WO2021149860A1 - 유산균 발효 타임 추출물을 유효성분으로 하는 아토피 피부염 및 피부주름 개선용 조성물 - Google Patents
유산균 발효 타임 추출물을 유효성분으로 하는 아토피 피부염 및 피부주름 개선용 조성물 Download PDFInfo
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- WO2021149860A1 WO2021149860A1 PCT/KR2020/001655 KR2020001655W WO2021149860A1 WO 2021149860 A1 WO2021149860 A1 WO 2021149860A1 KR 2020001655 W KR2020001655 W KR 2020001655W WO 2021149860 A1 WO2021149860 A1 WO 2021149860A1
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- WIPO (PCT)
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- atopic dermatitis
- fermented
- thyme extract
- composition
- production
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Definitions
- the present invention relates to a composition for improving atopic dermatitis and skin wrinkles comprising a thyme extract as an active ingredient, and more particularly, to a composition for improving atopic dermatitis and skin wrinkles containing a lactic acid bacterium fermented thyme extract as an active ingredient.
- Atopic dermatitis is a chronic, recurrent itchy dermatitis, a disease that occurs frequently in infancy and is accompanied by itching, dry skin, or characteristic eczema in patients or their families.
- Typical symptoms of atopic dermatitis appear on the hands, scalp, face, neck, elbows, and knees, etc. The skin becomes very dry, itchy and inflamed, peels off like scales, and when severely scratched, the skin thickens and wrinkles are formed.
- the cause of atopic dermatitis is not yet clearly defined, but an abnormal increase in IgE, a decrease in the number and function of T cells that play a central role in cellular immunity, infiltration of monocytes and macrophages, an increase in the number of mast cells and eosinophils, Immunological factors such as an increase in the number of CD4 + T lymphocytes have been reported (J Invest Dermatol., 96:523-526, 1991; J Invest Dermatol., 97:389-394, 1991; Immunol., 11:81).
- Th1/Th2 imbalance due to an increase in the number of Th2 cells compared to Th1 cells is known to be an important factor (Kor J Pharmacogn, 43 :59-65, 2012).
- chemokines are small-molecular proteins that exhibit chemoattractants and are divided into four types, C, CC, CXC, and CX3C, depending on their structure and function. It is believed to play an important role in differentiation and migration of Th1/Th2 balance.
- steroids that suppress the inflammatory response and cytokine production are mainly used as a treatment for atopic dermatitis, but when administered for a long period of time, it causes various side effects such as skin atrophy and growth retardation. there is.
- non-steroids also have various side effects such as symptoms such as erythema, itchiness, edema, erosion and lichenification, and weakening of immunity, it is difficult to treat fundamental atopic dermatitis (Arellano FM et al., J Invest Dermatol. 2007 Apr;127(4):808-16.).
- the present inventors further improved the treatment effect of atopic dermatitis of natural substances known to be effective in the treatment of atopic dermatitis, so that the effect of atopic dermatitis treatment can be further improved so that it can exhibit an effect equal to or greater than that of a compound such as a steroid.
- a natural substance fermented with thyme extract with Lactobacillus plantarum strain, a lactic acid bacterium effectively inhibits the production of MDC and TARC proteins, which are atopic factors, and inhibits the production of inflammatory cytokines such as IL-6 to improve atopic immunity or inflammatory response.
- the main object of the present invention is to provide a composition for improving atopic dermatitis and skin wrinkles, containing as an active ingredient a lactic acid bacterium fermented thyme extract having an excellent effect on improving atopic dermatitis and skin wrinkles.
- the present invention provides a cosmetic composition for improving atopic dermatitis and skin wrinkles containing Lactobacillus plantarum (Accession No.: KCTC 14013BP) fermented thyme extract as an active ingredient.
