JP5930507B2 - Hyaluronic acid production promoter - Google Patents

Description

  The present invention relates to a composition for maintaining and regulating skin barrier function or joint function, comprising taurine as an active ingredient.

Hyaluronic acid is a linear glycosaminoglycan with a molecular weight of 10 ⁷ Da and is widely distributed in skin, blood vessels, joints, and the vitreous of the eye. Responsible for holding, lubricating and buffering. Hyaluronic acid in the skin decreases with age, causing skin dryness, loss of elasticity, and generation of wrinkles. In joints, hyaluronic acid produced by synovial cells covers the cartilage surface and helps smooth operation of the joint function, but in osteoarthritis of the knee and rheumatoid arthritis, the amount of hyaluronic acid in the joint fluid decreases. , Joint dysfunction occurs.

  In the past, treatment methods have been used in which diseases associated with a decrease in hyaluronic acid, such as skin wrinkles and arthritis, are directly administered as topical hyaluronic acid, orally or intraarticularly. However, since the polymer hyaluronic acid is hardly absorbed percutaneously and is decomposed in the digestive tract, a sufficient effect cannot be obtained. Also, intra-articular injection requires a doctor's prescription and is not a technique that can be used on a daily basis.

  Cytokines such as interleukin-1 (IL-1) (non-patent document 1) and insulin-like growth factor-1 (IGF-1) (non-patent document 2) have been reported as drugs that increase hyaluronic acid production. None of these can be easily used as pharmaceuticals or cosmetics. Therefore, development of an inexpensive and highly safe drug that promotes hyaluronic acid production in vivo has been desired.

Postlethwaite AE et al. (1989) J Clin Invest 83: 629-636 Honda A et al. (1989) Biochim Biophys Acta 1014: 305-312

  An object of the present invention is to provide a material that promotes hyaluronic acid production that is effective in maintaining and regulating skin barrier function and joint function.

  The present inventors examined the action of taurine from the viewpoint of extracellular matrix metabolism of dermal fibroblasts and epidermal cells constituting human skin. Taurine is a hyaluronic acid synthase (HAS-2) gene in both cells. It has been found that it has an effect of promoting hyaluronic acid production resulting from increased expression of. Taurine did not affect the expression of type I collagen αI mRNA, suggesting that taurine may specifically promote hyaluronic acid production. Although male hormones are known to affect extracellular matrix metabolism, the expression of hyaluronic acid synthase (HAS-2) in human skin fibroblasts is the male hormone 5α-dihydrotestosterone (5α-DHT). ). Taurine restores this decrease in HAS-2 gene expression in a concentration-dependent manner, suggesting that it functions as a hyaluronic acid production promoting factor in human skin.

  Furthermore, the present inventors examined the effect of taurine on the extracellular matrix metabolism of human synovial cells. As with dermal fibroblasts and epidermal cells, taurine expressed hyaluronic acid synthase (HAS-2) gene. Due to the increase, it was found that it has a hyaluronic acid production promoting effect.

  Based on the above findings, the present inventors have found that taurine can function as a physiologically active substance responsible for maintaining and regulating skin barrier function and joint function by promoting hyaluronic acid production of skin and joints. The invention has been completed.

  Therefore, the present invention provides a composition for promoting the production of hyaluronic acid containing taurine as an active ingredient. The present invention also provides a composition for promoting gene expression of hyaluronic acid synthase (HAS-2) containing taurine as an active ingredient. Furthermore, the present invention provides a composition for recovering the gene expression of hyaluronic acid synthase (HAS-2), which is decreased by male hormone, containing taurine as an active ingredient.

  In a preferred embodiment, the present invention provides the above composition, which is an external preparation for skin. In a particularly preferred embodiment, the external preparation for skin is a pharmaceutical composition or a cosmetic.

  Moreover, this invention provides the said composition which attached | subjected the display to be used in order to accelerate | stimulate production of hyaluronic acid in another preferable aspect.

  The composition of the present invention containing taurine as an active ingredient has an action of promoting hyaluronic acid production in skin cells and joint cells. The effect of promoting hyaluronic acid production in the composition of the present invention can be exerted through the promotion of expression of the HAS-2 gene, which is a hyaluronic acid synthase, and the composition of the present invention is 5α- It is also possible to restore HAS-2 gene expression that has been reduced by the action of DHT. Therefore, the composition of the present invention is useful for maintaining moisture in the skin, maintaining the elasticity of the skin, preventing wrinkles associated with skin aging, and treating or preventing osteoarthritis and arthritis.

