WO2024140865A1 - UTILISATION D'ACIDE γ-AMINOBUTYRIQUE DANS LA PRÉVENTION ET/OU L'AMÉLIORATION DE LÉSIONS CELLULAIRES PROVOQUÉES PAR UN IRRITANT, ET PROCÉDÉ - Google Patents
UTILISATION D'ACIDE γ-AMINOBUTYRIQUE DANS LA PRÉVENTION ET/OU L'AMÉLIORATION DE LÉSIONS CELLULAIRES PROVOQUÉES PAR UN IRRITANT, ET PROCÉDÉ Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
Definitions
- irritants from different sources can cause different cell damages in the human body.
- heat stimulation, tobacco, alcohol, and other substances and their metabolites, lipopolysaccharides produced by pathogenic bacteria, etc. can all cause damage to cells.
- acetaldehyde-induced damage mainly involves two aspects: oxidative damage and carcinogenicity.
- Acetaldehyde has obvious cytotoxicity.
- Acetaldehyde can induce the body to produce a large number of free radicals, causing oxidative damage to macromolecules such as proteins, lipids, and DNA in cells.
- acetaldehyde can also covalently bind to DNA to form adducts, causing cross-linking and breakage of DNA double strands, leading to irreversible cell carcinogenesis.
- Porphyromonas gingivalis LPS and Escherichia coli LPS are different in structure and various biological functions (Bainbridge et al., 2002; Zhang et al., 2008); for another example, Porphyromonas gingivalis LPS can induce LBP expression through both TLR2 and TLR4, while Escherichia coli LPS can only induce LBP expression through TLR4 (Ding et al., 2012); the existence of these differences makes the inflammatory response of the two LPS to human dental pulp cells also very different (Mojtahedi et al., 2022), and ultimately leads to the difference in the host response they induce.
- ⁇ -aminobutyric acid in preventing and/or improving cell damage caused by stimuli, wherein the cell damage caused by the stimuli includes decreased expression of TJ-related proteins in cells caused by heat stimulation, One or more of increased cell permeability due to irritation, gum damage due to cigarette smoke, oral inflammation, or cell damage due to acetaldehyde.
- the TJ-related proteins include one or more of ZO-1 protein, occludin protein, claudin-1 protein, claudin-2 protein, and claudin-4 protein.
- thermo stimulation comprises a thermal stimulation at a temperature of 40° C. or above.
- cell damage caused by acetaldehyde comprises oxidative damage caused by acetaldehyde or cancer caused by acetaldehyde.
- FIG6 is a fluorescent photograph of type I collagen in different groups in Example 2.3;
- FIG7 shows the concentration of inflammatory factor IL-6 in each group in Example 3.
- FIG8 shows the concentration of inflammatory factor IL-6 in each group in Comparative Example 1;
- FIG9 shows the relative fluorescence intensity of FD4 in the bottom chamber culture medium after treatment with different groups in Comparative Example 2.1;
- Figure 10 is the relative fluorescence intensity of ZO-1 protein after treatment in different groups using semi-quantitative analysis of Image J software in Comparative Example 2.2.
- the present application provides a new application of ⁇ -aminobutyric acid and a method for realizing the application.
- the present application provides the use of ⁇ -aminobutyric acid in preventing and/or improving cell damage caused by stimulants, wherein the cell damage caused by the stimulants includes one or more of reduced expression of TJ-related proteins in cells caused by thermal stimulation, enhanced cell permeability caused by thermal stimulation, gingival damage caused by cigarette smoke, oral inflammation, or cell damage caused by acetaldehyde.
- GABA ⁇ -aminobutyric acid
- the present application provides the use of ⁇ -aminobutyric acid in preventing and/or improving the reduced expression of TJ-related proteins in cells caused by heat stimulation, and/or the enhanced cell permeability caused by heat stimulation.
- expression refers to the process by which cells store DNA sequences in their life processes. Genetic information is converted into a biologically active protein molecule through transcription and translation.
