CN116077359A - Use of tretinoin receptor agonist compounds in cosmetic compositions - Google Patents
Use of tretinoin receptor agonist compounds in cosmetic compositions Download PDFInfo
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- CN116077359A CN116077359A CN202211025067.1A CN202211025067A CN116077359A CN 116077359 A CN116077359 A CN 116077359A CN 202211025067 A CN202211025067 A CN 202211025067A CN 116077359 A CN116077359 A CN 116077359A
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- CN
- China
- Prior art keywords
- tretinoin
- tectorigenin
- skin
- aging
- cosmetic composition
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Images
Classifications
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- 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
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/18—Antioxidants, e.g. antiradicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Dermatology (AREA)
- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Birds (AREA)
- Gerontology & Geriatric Medicine (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Cosmetics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses application of a vitamin A acid receptor agonist compound in a cosmetic composition, and belongs to the technical field of biology. The application of the vitamin A acid receptor agonist compound with the structure shown in the formula (I), or the isotopic derivative, or the isomer, or the solvate, or the metabolite, or the drug carrier thereof in the cosmetic composition,
the vitamin A acid receptor agonist compound provided by the invention can be used as a functional raw material in a cosmetic composition for treating skin aging caused by photoaging and natural aging.
Description
The application is a divisional application, the application number of the application is 202110103230.0, the application date of the application is 2021-1-26, and the application name of the application is retinoic acid receptor agonist compound in a cosmetic composition.
Technical Field
The invention belongs to the technical field of biology, and particularly relates to application of a vitamin A acid receptor agonist compound in a cosmetic composition.
Background
With the improvement of living standard, people have increasingly strong demands on health and anti-aging of skin. The main causes of skin aging can be categorized into photoaging and natural aging. Among them, the photo aging is formed for a number of reasons, and the main reasons are related to the environment, especially, when the photo aging is repeatedly exposed to sunlight for a long time, the ultraviolet rays activate the tyrosinase activity in cells to secrete a large amount of melanin, so that skin pigmentation is serious. Natural aging, namely physiological aging, is particularly characterized in that free radicals and active oxygen in the body are increased, cells abnormally disappear, collagen substances are lost and degraded, the expression level of inflammatory factors is increased, and finally skin is in a state of loose skin, wrinkles and skin losing elasticity.
The tretinoin (also known as retinoic acid) receptor belongs to a sub-receptor in the nuclear receptor family, and the discovery of tretinoin receptor in 1987 explains the significance of the biological efficacy of tretinoin at the molecular level. According to the prior studies, tretinoin has been demonstrated to have metabolic effects that can affect bone growth and promote epithelial cell proliferation, differentiation, keratolysis, etc., and has been used as a drug for the treatment of numerous skin diseases such as acne, psoriasis, ichthyosis, etc. However, tretinoin has strong biological efficacy but also has strong irritation, and serious side effects are caused when it is used in daily cosmetics.
Disclosure of Invention
The present invention provides the use of a tretinoin receptor agonist compound in a cosmetic composition, said tretinoin receptor agonist compound having a biological efficacy not less than tretinoin and being far Jiang Yuwei A acid safe.
The invention provides an application of a vitamin A acid receptor agonist compound in a cosmetic composition, wherein the vitamin A acid receptor agonist compound has a structure shown in a formula (I), or an isotope derivative, an isomer, a solvate, a metabolite or a drug carrier thereof,
further, the cosmetic composition is in the form of at least one of a cream, an emulsion, a solution, a suspension, a gel, a stick, a lotion, or a powder.
Further, the emulsion is an oil-in-water emulsion, a water-in-oil emulsion, or a multiple emulsion.
Further, the gel is an aqueous gel, a hydroalcoholic gel, an alcoholic gel or an oleyl alcohol gel.
Further, the cosmetic composition further comprises an excipient which is a solvent, a thickener, a diluent, a surfactant, an antioxidant, a dye, a preservative, or a perfume.
Further, the cosmetic composition is used for treating skin aging caused by photoaging, natural aging.
Further, the natural aging includes oxidative aging of the skin and inflammatory aging of the skin.
Further, the photoaging is caused by exposure of the skin to ultraviolet light.