It is a graph which shows the promotion effect of taurine with respect to hyaluronic acid production in a human skin fibroblast. “**” and “***” indicate p <0.01 and p <0.001, respectively, for untreated cells (Control). It is a graph which shows the promotion effect of taurine with respect to the expression of HAS-2 gene in a human skin fibroblast. “**” and “***” indicate p <0.01 and p <0.001, respectively, for untreated cells (Control). It is a graph which shows the effect | action of a taurine with respect to expression of a type I collagen alpha1 gene in a human skin fibroblast. It is a graph which shows the recovery | restoration effect of the expression suppression of the HAS-2 gene of a human skin fibroblast by 5 (alpha) -DHT, and the expression suppression of the said gene by taurine. “**” indicates p <0.01 with respect to untreated cells (C). “#” Indicates p <0.05 with respect to cells treated with 5α-DHT. It is a graph which shows the promotion effect of taurine with respect to hyaluronic acid production in a human epidermal keratinocyte. “*” Indicates p <0.05 relative to untreated cells (Control). It is a graph which shows the promotion effect of taurine with respect to the expression of the HAS-2 gene in a human epidermal keratinocyte. “**” indicates p <0.01 with respect to untreated cells (Control). It is a graph which shows the promotion effect of taurine with respect to hyaluronic acid production in a human joint corneal cell. Interleukin-1α (IL-1α) was used as a positive control drug. “*” And “**” indicate p <0.05 and p <0.01, respectively, for untreated cells (Control). It is a graph which shows the promotion effect of taurine with respect to the expression of HAS-2 gene in a human joint synovial cell. Interleukin-1α (IL-1α) was used as a positive control drug. “*” And “**” indicate p <0.05 and p <0.01, respectively, for untreated cells (Control). It is a graph which shows the increase effect | action of a hyaluronic acid in the mouse | mouth epidermis which administered taurine for 16 weeks with drinking water. “*” Indicates p <0.05 relative to the taurine non-administered group (Control).

The present invention provides a composition for promoting hyaluronic acid production comprising taurine as an active ingredient. The present invention also provides a composition for promoting gene expression of hyaluronic acid synthase (HAS-2) containing taurine as an active ingredient. Furthermore, the present invention provides a composition for recovering the gene expression of hyaluronic acid synthase (HAS-2), which is decreased by male hormone, containing taurine as an active ingredient. In addition, human HAS-2 is registered as Accession No. NM_005328.2. The composition of the present invention is used for pharmaceutical compositions, cosmetics, foods and drinks, or research purposes (for example, in vitro and in vivo experiments). Can be in the form of a reagent. Since the composition of the present invention has an action of promoting the production of hyaluronic acid, for example, a pharmaceutical composition that is administered or ingested in order to promote the production of hyaluronic acid in the skin to prevent or improve wrinkles and rough skin And can be suitably used as a food or drink, or as a cosmetic to be applied. Also, a pharmaceutical composition that is administered or ingested to promote joint hyaluronic acid production to prevent, ameliorate, or treat joint disorders such as arthritis, joint pain, osteoarthritis, and rheumatoid arthritis, and joint cartilage damage It can be suitably used as a food or a food or drink.

  Furthermore, the composition of the present invention can be suitably used as a reagent for promoting the production of hyaluronic acid by applying it to cells and animals as experimental materials.

  The composition of the present invention can be formulated by a known pharmaceutical method. For example, coating agents, ointments, plasters, cataplasms, transdermal preparations, lotions, inhalants, aerosols, solutions, gels, capsules, tablets, pills, powders, granules, fine granules , Film coatings, pellets, lozenges, sublinguals, chewing agents, buccals, pastes, syrups, suspensions, elixirs, emulsions, injections, suppositories, etc. parenterally or orally Can be used.

  In these formulations, taurine is a medium or carrier that is acceptable as a pharmaceutical, cosmetic, or food and drink, specifically, sterile water, physiological saline, vegetable oil, solvent, base, emulsifier, suspending agent, interface. Activators, stabilizers, flavoring agents, fragrances, excipients, vehicles, preservatives, binders, diluents, tonicity agents, extenders, disintegrating agents, buffering agents, coating agents, lubricants, colorants , Sweeteners, thickeners, flavoring agents, solubilizers, or other additives can be appropriately selected and combined depending on the purpose of use.