- the expression conforms to the general definition in this field, specifically refers to the expression of TJ-related proteins, and reduced expression refers to a decrease or reduction in the amount of TJ-related proteins expressed or no expression of TJ-related proteins, that is, the expression of TJ-related proteins lower than the normal expression of TJ-related proteins in the animal body can be referred to as reduced expression of TJ-related proteins.
- the present application provides the use of ⁇ -aminobutyric acid in the preparation of personal care products for preventing and/or improving the reduced expression of TJ-related proteins in cells caused by thermal stimulation, and/or the enhanced cell permeability caused by thermal stimulation.
- the personal care products can be oral preparations or external preparations.
- the present application does not limit the specific preparation type, and those skilled in the art can choose from the existing technology according to the needs of use.
- the oral preparation can be a powder, granules, capsules, liquid preparations, suspensions, etc.
- the external preparation can be a patch, spray, cream, liquid smear preparation, etc.
- the amount of ⁇ -aminobutyric acid in the personal care product for preventing and/or reducing oral inflammation is not limited, as long as it can prevent and/or reduce oral inflammation.
- the amount of ⁇ -aminobutyric acid in the personal care product is 0.001wt% to 0.1wt%, for example, 0.002wt%, 0.003wt%, 0.004wt%, 0.005wt%, 0.006wt%, 0.007wt%, 0.008wt%, 0.009wt%, 0.01wt%, 0.015wt%, 0.02wt%, 0.025wt%, 0.03wt%, 0.035wt%, 0.04wt%, 0.045wt%, 0.046wt%, 0.047wt%, 0.048wt%, 0.049wt%, 0.05wt%, 0.06wt%, 0.07wt%, 0.08wt%, 0.09wt%, 0.1w
- the concentration of the ⁇ -aminobutyric acid in the product for preventing or inhibiting cell damage caused by acetaldehyde is 0.0001%-5%, preferably 0.01%-5%.
- the ⁇ -aminobutyric acid can be used in the above-mentioned product together with any one, any two, any three, or any four of the antibacterial agent, anti-caries agent, anti-sensitivity agent, anti-calculus agent, anti-inflammatory agent, whitening agent, moisturizing agent, or all of the above-mentioned ingredients.
- the whitening agent which can be a commonly used whitening agent in the art, for example, the whitening agent can be peroxide bleach, papain, glucose Oxidase, etc.
- the thermal stimulation described above can be any kind of thermal stimulation, as long as it can cause changes in the expression of TJ-related proteins or cause enhanced cell permeability.
- the thermal stimulation includes thermal stimulation at a temperature above 40°C, for example, it can be above 41°C, above 42°C, above 45°C, above 50°C, above 55°C, above 60°C, above 70°C, above 80°C, above 90°C, above 100°C, or above 110°C, preferably a thermal stimulation of 40-100°C.
- the present application provides the non-therapeutic use of ⁇ -aminobutyric acid for preventing and/or improving gingival damage caused by cigarette smoke.
- the present application provides a non-therapeutic method for preventing and/or improving gum damage caused by cigarette smoke, the method comprising administering ⁇ -aminobutyric acid in the oral cavity.
- the administration method may be any administration method in the art, including but not limited to applying, buccal administration, atomizing, oral administration, injection, and the like.
- the present application does not limit the dosage of ⁇ -aminobutyric acid in the cavity, and those skilled in the art can select it according to the conventional dosage of ⁇ -aminobutyric acid.
- it can be 0.01% to 10% by weight.
- the concentration of the ⁇ -aminobutyric acid is 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, etc.
- the gingival damage described in the present application includes, but is not limited to, one or more of fibroblast damage, lymphocyte damage, plasma cell damage, macrophage damage, etc. in the gingiva.
- the gingival damage includes gingival fibroblast damage.
- the present application provides a use of ⁇ -aminobutyric acid in preparing a product for preventing or inhibiting gum damage caused by smoking.
- ⁇ -aminobutyric acid is used as the sole active ingredient in the preparation of a product/personal care product for preventing or improving cell damage caused by smoking/cigarette smoke.
- ⁇ -aminobutyric acid is used as the sole active ingredient for preventing and/or improving gum damage caused by cigarette smoke.