- Lactobacillus plantarum accesion No.: KCTC 14013BP
- the present inventors have worked diligently to further improve the effect of natural substances known to be effective in the treatment of atopic dermatitis through fermentation of natural products to further improve the therapeutic effect of atopic dermatitis, thereby exhibiting an effect equal to or greater than that of compounds such as steroids. , it was confirmed that the thyme fermented extract fermented with lactic acid bacteria was excellent in improving atopic dermatitis.
- Lactobacillus plantarum subspecies plantarum ( Lactobacillus plantarum subsp. plantarum ) SDCM1002”, and deposited with the Korea Research Institute of Bioscience and Biotechnology Biological Resources Center as of November 4, 2019 with deposit number KCTC 14013BP.
- Lactobacillus plantarum subspecies plantarum SDCM1002 accession number: KCTC 14013BP
- strain of the present invention is used in the same meaning as the Lactobacillus plantarum (accession number: KCTC 14013BP).
- Thyme (Thymus vulgaris) of the present invention means a dicotyledonous perennial plant of the order Lamiaceae.
- skin wrinkle refers to fine lines caused by the deterioration of the skin, and may be caused by a genetic cause, a decrease in collagen present in the dermis of the skin, an external environment, and the like.
- active ingredient refers to a component that alone exhibits the desired activity, or can exhibit activity together with a carrier having no activity by itself.
- extract is an extract obtained by extraction treatment of plants, a diluted or concentrated liquid of the extract, a dried product obtained by drying the extract, a prepared or purified product of the extract, or a mixture thereof, such as an extract It includes extracts of all formulations that can be formed by themselves and using extracts.
- the extract of the present invention may be prepared and used in the form of a dry powder after extraction.
- the method of extracting the extract is not particularly limited, and may be extracted according to a method commonly used in the art.
- Non-limiting examples of the extraction method include hot water extraction, ultrasonic extraction, filtration, reflux extraction, and the like, and these may be performed alone or in combination of two or more extraction methods.
- the extract extracted with hot water or chilled extract is filtered to remove floating solid particles, for example, using nylon or the like to filter the particles, or filtered using freeze filtration, etc., and then used as it is, freeze-dried, hot-air dried, It can be used by drying it using spray drying or the like.
- the cosmetic composition of the present invention is characterized in that it inhibits TARC (Thymus and activation-regulated chemokine) and MDC (macrophage-derived chemokine) production (see FIGS. 2 and 3 ), and inhibits the production of inflammatory cytokines such as IL-6 By suppressing (see FIG. 4), it is very effective in suppressing atopic immunity or inflammatory response.
- TARC Thymus and activation-regulated chemokine
- MDC macrophage-derived chemokine
- the cosmetic composition of the present invention is characterized in that it inhibits the production of MMP-1 protein and increases the production of type 1 procollagen protein (see FIGS. 5 and 6 ).
- the composition comprises a solution, an external ointment, a cream, a foam, a nourishing lotion, a softening lotion, a mask pack, a softening water, an emulsion, a makeup base, an essence, a soap, a liquid detergent, Select from the group consisting of bath products, sunscreen creams, sun oils, suspensions, emulsions, pastes, gels, lotions, powders, soaps, surfactant-containing cleansers, oils, powder foundations, emulsion foundations, wax foundations, patches and sprays It can be prepared in a dosage form, but is not limited thereto.
- the cosmetic composition of the present invention may further include one or more cosmetically acceptable carriers to be formulated in general skin cosmetics, and conventional ingredients include, for example, oil, water, surfactant, humectant, lower alcohol, A thickener, a chelating agent, a colorant, a preservative, a fragrance, etc. may be appropriately mixed, but the present invention is not limited thereto.
- the cosmetically acceptable carrier included in the cosmetic composition of the present invention varies depending on the formulation.
- the formulation of the present invention is an ointment, paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide or Mixtures thereof may be used.
- lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder, or a mixture thereof may be used as a carrier component.
- additional chlorophyll It may contain propellants such as fluorohydrocarbons, propane/butane or dimethyl ether.