  When the composition of the present invention is an external preparation for skin, for example, it is provided as a coating agent, ointment, plaster, cataplasm, transdermal preparation, lotion, inhalant, aerosol, liquid, gel, etc. can do. Examples of external preparations for skin include pharmaceutical compositions, lotions, creams, emulsions, packs, hair for the prevention, amelioration, or treatment of symptoms and diseases caused by excessive production of sebum and a decrease in hyaluronic acid. Cosmetics such as tonics, shampoos, rinses, soaps, bathing agents (including quasi-drugs such as so-called medicinal cosmetics) and the like.

  When the composition of the present invention is used as a food or drink, the food or drink can be, for example, a health food, a functional food, a food for specified health use, a dietary supplement, a food for a sick person, or a food additive. Specific examples of food and drink include liquid foods such as drinks, soups, milk beverages, soft drinks, tea beverages, alcoholic beverages, jelly-like beverages, functional beverages; oils such as edible oils, dressings, mayonnaise, margarines Products containing carbohydrates; Foods containing carbohydrates such as rice, noodles, and bread; Livestock processed foods such as ham and sausage; Fish processed foods such as kamaboko, dried fish, and salted vegetables; Vegetable processed foods such as pickles; Solid foods; fermented foods such as miso and fermented beverages; various confectionery products such as confectionery, Japanese confectionery, candy, gums, gummi, frozen confectionery, ice confectionery; retort products such as curry, ankake, Chinese soup; Examples include instant foods such as instant miso soup and foods for microwave ovens. Furthermore, health foods and drinks prepared in the form of powder, granules, tablets, capsules, liquid, paste or jelly are also included. Manufacture of the food-drinks in this invention can be implemented with a manufacturing technique well-known in the said technical field.

  When the composition of the present invention is applied to a living body, the amount to be applied is appropriately selected according to age, weight, symptom, health condition, type of composition (pharmaceuticals, cosmetics, food and drink, etc.) and the like. The effective application amount of taurine in the composition of the present invention is usually 100 mg to 6000 mg per day for an adult, preferably 500 mg to 3000 mg.

  Thus, the present invention also provides a method for promoting hyaluronic acid production in a subject, characterized by administering or ingesting the composition of the present invention to the subject. The present invention also provides a method for preventing or treating a disease caused by a decrease in hyaluronic acid production in a subject, which comprises administering the composition of the present invention to the subject.

  The product of the composition of the present invention (pharmaceuticals, cosmetics, foods and drinks, reagents) or instructions thereof are used to promote the production of hyaluronic acid, the gene expression of hyaluronic acid synthase (HAS-2) May be used, and may be used to restore the gene expression of hyaluronan synthase (HAS-2) decreased by male hormones. Here, “labeled product or instructions” means that the product body, container, packaging, etc. are marked, or instructions, package inserts, promotional materials, or other printed materials that disclose product information. It means that the display is attached to. Moreover, in these indications, the information regarding being used for the prevention or treatment of the disease resulting from the reduction | decrease in the production of hyaluronic acid can be included.

  EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example and a comparative example, this invention is not limited to a following example.

[Example 1] Effect of taurine on hyaluronic acid production of cultured human fibroblasts Human fibroblasts (RIKEN BioResource Center) in a 100 mm dish (AGC Technograss) with 10% calf serum (SAFC bioscience) The cells were cultured in Dulbecco's modified Eagle's medium (DMEM). When the cell occupancy per dish reaches 90% or higher, the cells are detached using a phosphate buffer containing 0.25% trypsin and 0.02% EDTA and placed in a 48-well multiplate or 60 mm dish (AGC Techno Glass). Each was seeded at a cell number of 1 × 10 ⁴ cells / well or 3 × 10 ⁴ cells / dish. Taurine dissolved in sterile distilled water (final concentration 6.25-50 mM) or taurine and 5α-dihydrotestosterone (5α-DHT) (final concentration 20 μM) when cell occupancy per well or dish reaches 90% or higher Was added to the culture and cultured for 24 hours.

  Extraction of total RNA from the cells was performed by adding isogen (Nippon Gene) to the cells and lysing the cells. Chloroform was added to the cell lysate and mixed, followed by centrifugation (10 minutes at 10,000 rpm), the aqueous layer was recovered, and the same dose of isopropanol was added and mixed. After centrifugation (10 minutes at 10,000 rpm), the supernatant was removed and the precipitated RNA was recovered. The RNA was mixed with 75% ethanol, the supernatant was removed, and the RNA was air-dried. The extracted total RNA was dissolved in sterile distilled water containing no nucleolytic enzyme, and the amount of RNA was quantified by measuring the absorbance at 260 nm.