- ⁇ -aminobutyric acid is used as the sole active ingredient for the non-therapeutic purpose of preventing and/or improving gingival damage caused by cigarette smoke.
- the present application uses ⁇ -aminobutyric acid in the preparation of personal care products for preventing and/or improving gum damage caused by cigarette smoke or in non-therapeutic uses for preventing and/or improving gum damage caused by cigarette smoke, which can significantly inhibit the increase in the content of reactive oxygen species after oxidative stimulation of gingival fibroblasts by cigarette smoke extracts.
- ⁇ -aminobutyric acid can inhibit gingival oxidative damage caused by cigarette smoke extracts.
- it can also inhibit the increase in the content of tumor necrosis factor after stimulation by cigarette smoke extracts.
- ⁇ -aminobutyric acid can inhibit the increase in the content of gingival inflammatory factors caused by cigarette smoke extracts and relieve gingival inflammatory stimulation.
- the new use of GABA provided in the present application and the method for realizing the use can improve oral health, relieve oral discomfort caused by smoking, etc., and prevent the formation of oral diseases, such as oral tumors, and protect the oral cavity, and has broad application prospects.
- the present application also provides use of ⁇ -aminobutyric acid for preventing and/or alleviating oral inflammation.
- the present application provides the use of ⁇ -aminobutyric acid for the non-therapeutic purpose of preventing and/or alleviating oral inflammation.
- the present application provides a method for preventing and/or alleviating oral inflammation for non-therapeutic purposes, the method comprising administering ⁇ -aminobutyric acid in the oral cavity.
- the administration method may be any administration method in the art, including but not limited to applying, buccal administration, atomization, oral administration, injection, and the like.
- the oral inflammation is oral inflammation caused by Porphyromonas gingivalis lipopolysaccharide.
- the oral inflammation is gingivitis caused by Porphyromonas gingivalis lipopolysaccharide.
- the new use of GABA and the method for achieving the use provided in the present application can improve oral health, relieve oral inflammation, especially oral inflammation caused by Porphyromonas gingivalis lipopolysaccharide, protect the oral cavity, and have broad application prospects.
- the present application further provides a method for inhibiting cell damage caused by acetaldehyde for non-therapeutic purposes, comprising applying a product containing ⁇ -aminobutyric acid or the above-mentioned product to the site of the damage, which can reduce the cell damage caused by acetaldehyde.
- the product containing GABA or the above-mentioned product is applied or sprayed to the site of cell damage in the subject, for example, applied or sprayed to the oral cavity of the subject.
- Acetaldehyde-induced cell damage mainly involves two aspects: oxidative damage and carcinogenesis. There is currently no effective treatment for oxidative damage and carcinogenesis. The inventors of the present application creatively discovered that ⁇ -aminobutyric acid can slow down the damage caused by acetaldehyde, which provides a new basis for treating oxidative damage and carcinogenesis caused by acetaldehyde.
- the present application also provides a method for preventing and/or improving cell damage caused by the stimulants as described above, the method comprising applying ⁇ -aminobutyric acid to the stimulated site, wherein the cell damage caused by the stimulant comprises one or more of reduced expression of TJ-related proteins in cells caused by thermal stimulation, increased cell permeability caused by thermal stimulation, gingival damage caused by cigarette smoke, oral inflammation, or cell damage caused by acetaldehyde.
- % means wt%, i.e., weight percentage.
- the reagents or instruments used without indicating the manufacturer are all conventional reagent products that can be obtained commercially.
- Test method Ca9-22 cells (human oral epithelial cancer cells) were inoculated into the upper chamber of Transwell at a density of 30,000 cells/well and cultured at 37°C and 5% CO2 for later use. After 24 hours of cell attachment, 100 ⁇ g/mL of GABA was added to the experimental group, 100 ⁇ L/well, and a control group and a blank group were set up at the same time. After incubation for 72 hours, the 24-well plate was placed in a 41.5°C incubator for 3 hours. 100 ⁇ L of 1 mg/ml fluorescein isothiocyanate-dextran (FD4) was added to the culture medium in the upper chamber of Transwell.