- a solvent, solubilizer or emulsifier is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylglycol oil may be used, and in particular, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol fatty ester, fatty acid ester of polyethylene glycol or sorbitan may be used. there is.
- the formulation of the present invention is a suspension
- a liquid diluent such as water, ethanol or propylene glycol
- a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters; Crystalline cellulose, aluminum metahydroxide, bentonite, agar or tracanth may be used.
- the formulation of the present invention is a soap
- alkali metal salts of fatty acids fatty acid hemiester salts, fatty acid protein hydrolysates, isethionate, lanolin derivatives, aliphatic alcohols, vegetable oils, glycerol, sugar, etc. may be used as carrier components.
- the present invention provides a food composition for improving atopic dermatitis and skin wrinkles containing Lactobacillus plantarum (Accession No.: KCTC 14013BP) fermented thyme extract as an active ingredient.
- Lactobacillus plantarum accesion No.: KCTC 14013BP
- the Lactobacillus plantarum (Accession No.: KCTC 14013BP) strain and the improvement of atopic dermatitis and skin wrinkles are the same as those described in the cosmetic composition.
- the food composition of the present invention has an excellent effect of inhibiting TARC (Thymus and activation-regulated chemokine) and MDC (macrophage-derived chemokine) production, inhibiting MMP-1 protein production, and increasing type 1 procollagen protein production. It can be usefully used as a food composition for improving atopic dermatitis and skin wrinkles.
- the food composition may be used in the form of health functional food, but is not limited thereto.
- the food composition of the present invention may be included in the form of a fraction of Lactobacillus plantarum (Accession No.: KCTC 14013BP) fermentation thyme extract or a processed product thereof.
- the composition may include a food pharmaceutically acceptable food supplement additive in addition to the active ingredient.
- food supplementary additive means a component that can be added to food as an auxiliary, added to the manufacture of health functional food of each formulation can be appropriately selected and used by those skilled in the art.
- food supplement additives include various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents and fillers, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners , pH adjuster, stabilizer, preservative, glycerin, alcohol, carbonation agent used in carbonated beverages, etc., but the above examples are not limited to the type of food supplement additive of the present invention.
- the food composition of the present invention may include a health functional food.
- health functional food refers to a food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. using raw materials or ingredients useful for the human body.
- functionality refers to obtaining useful effects for health purposes, such as regulating nutrients or physiological actions with respect to the structure and function of the human body.
- the health functional food of the present invention can be prepared by a method commonly used in the art, and at the time of manufacture, it can be prepared by adding raw materials and components commonly added in the art.
- the dosage form of the health functional food may also be manufactured without limitation as long as it is a dosage form recognized as a health functional food.
- the food composition of the present invention can be prepared in various forms, and unlike general drugs, it has the advantage of not having side effects that may occur during long-term administration of the drug using food as a raw material, and has excellent portability, It can be taken as a supplement to enhance the effect of improving skin wrinkles.
- the health functional food of the present invention can take, and it may include any food in a conventional sense, and may be used interchangeably with terms known in the art, such as functional food.
- the health functional food of the present invention can be prepared by mixing known additives with other suitable auxiliary ingredients that may be included in the food according to the selection of those skilled in the art.
- Examples of foods that can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages and There are vitamin complexes and the like, and it can be prepared by adding the cosmetic composition for improving atopic dermatitis and skin wrinkles according to the present invention as a main component to juice, tea, jelly, juice, and the like. Also included are foods used as feed for animals.
- the present invention provides a pharmaceutical composition for treating or preventing atopic dermatitis containing Lactobacillus plantarum (Accession No.: KCTC 14013BP) fermented thyme extract as an active ingredient.
- Lactobacillus plantarum accesion No.: KCTC 14013BP
- the Lactobacillus plantarum accesion No.: KCTC 14013BP
- strain and the improvement of atopic dermatitis and skin wrinkles are the same as those described in the cosmetic composition.