The invention has the following beneficial effects:
the vitamin A acid receptor agonist compound or the pharmaceutically acceptable salt thereof can be used as a functional raw material in a cosmetic composition for treating skin aging caused by photoaging and natural aging, has an anti-aging effect which is not weaker than that of vitamin A acid, and is far in safety Jiang Yuwei A acid.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions of the prior art, the drawings which are used in the description of the embodiments or the prior art will be briefly described, it being obvious that the drawings in the description below are only some embodiments of the invention, and that other drawings can be obtained according to these drawings without inventive faculty for a person skilled in the art.
FIG. 1 is a graph showing the effect of detecting the toxicity of tretinoin and tectorigenin in example 1 of the present invention;
FIG. 1-1 is a graph showing the toxicity test effect of tretinoin; FIGS. 1-2 are graphs showing the toxicity detection effects of tectorigenin;
FIG. 2 shows the effect of tretinoin, tectorigenin on tretinoin receptor promoter activity in example 2 of the present invention;
FIG. 3 shows the protective effect of tectorigenin and tretinoin on UV-induced cell damage in example 3 of the present invention * P<0.05， ** P<0.01vs model)；
FIG. 4 shows the effect of tectorigenin and tretinoin on MDA content in example 4 of the present invention * P<0.05， ** P<0.01vs model)；
FIG. 5 shows the effect of tectorigenin and tretinoin on SOD activity in example 5 of the present invention * P<0.05， ** P<0.01vs model)；
FIG. 6 shows the effect of tectorigenin and tretinoin on the active oxygen content of cells in example 6 of the present invention * P<0.05， ** P<0.01vs model)；
FIG. 7 shows the effect of tectorigenin and tretinoin on inflammatory factor expression in example 7 of the present invention * P<0.05， ** P<0.01vs model)；
FIG. 8 shows the effect of tectorigenin and tretinoin on MMPs mRNA expression in example 8 of the present invention * P<0.05， ** P<0.01vs model)；
FIG. 9 is a graph of the results of tectorigenin volunteer test of example 10 of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and fully with reference to the accompanying drawings, in which it is evident that the embodiments described are only some, but not all embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The starting materials, reagents or apparatus used in the following examples are all available from conventional commercial sources or may be obtained by methods known in the art unless otherwise specified. The method is a conventional method unless otherwise specified.
An embodiment of the present invention provides the use of a retinoid receptor (RAR) agonist compound having a structure represented by formula (I), or a pharmaceutically acceptable salt thereof, in a cosmetic composition,
wherein R is 1 ，R 2 ，R 3 Independently selected from hydrogen and unsubstituted C 1 -C 10 An alkyl group, a hydroxyl group,
hydroxy, glycoside.
In one embodiment of the invention, R 1 ，R 2 ，R 3 Independently selected from hydrogen.
Specifically, when R1, R2, R3 are each independently selected from hydrogen, they have a structure represented by formula (I-1):
Specifically, a retinoid receptor (RAR) agonist compound having a structure represented by formula (i), or an isotopic derivative thereof, or an isomer thereof, or a solvate thereof, or a metabolite thereof, or a pharmaceutical carrier thereof, etc., can also be used in a cosmetic composition.
In one embodiment of the present invention, the compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof is present in the cosmetic composition at a concentration of 0.1% to 10% by mass. Specifically, the content may be 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, etc.
In a preferred embodiment of the present invention, the compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof is present in the cosmetic composition at a concentration of 0.1% to 5% by mass volume (g/100 mL).
In one embodiment of the present invention, the cosmetic composition may be in the form of at least one of a cream, an emulsion, a solution, a suspension, a gel, a stick, a lotion, or a powder.
In one embodiment of the invention, the emulsion comprises an oil-in-water emulsion, a water-in-oil emulsion, or a multiple emulsion; the gel comprises an aqueous gel, a hydroalcoholic gel, an alcoholic gel or an oleyl alcohol gel.
In particular, the cosmetic composition comprises a cosmetically acceptable medium, i.e. a medium compatible with the skin and the keratinized skin appendages.
The cosmetic composition further comprises excipients necessary for its formulation, such as solvents, thickeners, diluents, surfactants, antioxidants, dyes, preservatives, fragrances and the like.
The cosmetic composition can be used as skin care or skin cosmetic, applied to skin and lips and/or keratinized skin appendages, etc.
