cells were washed three times with the PBST once every 10 minutes, and the secondary antibody (anti-rabbit IgG, SC-2004, Santacruz biotechnology, USA) was diluted 1: 1000 and reacted for 1 hour.

After the reaction, the plate was washed three times with PBST once every 10 minutes, and then mixed with ECL (Amersham Pharmacia Biotech) solution at a ratio of 1: 1 and poured on a nitrocellulose membrane (NC membrane) to emit light. The film was sensitized and developed. Actin content was measured in the same manner using an antibody against actin (SC-1616, Santacruz biotechnology, USA).

As a result of the measurement, specifically, the effect of inhibiting NO production (Fig. 4A), the effect of suppressing PGE ₂ formation (Fig. 4B), the effect of suppressing iNOS protein expression level (Fig. 4C) and the inhibitory effect of COX- (Fig. 4D), which is shown in Fig.

As shown in FIGS. 4A to 4D, inhibition of inflammation-related NO production (FIG. 4A) and PGE ₂ production (FIG. 4B) was suppressed as the concentration of Griseoazine A was increased when Griseo's rasin A was treated (Fig. 4C) and COX-2 (Fig. 4D), which are known as inflammatory mediators, were significantly inhibited in a concentration-dependent manner.

Example  3. Mouse-derived macrophages RAW264 Lt; RTI ID = 0.0 > inflammatory < / RTI & TNF -α, IL -1β and IL -6 protein and mRNA  Expression inhibitory effect

The amount of protein expression and mRNA production of TNF-α, IL-1β, and IL-6, which are inflammatory cytokines in RAW264.7 cells, mouse-derived macrophages of Griseo's rasin A isolated in Example 1, , And anti-inflammatory effects were confirmed.

Specifically, RAW264.7 cells, which are mouse-derived macrophages, were treated with 5, 10, 20 and 40 μM griseuracin A for 3 hours, followed by inflammatory reaction with lipopolysaccharide (LPS) , And cultured in a 5% CO2 incubator for 6 hours. After the culture, the amount of protein expression and mRNA production of inflammatory cytokines were confirmed by Western blotting and RT-PCR, and the results are shown in FIG.

As shown in FIG. 5, when the expression levels of TNF-a (FIG. 5A), IL-1 beta (FIG. 5B) and IL-6 (FIG. 5C), which were increased by LPS treatment when griseuracin A was treated, And mRNA expression of cytokines of TNF-? (Fig. 5d), IL-1? (Fig. 5e) and IL-6 (Fig. 5f) was also inhibited in a concentration-dependent manner.

Example  4. Mouse-derived macrophages RAW264 .7 in cells NF κB ( p65 , p50 ) Nucleus  With transcriptional repression NF -KB p65 Cohesion  Inhibitory effect

The anti-inflammatory effect of Glycus rasin A on the NF-kB related pathway in RAW264.7 cells was confirmed. The anticancer effect was evaluated in order to investigate NF-κB p65 and p50 nuclear transfer inhibition and NF-κB p65 binding ability inhibition (Kim et al al ., < / RTI > European Journal of Pharmacology, 721, pp. 267-276 (2013)) and western blot analysis described in Example 2 above.

Specifically, RAW 264.7 cells were pretreated with 20 or 40 μM griseuracin A for 3 hours and then induced with inflammatory response by lipopolysaccharide and cultured in a 5% CO 2 incubator for 1 hour. Nuclear isolation experiments were carried out to confirm the inhibition of NF-κB p65, p50 (SC-8008, SC-7178, Santacruz biotechnology, USA) nuclear transfer inhibition and NF-κB p65 binding capacity after the incubation. 6. 6a shows the expression levels of NF-κB p65 and p50 in the nucleus, and FIG. 6b shows the binding activity of NF-κB p65.

As shown in FIG. 6, the degree of nuclear transfer of NF-κB p65 and p50 (FIG. 6A) and the binding capacity of NF-κB p65 (FIG. 6B), which were increased when lipopolysaccharide was treated, And the concentration - dependent decrease was observed.

Example  5. Mouse-derived macrophages RAW264 .7 in cells HO -1 < / RTI > Nrf2 Of transcription into the nucleus of

In order to examine the expression level of HO-1 protein in RAW264.7 cells, a mouse-derived macrophage of Griseo's rasin A, Western blot analysis was carried out in the same manner as in Experimental Example 2 .