- the pharmaceutical composition of the present invention inhibits TARC (Thymus and activation-regulated chemokine) and MDC (macrophage-derived chemokine) production, and has an excellent effect of inhibiting IL-6 protein production, so a pharmaceutical composition for treating or preventing atopic dermatitis can be usefully used as
- treatment of the present invention means any action in which the symptoms of the atopic dermatitis disease are improved or beneficially changed by administration of the composition according to the present invention, and the term “prevention” refers to the atopic dermatitis by administration of the composition according to the present invention. It means any action that suppresses or delays the onset of related diseases.
- the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier.
- Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like.
- the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components.
- a lubricant e.g., a talc, a kaolin, a kaolin, a kaolin, a kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, a talct, a talct, a talct, a talct, a sorbitol, mannitol, mannitol
- the pharmaceutical composition of the present invention may be administered orally or parenterally. According to one embodiment of the present invention, it is administered by a parenteral method, and according to another embodiment of the present invention, it is administered by a transdermal administration method.
- a suitable dosage of the pharmaceutical composition of the present invention is variously prescribed depending on factors such as formulation method, administration method, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity of the patient.
- a preferred dosage of the pharmaceutical composition of the present invention is within the range of 0.0001-100 mg/kg for adults.
- the pharmaceutical composition of the present invention is prepared in unit dosage form by formulating using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by a person of ordinary skill in the art to which the present invention pertains. or may be prepared by incorporation into a multi-dose container.
- the formulation may be in the form of a solution, suspension, syrup, or emulsion in oil or aqueous medium, or may be in the form of an extract, powder, powder, granule, tablet or capsule, and may additionally include a dispersant or stabilizer.
- the present invention provides a composition for improving atopic dermatitis and skin wrinkles containing Lactobacillus plantarum (Accession No.: KCTC 14013BP) fermented thyme extract as an active ingredient.
- Lactobacillus plantarum accesion No.: KCTC 14013BP
- the lactic acid bacteria fermented thyme extract of the present invention effectively inhibits the production of TARC and MDC proteins, which are atopic factors, and inhibits the production of inflammatory cytokines such as IL-6, which is very effective in suppressing atopic immunity or inflammatory response, Since it is effective in preventing and improving skin wrinkles through inhibition of MMP-1 protein production and promotion of type 1 procollagen protein production, it can be usefully used as a cosmetic, food, and pharmaceutical composition for improving atopic dermatitis and skin wrinkles.
- the lactic acid bacteria fermented thyme extract is a fermented extract obtained by fermenting the natural thyme extract with lactic acid bacteria, which is not only very safe for the human body, but also has excellent stability.
- 1 is a graph showing the measurement of the cytotoxicity of the lactic acid bacteria fermentation thyme extract of the present invention.
- Figure 2 is a graph showing the measurement of the expression change of TARC in human keratinocytes (HaCaT, Human immortalized keratinocytes) treated with lactic acid bacteria fermentation thyme extract.
- FIG. 3 is a graph showing the measurement of the expression change of MDC in human keratinocytes (HaCaT, Human immortalized keratinocyte) treated with lactic acid bacteria fermentation thyme extract.
- 5 is a graph showing the measurement of the expression change of MMP-1 protein in human fibroblasts treated with lactic acid bacteria fermentation time extract.
- FIG. 6 is a graph showing changes in the expression of type 1 procollagen protein in human fibroblasts treated with lactic acid bacteria fermentation thyme extract.
- the thyme was washed with running water to remove impurities. After adding 6 L of purified water to 600 g of thyme, the mixture was extracted by stirring at room temperature for 3 days. The process was carried out in 3-Batch. After collecting the obtained extract, it was concentrated under reduced pressure at 40° C. or lower to obtain a concentrated extract in the form of an extract. After the concentrated thyme extract was dissolved in 10 mL of purified water at a ratio of 1 mg, the Lactobacilus plantarum strain was inoculated and cultured for 24 hours in an incubator at 55°C.