In one embodiment of the invention, the cosmetic composition is used for treating skin aging caused by photoaging and natural aging. The skin aging caused by light aging or natural aging can be single skin aging or aging caused by the two effects.
In particular, the photoaging pathway is caused by exposure to ultraviolet light.
Specifically, the natural aging includes oxidative aging, inflammatory aging. The oxidative aging is mainly caused by abnormal levels of free radicals and active oxygen in the body; the inflammatory aging is mainly caused by the over-expression of inflammatory factors such as IL1, IL6, TNF-alpha and the like.
Specifically, the manifestations of aging include reduced skin elasticity, reduced collagen content, increased occurrence of acne spots, and the like.
The invention will be described in detail with reference to examples.
Example 1Detection of cytotoxicity by tretinoin and tectorigenin
Toxicity of VA acid (control compound) and tectorigenin to mouse fibroblast NIH-3T3 was separately tested using MTT method.
First, mouse fibroblast cells NIH-3T3 were seeded into 96-well plates at 5000 cells/well density at 37℃in 5% CO 2 After 24h culture in an incubator, 1-7 groups of mouse fibroblast samples are added with tretinoin with the same volume and the concentrations of 1 mu M, 2 mu M, 4 mu M, 8 mu M, 16 mu M, 32 mu M and 64 mu M respectively, 8-13 groups of mouse fibroblast samples are added with tectorigenin with the same volume and the concentrations of 10 mu M, 20 mu M, 40 mu M, 80 mu M, 160 mu M and 320 mu M respectively, and a group of mouse fibroblast sample control groups are arranged at the same time, and three-hole mouse fibroblast samples are arranged in each group. After further incubation for 24h, 25 μLMTT was added per well and incubation was continued for 4h. Formazan was dissolved in DMSO and the OD at 490nm was detected with an enzyme-labeled instrument.
The results are shown in FIG. 1, where tretinoin and tectorigenin were toxic to mouse fibroblasts, respectively.
As shown in FIG. 1-1, toxicity to mouse fibroblasts was gradually increased with increasing dose of tretinoin added, with an IC50 value of 9.7. Mu.M.
As shown in FIGS. 1-2, tectorigenin showed no cytotoxicity to NIH-3T3 cells in the concentration range of 0-320. Mu.M.
Example 2Detection of the influence of tretinoin, tectorigenin on tretinoin receptor Activity
The experimental method comprises the following steps:
a. plasmid amplification and plasmid big extraction
(1) Taking DH5 alpha competent cells out of a refrigerator at the temperature of minus 80 ℃, thawing the cells to a molten state on ice, and uniformly mixing the customized plasmids RAR-alpha, RAR-beta, RAR-gamma and PG5 in a test tube according to 1uL plasmid plus 20uL competent cells, wherein the RAR-alpha, the RAR-beta and the RAR-gamma are respectively provided with two groups which are named (1) - (6) in sequence;
(2) The mixture obtained by the step (1)Competent cellsAfter heat shock is carried out on the test tube in a water bath at 42 ℃ for 90 seconds, the test tube is rapidly transferred to an ice bath for 4 minutes, 200uL of LB culture medium without antibiotics is added into the test tube, and the test tube is evenly mixed and then is placed at 37 ℃ for culture at 220rpm for 1 hour;
(3) The transformed competent cells are coated on LB agarose medium containing 0.1% of ampicillin resistance, placed in a 37 ℃ incubator and cultured for 12-18 h in an inverted manner;
(4) Selecting single smooth microcolonies from the plates into LB liquid medium containing 0.1% of ampicillin resistance, uniformly mixing, and then placing at 37 ℃ for culturing at 220rpm for overnight to obtain bacterial liquid;
(5) And (3) carrying out plasmid large extraction on the bacterial liquid obtained in the step (4) according to the specification of an endotoxin-free plasmid large extraction kit, and then carrying out plasmid concentration detection by using an instrument (nanodorp) capable of rapidly quantifying DNA, RNA and protein.
b. Effect of samples on Retinoic Acid Receptor (RAR) Activity
293 cells are inoculated in a 96-well plate and cultured in an incubator with 5% CO2 at 37 ℃ until the cells adhere, each group of RAR-alpha, RAR-beta and RAR-gamma plasmids are respectively transfected with PG5 reporter plasmids according to a certain proportion, and after continuous culture for 24 hours, (1), (3) and (5) are respectively added with 1.5 mu M of tretinoin and then incubated for 2 hours, and (2), (4) and (6) are respectively added with 1.5 mu M of tectorigenin and then incubated for 2 hours. After 4h of action, the cells were digested and the transcriptional activity of the different transcription factors described above was determined using a luciferase assay kit, the results are shown in FIG. 2.