  The hyaluronic acid secreted into the culture broth was quantified with a hyaluronic acid ELISA kit (Biochemical Biobusiness). In other words, hyaluronic acid in the culture solution was bound to hyaluronic acid binding protein (HABP) immobilized on the microplate of the kit, then peroxidase-bound HABP was added and reacted, followed by tetramethylbenzidine and hydrogen peroxide And the absorbance at 450 nm was measured with a microplate reader. The amount of hyaluronic acid was calculated from a calibration curve created simultaneously using a standard hyaluronic acid solution.

The gene expression of hyaluronan synthase (HAS-2) in the cells was measured by real-time PCR (RT-PCR). The reverse transcription reaction using the ^{QuantiTect R Reverse Transcription Kit (QIAGEN)} , according to the procedure of attachment, was synthesized single-stranded cDNA. Real-time polymerase chain reaction (PCR) uses single-stranded cDNA as a template, human hyaluronic acid synthase 2 (HAS-2), human type I collagen α1, and human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) This was carried out using primers specific for. After the reaction was completed, the expression level of each gene was normalized using GAPDH as an internal standard gene. Thereafter, the relative gene expression level of the taurine-treated group relative to the untreated group was calculated. The primers used for PCR are as follows:
Human HAS-2 (Accession No. NM_005328.2) Sense primer: 5'-GACAGGCATCTCACGAACCG-3 '/ SEQ ID NO: 1
Human HAS-2 (Accession No. NM_005328.2) antisense primer: 5'-CAACGGGTCTGCTGGTTTAGC-3 '/ SEQ ID NO: 2
Human collagen-Iα1 (Accession No. NM_000088.3) sense primer: 5′-CTCCAGGGCTCCAACGAGAT-3 ′ / SEQ ID NO: 3
Human collagen-Iα1 (Accession No. NM_000088.3) antisense primer: 5′-CAGCCATCGACAGTGACG-3 ′ / SEQ ID NO: 4
Human GAPDH (Accession No. NM_002046.3) sense primer: 5′-CATCCCTGCCTCTACTGGCG-3 ′ / SEQ ID NO: 5
Human GAPDH (Accession No. NM_002046.3) antisense primer: 5'-AGCTTCCCGTTCAGCTCAGG-3 '/ SEQ ID NO: 6
As a result, taurine increased hyaluronic acid production in a concentration-dependent manner in cultured human fibroblasts (FIG. 1) and at the same time increased gene expression of hyaluronic acid synthase (HAS-2) (FIG. 2). On the other hand, taurine did not affect type I collagen α1 gene expression in cultured human fibroblasts (FIG. 3). In addition, hyaluronic acid synthase (HAS-2) gene expression in cultured human fibroblasts was significantly decreased by the male hormone 5α-dihydrotestosterone (5α-DHT), but taurine concentration was dependent on HAS-2. Gene expression was restored (Figure 4).

[Example 2] Effect of taurine on hyaluronic acid production by human epidermal keratinocytes Human epidermal keratinocytes (Kohjin Bio) in a 60 mm dish (AGC Technograss) serum-free medium for normal human epidermis keratinocytes (Kohjin) Bio). When cell occupancy per dish reaches 80% or more, cells are detached using EDTA trypsin solution (Kohjin Bio), D-PBS (-) (Kohjin Bio) and trypsin inhibitor solution (Kohjin Bio), A 35 mm dish (AGC technograss) was seeded at 1 × 10 ⁵ cells / dish. When the cell occupancy per dish reached 80% or more, the cells were cultured in a serum-free basal medium containing taurine (final concentration: 6.25 to 50 mM) for 24 hours.

  Extraction of total RNA from the cells was performed by adding isogen (Nippon Gene) to the cells and lysing the cells. Chloroform was added to the cell lysate and mixed, followed by centrifugation (10 minutes at 10,000 rpm), the aqueous layer was recovered, and the same dose of isopropanol was added and mixed. After centrifugation (10 minutes at 10,000 rpm), the supernatant was removed and the precipitated RNA was recovered. After 75% ethanol was added to RNA and mixed, the supernatant was removed and the RNA was air-dried. The extracted total RNA was dissolved in sterile distilled water containing no nucleolytic enzyme, and the amount of RNA was quantified by measuring the absorbance at 260 nm.