- the culture was sterilized at 121° C. for 15 minutes to inactivate the strain, and then centrifuged to collect only the supernatant.
- the lactic acid bacteria fermentation thyme extract thus obtained was concentrated under reduced pressure at 55° C. using a vacuum concentrator (Rotary evaporator N-1000, EYELA, Japan), and then lyophilized to prepare a powder.
- Example 2 The effect of the lactic acid bacteria fermentation thyme extract prepared in Example 1 on the growth of human keratinocytes (HaCaT, Human immortalized keratinocyte) was confirmed using MTT colorimetric assay.
- DMEM Dulbeccos modified Eagles medium
- FBS fetal bovine serum, Cambrex
- the lactic acid bacteria fermented thyme extract and thyme extract did not significantly affect the cell viability of human keratinocytes, and as a positive control, it showed a result of promoting the survival of human keratinocytes somewhat compared to tacrolimus.
- the lactic acid bacteria fermented thyme extract was not toxic to the human body (see FIG. 1).
- a 63% reduction in TARC production was measured in the lactic acid bacteria fermentation thyme extract treated group (10 ⁇ g/mL) compared to the tacrolimus (10 ⁇ g/mL) treated group used as a positive control, Compared to the thyme extract, the production amount reduced by 52% (10 ⁇ g/mL) and 49% (100 ⁇ g/mL), respectively, was measured, so that the lactic acid bacteria fermented thyme extract of the present invention is very effective for atopy, and is an immunosuppressive compound used for conventional atopy. It was confirmed that it can be used as a natural drug that can replace it because it has a superior effect than tacrolimus.
- a 67% reduction in MDC production was measured in the lactic acid bacteria fermentation thyme extract treated group (10 ⁇ g/mL) compared to the tacrolimus (10 ⁇ g/mL) treated group used as a positive control, and the lactic acid bacteria fermentation process was not performed.
- the amount of MDC production reduced by 27% (10 ⁇ g/mL) and 56% (100 ⁇ g/mL), respectively, was measured, so that the lactic acid bacteria fermented thyme extract of the present invention is very effective for atopy, and is an immunosuppressant used for conventional atopy. It was confirmed that it can be used as a natural drug that can replace it because it has an excellent effect compared to the tacrolimus compound.
- Atopic dermatitis is further expanded through an inflammatory reaction, and symptoms of atopic dermatitis clinically tend to worsen through skin redness, skin hypersensitivity reaction, or photosensitivity reaction. Therefore, in order to effectively improve the skin condition in which atopic dermatitis has occurred, early blocking of the inflammatory response is a very important factor in the treatment of acne symptoms.
- Inflammatory mediators such as IL-6 are involved in the inflammatory response mechanism caused by atopic dermatitis, and the inflammatory response is amplified by the action of inflammatory mediators. can be effectively blocked.
- HaCaT human keratinocytes
- UVB was irradiated at 144 mJ/cm 2 conditions
- lactic acid bacteria fermentation time extract (1, 10, and 100 ⁇ g/ml, respectively) was treated in DMEM without FBS. and further incubated for 24 hours. After incubation, the supernatant was taken and the amount of IL-6 protein produced was analyzed using an enzyme-linked immunosorbent assay (ELISA, Enzyme-Linked Immunosorbent Assay) kit.
- ELISA enzyme-linked immunosorbent assay
- UVB-induced IL-6 protein production was inhibited during treatment with lactic acid bacteria fermented thyme extract, and this ability to inhibit production of IL-6 protein was found to be concentration-dependent.