As can be seen from FIG. 2, while tectorigenin is inferior to tretinoin in activating RAR-alpha, RAR-beta, RAR-gamma is the most important target for improving skin problems, and tectorigenin is significantly more potent than tretinoin in activating RAR-gamma activity, about 3 times more potent than tretinoin. Thus, tectorigenin has a better skin improvement therapeutic effect than tretinoin.
Example 3MTT method for detecting effect of tretinoin and tectorigenin on cell ultraviolet induction injury resistance
Inoculating human immortalized keratinocyte HaCaT into 96-well plate, adjusting cell density to 1000-10000 holes, and adjusting temperature to 37deg.C and CO content to 5% 2 Is cultured overnight in an incubator. A control group, a UV-B model group and a dosing group were set, the dosing group was set with groups I-IV to which 0.375. Mu.M tretinoin, 0.18. Mu.M tretinoin, 1.5. Mu.M tectorigenin and 0.75. Mu.M tectorigenin were added, respectively, prior to UV-B induction, and the dosing group was set with groups V-VIII to which 0.375. Mu.M tretinoin, 0.18. Mu.M tretinoin, 1.5. Mu.M tectorigenin and 0.75. Mu.M tectorigenin were applied, respectively, after UV-B induction. HaCaT cells were subjected to 70mJ/c using ultraviolet light as the UV-B sourcem 2 Is used to induce cell damage. After replacing the fresh medium and continuing the culture for 14 hours, 25. Mu.L MTT was added to each well and incubation was continued for 4 hours. Formazan was then dissolved in DMSO and the OD at 490nm was detected with an enzyme-labeled instrument, as shown in fig. 3.
As can be taken from fig. 3, UV-B induction can significantly reduce the viability of cells. Compared with the UV-B model group, the administration group obviously improves the cell activity, the cell activity of the pre-protection I-IV group before the UV-B induction is higher than that of the administration V-VIII group after the induction, and the effect of tectorigenin on ultraviolet injury resistance is stronger than that of tretinoin. Experimental results show that tectorigenin can protect ultraviolet-induced cell injury whether in a pre-protection mode or in a mode of drug intervention after injury.
Example 4Influence of tectorigenin and tretinoin on MDA content of ultraviolet induced HaCaT cells
Malondialdehyde (MDA) is a natural product of oxidation of biological lipids. Lipid oxidation occurs when animal or plant cells are subjected to oxidative stress. Some fatty acids gradually decompose to a complex series of compounds, including MDA, after oxidation. The level of lipid oxidation can be detected by detecting the level of MDA at this time. MDA and thiobarbituric acid (TBA) react to generate a chromogenic reaction of a red product, and then MDA in cell lysate is quantitatively detected by a colorimetric method to judge the lipid oxidation level in cells.
Human immortalized keratinocytes HaCaT were seeded at 50% density in 12-well plates at 37℃in 5% CO 2 Is cultured overnight in an incubator. A control group, a UV-B model group, and an administration group were set, and 1.5 μm tectorigenin, 0.75 μm tectorigenin, 0.375 μm tretinoin, and 0.18 μm tretinoin-treated cells were added to each of the administration groups, respectively, for 6 hours. 70mJ/cm was performed on UV-B model and dosing groups using ultraviolet light as the UV-B source 2 Inducing oxidative stress in cells without affecting cell viability. After replacing the fresh culture medium and continuing to culture for 14 hours, intracellular Malondialdehyde (MDA) content was detected using a lipid oxidation detection kit, and absorbance values were measured at 532nm, the results are shown in FIG. 4.
As can be seen from fig. 4, UV-B was able to induce oxidative stress in HaCaT cells, significantly increasing intracellular Malondialdehyde (MDA) content. After the HaCaT cells are treated by tretinoin and tectorigenin respectively, the content of MDA produced by the UV-B induced HaCaT can be reduced. HaCaT cells with 1.5. Mu.M tectorigenin added showed a strong lipid oxidation resistance, and tectorigenin treated groups (groups a and b) had a higher lipid oxidation resistance than tretinoin treated groups (groups c and d). The results demonstrate that tectorigenin is effective in reducing UV-B induced oxidative stress and lipid peroxidation of HaCaT cells.