  The hyaluronic acid secreted into the culture broth was quantified with a hyaluronic acid ELISA kit (Biochemical Biobusiness). In other words, hyaluronic acid in the culture solution was bound to hyaluronic acid binding protein (HABP) immobilized on the microplate of the kit, then peroxidase-bound HABP was added and reacted, followed by tetramethylbenzidine and hydrogen peroxide And the absorbance at 450 nm was measured with a microplate reader. The amount of hyaluronic acid was calculated from a calibration curve created simultaneously using a standard hyaluronic acid solution.

The gene expression of hyaluronic acid synthase (HAS-2) in the cells was measured by real-time PCR (RT-PCR). In the reverse transcription reaction, using the ^{QuantiTect R Reverse Transcription Kit (QIAGEN)} , according to the procedure of attachment, it was synthesized single-stranded cDNA. Real-time polymerase chain reaction (PCR) uses single-stranded cDNA as a template and primers specific for human hyaluronan synthase 2 (HAS-2) and human glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Implemented. After the reaction was completed, the expression level of each gene was normalized using GAPDH as an internal standard gene. Thereafter, the relative gene expression level of the taurine-treated group relative to the untreated group was calculated. The primers used for PCR are as follows:
Human HAS-2 (Accession No. NM_005328.2) Sense primer: 5'-GACAGGCATCTCACGAACCG-3 '/ SEQ ID NO: 7
Human HAS-2 (Accession No. NM — 005328.2) antisense primer: 5′-CAACGGGTCTGCTGGTTTAGC-3 ′ / SEQ ID NO: 8
Human GAPDH (Accession No. NM_002046.3) sense primer: 5'-CATCCCTGCCTCTACTGGCG-3 '/ SEQ ID NO: 9
Human GAPDH (Accession No. NM_002046.3) antisense primer: 5'-AGCTTCCCGTTCAGCTCAGG-3 '/ SEQ ID NO: 10
As a result, in human epidermal keratinocytes, taurine increased hyaluronic acid production (FIG. 5) and simultaneously increased hyaluronic acid synthase (HAS-2) gene expression (FIG. 6).

[Example 3] Effect of taurine on hyaluronan production by human synovial cells Human articular synovial cells (Dainippon Pharmaceutical Co., Ltd.) in a 100mm dish (AGC Techno Glass) containing 10% calf serum (SAFC bioscience) The cells were cultured in Dulbecco's modified Eagle's medium (DMEM). When the cell occupancy per dish reaches 90% or higher, the cells are detached using a phosphate buffer containing 0.25% trypsin and 0.02% EDTA and placed in a 48-well multiplate or 60 mm dish (AGC Techno Glass). Each cell was seeded at a cell number of 1 × 10 ⁴ cells / dish or 3 × 10 ⁴ cells / dish. When the cell occupancy per well or dish reached 90% or more, taurine dissolved in sterilized distilled water was added to the culture solution to a final concentration of 6.25-50 mM, and cultured for 24 hours.

  Extraction of total RNA from the cells was performed by adding isogen (Nippon Gene) to the cells and lysing the cells. Chloroform was added to the cell lysate and mixed, followed by centrifugation (10 minutes at 10,000 rpm), the aqueous layer was recovered, and the same dose of isopropanol was added and mixed. After centrifugation (10 minutes at 10,000 rpm), the supernatant was removed and the precipitated RNA was recovered. After 75% ethanol was added to RNA and mixed, the supernatant was removed and the RNA was air-dried. The extracted total RNA was dissolved in sterile distilled water containing no nucleolytic enzyme, and the amount of RNA was quantified by measuring the absorbance at 260 nm.

  The hyaluronic acid secreted into the culture broth was quantified with a hyaluronic acid ELISA kit (Biochemical Biobusiness). In other words, hyaluronic acid in the culture solution was bound to hyaluronic acid binding protein (HABP) immobilized on the microplate of the kit, then peroxidase-bound HABP was added and reacted, followed by tetramethylbenzidine and hydrogen peroxide And the absorbance at 450 nm was measured with a microplate reader. The amount of hyaluronic acid was calculated from a calibration curve created simultaneously using a standard hyaluronic acid solution.