- FD4 fluorescein isothiocyanate-dextran
- GABA ⁇ -Aminobutyric acid
- Ca9-22 cell complete culture medium containing 10% FBS and 1% penicillin-streptomycin
- Control group No GABA was added, and the cells were incubated at 41.5°C.
- GABA ⁇ -aminobutyric acid
- HGF-1 cell complete culture medium containing 10% FBS, 1% penicillin-streptomycin
- Test method Prepare a DCFH-DA (2',7'-dichlorodihydrofluorescein diacetate) solution with a final concentration of 10 ⁇ M using phenol red-free culture medium.
- HGF-1 cells were seeded into 96-well plates at a density of 30,000 cells/well and cultured at 37°C and 5% CO2 for later use. After 24 hours of cell attachment, a blank group, a control group, and experimental groups containing 1, 10, and 100 ⁇ g/mL GABA were set up, 100 ⁇ L/well. After 24 hours of incubation, 200 ⁇ L of 5% CSE solution was added to each well (only culture medium was added to the blank group and control group). After 3 hours of incubation, the supernatant was aspirated, washed with DPBS solution, 200 ⁇ L of 10 ⁇ M DCFH-DA working solution was added, incubated for 30 minutes, and washed with DPBS solution. The fluorescence intensity was measured at an excitation wavelength of 485 nm and an emission wavelength of 538 nm. Among them,
- Control group no GABA was added, but CSE was used for treatment.
- Graphpad Prism statistical software was used for analysis and processing. Pairwise comparison was performed using t-test, *P ⁇ 0.05 indicated statistical difference, **P ⁇ 0.01 indicated significant statistical difference, and ***P ⁇ 0.001 indicated extremely significant statistical difference.
- HGF-1 cells were cultured in a T75 culture flask using DMEM medium until the cell density reached about 80%, inoculated in a 24-well plate with a coverslip, and cultured at 37°C, 5% CO 2. After 24 hours, the supernatant was aspirated, and the experimental group was incubated with 100 ⁇ g/mL GABA and 5% CSE, and a control group and a blank group were set up at the same time. Incubated in a 37°C, 5% CO 2 incubator for 72 hours. The supernatant was aspirated, the cells were washed twice, and then fixed with ice methanol at -20°C, and then type I collagen primary antibody was added and incubated overnight at 4°C.
- Experimental group 100 ⁇ g/mL GABA was added and CSE treatment was performed.
- Example 3.1 According to the method of Example 3.1, an experimental sample solution containing a final concentration of 0.01 wt% GABA+1 ⁇ g/ml Pg.LPS was prepared, and the concentration of the inflammatory factor IL-6 was calculated. Other experimental processes not mentioned were the same as those in Example 3.1.
- Example 3.1 According to the method of Example 3.1, an experimental sample solution containing a final concentration of 1 ⁇ g/ml Pg.LPS was prepared, and the concentration of the inflammatory factor IL-6 was calculated. Other experimental processes not mentioned were the same as those in Example 3.1.
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- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
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Abstract
L'invention concerne une utilisation d'acide γ-aminobutyrique dans la prévention et/ou l'amélioration de lésions cellulaires provoquées par un irritant, les lésions cellulaires provoquées par un irritant comprenant une ou plusieurs parmi une expression de protéine associées à TJ réduite dans des cellules provoquées par une irritation thermique, une augmentation de la perméabilité cellulaire provoquée par une irritation thermique, un endommagement de gencive provoqué par la fumée de cigarette, une inflammation buccale ou un dommage cellulaire provoqué par l'acétaldéhyde.
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211694759.5 | 2022-12-28 | ||
CN202211694759.5A CN116459243A (zh) | 2022-12-28 | 2022-12-28 | γ-氨基丁酸在制备预防或抑制由乙醛引起的细胞损伤产品中的应用 |
CN202310735834.6A CN116617199A (zh) | 2023-06-20 | 2023-06-20 | γ-氨基丁酸在预防和/或改善由热刺激导致的相关细胞改变的用途及实现该用途的方法 |
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