Example 5Influence of tectorigenin and tretinoin on ultraviolet induced HaCaT cell SOD activity
Superoxide dismutase (SOD) can catalyze superoxide anion to perform disproportionation to generate hydrogen peroxide (H) 2 O 2 ) And oxygen (O) 2 ) Is an important antioxidant enzyme in organisms. The oxidative stress induced by UV-B on HaCaT cells can inhibit the enzymatic activity of SOD.
Human immortalized keratinocytes HaCaT were seeded at 50% density in 12-well plates at 37℃in 5% CO 2 Is cultured overnight in an incubator. A control group, a UV-B model group and a dosing group were set, and i-iv groups were set with 0.375. Mu.M tretinoin, 0.18. Mu.M tretinoin, 1.5. Mu.M tectorigenin, and 0.75. Mu.M tectorigenin-treated cells, respectively, for 6h. 70mJ/cm was performed on UV-B model and dosing groups using ultraviolet light as the UV-B source 2 Inducing oxidative stress in cells without affecting cell viability. After replacing the fresh culture medium and continuing the culture for 14 hours, the total SOD detection kit was used to detect the intracellular superoxide dismutase content and the absorbance value was measured at 450 nm. And calculating the activity of SOD in the sample according to the formula I and the formula II, and the result is shown in figure 5.
Formula I: percent inhibition= (a Blank control 1 －A Sample of )/(A Blank control 1 －A Blank control 2 )×100％
Formula II: SOD enzyme activity unit = inhibition percentage/(1-inhibition percentage) units in test sample
As can be seen from FIG. 5, the SOD activity of the administration group was improved as compared with the model group, and the cells treated with 1.5. Mu.M tectorigenin showed an extremely strong protective effect on the SOD activity. The result proves that the tectorigenin can enhance the SOD enzyme activity and improve the damage of the cell SOD activity after the UV-B induction.
Example 6Influence of tectorigenin and tretinoin on intracellular active oxygen levels
Human immortalized keratinocytes HaCaT were seeded at 50% density in 12-well plates at 37℃in 5% CO 2 Is cultured overnight in an incubator. Control, positive control, UV-B model and dosing groups were set, with groups A and B being added with 0.375. Mu.M tretinoin, 1.5. Mu.M tectorigenin treated cells, respectively, for 6h. 70mJ/cm was performed on UV-B model and dosing groups using ultraviolet light as the UV-B source 2 Inducing oxidative stress in cells without affecting cell viability. After replacing the fresh medium and continuing to culture for 14 hours, intracellular ROS levels were detected using a reactive oxygen species detection kit. Fluorescence intensity was measured by flow cytometry at an excitation wavelength of 488nm and an emission wavelength of 525nm, the results of which are shown in FIG. 6.
As shown in FIG. 6, the ROS positive cell rate of the 1.5. Mu.M tectorigenin treatment group was much lower than that of the tretinoin treatment group, while ensuring drug safety. This result demonstrates that tectorigenin has a significant advantage in reducing cellular reactive oxygen species.
Example 7Influence of tectorigenin and tretinoin on inflammatory factor content
Human immortalized keratinocytes HaCaT were seeded at 50% density in 6-well plates at 37℃in 5% CO 2 Is cultured overnight in an incubator. Control, UV-B model and dosing groups were set, and C-F groups were set with 0.375. Mu.M tretinoin, 0.18. Mu.M tretinoin, 1.5. Mu.M tectorigenin, and 0.75. Mu.M tectorigenin-treated cells, respectively, for 6h. 70mJ/cm was performed on UV-B model and dosing groups using ultraviolet light as the UV-B source 2 Inducing oxidative stress in cells without affecting cell viability. After replacing fresh medium and continuing to culture for 14 hours, the concentration of TNF- α (EK 0525, boster), IL-1β (EK 0392, boster), IL-6 (EK 0410, boster) in the cells was measured using ELISA kit and absorbance was measured at 450nmThe results are shown in FIG. 7.