The gene expression of hyaluronic acid synthase (HAS-2) in the cells was measured by real-time PCR (RT-PCR). In the reverse transcription reaction, using the ^{QuantiTect R Reverse Transcription Kit (QIAGEN)} , according to the procedure of attachment, it was synthesized single-stranded cDNA. Real-time polymerase chain reaction (PCR) uses single-stranded cDNA as a template and primers specific for human hyaluronan synthase 2 (HAS-2) and human glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Implemented. After the reaction was completed, the expression level of each gene was normalized using GAPDH as an internal standard gene. Thereafter, the relative gene expression level of the taurine-treated group relative to the untreated group was calculated. The primers used for PCR are as follows:
Human HAS-2 (Accession No. NM — 005328.2) sense primer: 5′-GACAGGCATCTCACGAACCG-3 ′ / SEQ ID NO: 11
Human HAS-2 (Accession No. NM — 005328.2) antisense primer: 5′-CAACGGGTCTGCTGGTTTAGC-3 ′ / SEQ ID NO: 12
Human GAPDH (Accession No. NM_002046.3) sense primer: 5'-CATCCCTGCCTCTACTGGCG-3 '/ SEQ ID NO: 13
Human GAPDH (Accession No. NM_002046.3) antisense primer: 5'-AGCTTCCCGTTCAGCTCAGG-3 '/ SEQ ID NO: 14
As a result, in human synovial cells, taurine increased hyaluronic acid production (FIG. 7) and simultaneously increased hyaluronic acid synthase (HAS-2) gene expression (FIG. 8).

[Example 4] Effect of taurine administration on mouse skin hyaluronic acid content
After acclimatization of 5 week old HR-1 mice (Japan SLC), drinking water in which 3% of taurine was dissolved was given from 8 to 24 weeks of age. The control group received only purified water. After the administration, the back skin of the mouse was removed and a tissue section was prepared. Next, after reacting the tissue section with biotin-labeled hyaluronic acid binding protein (HABP) (2 ng / ml phosphate buffer) (Biochemical Biobusiness), streptavidin-FITC (1000-fold diluted with phosphate buffer) Fluorescein isothiocyanate) (Sigma Aldrich) was added, and HABP bound to hyaluronic acid was fluorescently stained. The tissue sections were divided into 5 to 8 measurement fields, and the fluorescence intensity per unit area (μm ² ) of the epidermis and dermis in each field was measured by Lumina Vision (Mitani Corporation). The ratio of the fluorescence intensity of the epidermis to the fluorescence intensity of the dermis was calculated as the amount of hyaluronic acid in the epidermis, and compared between the taurine administration group and the non-administration group.

  As a result, a significant increase in hyaluronic acid was observed in the epidermis of mice administered with taurine compared to the epidermis of control mice not administered with taurine (FIG. 9).

  Since the composition containing taurine of the present invention as an active ingredient has an action of promoting hyaluronic acid production in dermal fibroblasts and synovial synovial cells, in particular, symptoms and diseases caused by a decrease in hyaluronic acid production ( For example, it is useful as a pharmaceutical or cosmetic applied to wrinkles, rough skin, joint disorders, and articular cartilage damage. Therefore, the present invention can greatly contribute to fields such as medicine and beauty. The composition of the present invention is also useful as a reagent for research and development purposes such as elucidating the mechanism of action of taurine in maintaining and regulating skin barrier function and joint function.

SEQ ID NOs: 1-14 <223> Artificially synthesized primer sequences

Claims (5)

An oral composition for promoting the production of hyaluronic acid, which is applied to humans whose taurine is an active ingredient and whose gene expression of hyaluronic acid synthase (HAS-2) is reduced Oral for promoting hyaluronic acid synthase (HAS-2) gene expression, applied to humans with taurine as an active ingredient and reduced hyaluronic acid synthase (HAS-2) gene expression Composition Taurine is an active ingredient and is applied to humans whose hyaluronan synthase (HAS-2) gene expression is reduced by male hormones. Hyaluronic acid synthase (HAS-2) genes reduced by male hormones Oral composition for restoring expression The oral composition according to any one of claims 1 to 3 , which is a pharmaceutical composition. An indication that it is used to produce hyaluronic acid, an indication that it is used to promote gene expression of hyaluronic acid synthase (HAS-2), or that of hyaluronic acid synthase (HAS-2) that has been reduced by male hormones The oral composition according to any one of claims 1 to 4 , which is labeled to be used to restore gene expression.