- the lactic acid bacteria fermented thyme extract of the present invention is very effective in suppressing atopic immune or inflammatory response, and through lactic acid bacteria fermentation, the thyme extract can dramatically improve the conventional immune or inflammatory response. was able to confirm
- DMEM culture solution 2ml of DMEM culture solution was put in a 40mm cell culture dish, and human fibroblasts were inoculated at a concentration of about 1.2x10 5 , and then cultured at 37° C., 5% CO 2 environment for 24 hours. Thereafter, after irradiating UVB with 144mJ/cm 2 conditions, the medium containing the lactic acid bacteria fermentation thyme extract prepared in Example 1 (1, 10, and 100 ⁇ g/ml, respectively) was replaced and cultured for 3 days. Thereafter, the culture medium was harvested and centrifuged for 5 minutes at 4° C., 7,500 rpm, and MMP-1 (Human Total MMP-1 kit, R&D Systems, Inc., Minneapolis, MN, USA) using an ELISA method. ) The change in the expression level of the protein was confirmed.
- MMP-1 Human Total MMP-1 kit, R&D Systems, Inc., Minneapolis, MN, USA
- human fibroblasts treated with UV irradiation at a dose of 144mJ/cm 2 increased the production of MMP-1 protein by about 3 times compared to the UV-untreated group.
- the increase in the production of MMP-1 protein due to the UV irradiation treatment showed a phenomenon that was decreased by the treatment of the thyme extract, 2%, 14%, and It exhibited the effect of inhibiting the production of MMP-1 protein reduced by 25%.
- the effect of inhibiting the production of MMP-1 protein of thyme as described above was further increased by the lactic acid bacterium fermentation treatment.
- the inhibitory effect on the production of MMP-1 protein was further reduced to 9%, 37%, and 54%.
- the lactic acid bacteria fermented thyme extract of the present invention can be effectively used to prevent and improve skin wrinkles by effectively inhibiting the production of MMP-1 protein, which is the cause of wrinkles.
- DMEM culture solution 2ml of DMEM culture solution was put in a 40mm cell culture dish, and human fibroblasts were inoculated at a concentration of about 1.2x10 5 , and then cultured at 37° C., 5% CO 2 environment for 24 hours. Then, after irradiating UVB with 144mJ/cm 2 conditions, cultured by replacing the medium containing the lactic acid bacteria fermentation thyme extract prepared in Example 1 (10 and 100 ⁇ g/ml, respectively). Thereafter, the culture medium was harvested, centrifuged for 5 minutes at 4°C and 7500 rpm, and the protein expression level of type 1 procollagen (Procollagen Type IC Peptide EIA Kit, Takara, Shiga, Japan) was changed using an ELISA method. was confirmed.
- type 1 procollagen Procollagen Type IC Peptide EIA Kit, Takara, Shiga, Japan
- human fibroblasts treated with UV irradiation at a dose of 144mJ/cm 2 reduced the production of type 1 procollagen protein by about 2.3 times compared to the UV-untreated group.
- the decrease in the production of type 1 procollagen protein due to the UV irradiation treatment showed a phenomenon that increased again by the treatment of the thyme extract.
- the thyme extract treatment group exhibits an effect of increasing the expression level when compared to the untreated group, respectively, at 10 and 100 ⁇ g/ml dose, 109% and 138% It showed the effect of increasing the production of the improved type 1 procollagen protein.
- the effect of increasing the production of type 1 procollagen protein of thyme as described above was further increased by the lactic acid bacterium fermentation treatment, and in the lactic acid bacterium fermented thyme extract treatment group of the present invention, at 10 and 100 ⁇ g/ml dose, respectively. It exhibited an effect of increasing the production of type 1 procollagen protein, which was further increased to 153% and 234% compared to the untreated group.
- the lactic acid bacteria fermented thyme extract of the present invention can be effectively used for preventing and improving skin wrinkles by effectively promoting the production of type 1 procollagen protein that suppresses wrinkle formation.
- the composition containing the lactic acid bacteria fermented thyme extract of the present invention as an active ingredient effectively inhibits the production of TARC and MDC proteins, which are atopic factors, and inhibits the production of inflammatory cytokines such as IL-6 to prevent atopic immunity.
- TARC and MDC proteins which are atopic factors
- inflammatory cytokines such as IL-6
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