Specifically, 10 μM CoPP was used to induce the expression of HO-1 in RAW264.7 cells. Griseus rasin A was treated at 5, 10, 20 and 40 μM for 12 hours in a 5% CO 2 incubator Lt; / RTI > The degree of m-RNA production (FIG. 7A) and the degree of protein expression (FIG. 7B) of the Heme Oxygenase-1 and HO-1 were confirmed after the above cultivation and are shown in FIG.

As shown in FIG. 7, the mRNA production amount (FIG. 7A) and the protein expression amount (FIG. 7B) of HO-1 were significantly increased as the concentration of griseuracil A was increased, It was confirmed that the expression of HO-1 was induced.

In addition, the transfer of Nrf2, one of the transcription factors acting on HO-1 expression, into the nucleus was confirmed by Western blot analysis of nuclear and cytoplasm.

Specifically, the mouse-derived macrophage RAW264.7 cells were treated with 40 μM griseuracin A for 20, 40, 80, 100, and 120 minutes, and the cytoplasm and nucleus were then separated and analyzed for Nrf2 Western blot analysis was performed, and the results are shown in Fig.

As shown in Fig. 7, the amount of Nrf2 in the cytoplasm decreased (Fig. 7C and Fig. 7D) with the lapse of time after the initial treatment with griseus rasin, and the amount of Nrf2 in the nucleus increased (Figs. 7C and 7E ), Griseuracin treatment increased the transcription of Nrf2, one of the transcription factors acting on HO-1 expression in RAW264.7 cells, into the nucleus.

Example  6. Mouse-derived macrophages RAW264 .7 in cells HO -1 inhibition of inflammatory response

Whether or not the expression of HO-1 protein is induced in RAW264.7 cells, which is a mouse-derived macrophage of Griseo's rasin A, and the expression of HO-1 is expressed in mouse-derived macrophages RAW264.7 cells To investigate the effect of lipopolysaccharide on the inflammatory response, 10 μM pretreatment of HO-1 expression inhibitor, SnPP, 40 μM Griseurzacin A, and lipopolysaccharide treatment Respectively.

Specifically, 10 μM of SnPP, an inhibitor of HO-1 expression, was treated with 40 μM Griseurzacin A followed by lipopolysaccharide, an inflammatory drug, and NO, PGE ₂ , TNF-a, IL-1b and IL-6, and the degree of expression of iNOX and COX-2. The results are shown in FIG.

As shown in FIG. 8, the production of NO (FIG. 8A) and PGE ₂ (FIG. 8B) induced by lipopolysaccharide induced in mouse RAW 264.7 cells and the production of cytokines TNF-α IL-1? (Fig. 8d), and IL-6 (Fig. 8e) were effectively inhibited by griseuracil A. In addition, it was confirmed that the expression of iNOX and COX-2, which is increased by treatment with LPS by griseuracil A, was also effectively inhibited.

Furthermore, it was further confirmed that, when pretreated with SnPP as an inhibitor of the HO-1 protein expression, cytokine reduction was not suppressed, and overexpression of iNOS and COX-2 inhibited by griseuracin A was not inhibited .

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the invention is not limited to the disclosed exemplary embodiments, Of the right.

Claims (8)

A pharmaceutical composition for antiinflammatory, comprising as an active ingredient any one selected from the group consisting of Griseusrazin A, a pharmaceutically acceptable salt thereof, and a combination thereof. The method according to claim 1,
Wherein said Griseuszin A has the structure of formula (I).
[Chemical Formula 1]

A cosmetic composition having anti-inflammatory activity comprising, as an active ingredient, any one selected from the group consisting of Griseusrazin A, a pharmaceutically acceptable salt thereof, and a combination thereof. The method of claim 3,
Wherein the Griseus rasin A has the structure of formula (I).
[Chemical Formula 1]

A pharmaceutical composition for the treatment or prophylaxis of inflammatory diseases, which comprises as an active ingredient any one selected from the group consisting of Griseusrazin A, a pharmaceutically acceptable salt thereof, and a combination thereof. 6. The method of claim 5,
The pharmaceutical composition for treating or preventing an inflammatory disease according to claim 1, wherein the Griseusrazin A has the structure of Formula (1).
[Chemical Formula 1]

A health functional food composition for preventing or ameliorating an inflammatory disease comprising, as an active ingredient, any one selected from the group consisting of Griseusrazin A, a pharmaceutically acceptable salt thereof, and a combination thereof. 8. The method of claim 7,
Wherein said Griseusrazin A has the structure of formula (1).
[Chemical Formula 1]

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