As can be seen from FIG. 7, the ultraviolet induced HaCaT cells promote the expression of inflammatory factors TNF- α, IL-1β, IL-6, as compared to the control group. The cells are treated by tectorigenin and tretinoin, and the expression of inflammatory factors is inhibited. Tectorigenin has higher inhibitory activity on the expression of UV-B induced inflammatory factor than tretinoin. The result proves that tectorigenin can effectively inhibit the production of inflammatory factors and play an anti-inflammatory role.
Inflammatory aging refers to a chronic pro-inflammatory state of the body that develops during aging and increases progressively as aging progresses. The results of the test of FIG. 7 demonstrate that tectorigenin has significant inhibitory effects on the expression of inflammatory factors such as TNF- α, IL-1 β, IL-6 and IL-8, and thus tectorigenin may exert anti-aging effects by inhibiting the inflammatory aging pathway.
Example 8Influence of tectorigenin on the expression of matrix metalloproteinases MMP1, MMP3 and MMP9mRNA
Matrix Metalloproteinases (MMPs) have the function of degrading various components of the extracellular matrix (ECM), and are classified into 6 classes, collagenase, gelatinase, matrix degrading agents, matrix lysin, furin-activated MMPs and other secreted MMPs, based on the substrate of action and fragment homology. Collagenase can specifically hydrolyze three-dimensional helical structures of natural collagen, and is closely related to aging and tumor invasion and metastasis. MMP-9 is a glycosylated type IV collagenase; MMP-3 can act on PG, LN, FN, III type and IV type collagen and gelatin; MMP-1 can be activated by MMP-3 and is highly expressed under various stimuli.
Human immortalized keratinocytes HaCaT were inoculated at 50% density into 10cm cell culture dishes at 37℃and 5% CO 2 Is cultured overnight in an incubator. The UV-B model and dosing groups were set, and groups G and F were treated with 0.375. Mu.M tretinoin, 1.5. Mu.M tectorigenin for 6h, respectively. 70mJ/cm was performed on UV-B model and dosing groups using ultraviolet light as the UV-B source 2 UV-B radiation of (c). The fresh culture medium was changed and the culture was continued for 14 hours. Extraction of total RNA from cells by Trizol method, synthesis of cD by reverse transcription of Quant cDNA first Strand Synthesis kit (KR 103)The first strand of NA, superReal PreMix Plus (SYBR Green) kit, performs quantitative polymerase chain reaction. Relative gene expression was calculated using the standard curve method with GAPDH as an internal reference. And obtaining the Ct value of each experimental group, and calculating to obtain the 2-delta Ct value. If the 2 a-a Ct value of the experimental group is reduced compared to the model group, it indicates that the detected gene expression is reduced. The primer sequences used were as follows:
the results are shown in FIG. 8. As can be seen from FIG. 8, both tretinoin and tectorigenin treatments reduced the expression of mRNA of matrix metalloproteinases MMP-1, MMP-3, MMP-9, and tectorigenin had a greater inhibitory effect. The tectorigenin can inhibit the degradation process of collagen by inhibiting the expression of matrix metalloproteinase, thereby playing an anti-aging role.
Example 9Multiple skin irritation evaluation of Rabbit
The test substance is 5% tretinoin and 5% tectorigenin. The sample is sample powder or prepared sample solution, and the sample gel with 5% concentration is prepared by compounding the sample and sodium carboxymethyl cellulose and then is directly smeared as the sample.
The experimental method comprises the following steps:
the hairs on both sides of the back spine of the rabbit are removed and divided into four areas 24 hours before the experiment, the skin is not damaged, 0.5mL of the test object and the blank control sample are respectively smeared on the left upper part (blank), the left lower part (5% tectorigenin), the right upper part (5% tretinoin) and the right lower part (blank), and smeared once a day for 14 continuous days.
Starting from the next day, shearing and cleaning before each application, observing and recording whether erythema, edema and the like appear at the application part after 1h, scoring according to a skin irritation response scoring table (table 1) in cosmetic safety technical Specification (2015 edition), calculating average integral of skin reactions of each animal after the experiment is finished, and grading skin irritation intensity according to a skin irritation intensity grading table (table 2). The results are shown in Table 3.
From Table 3, 5% tretinoin is slightly irritating to rabbit skin multiple times, and 5% tectorigenin is non-irritating to rabbit skin multiple times, indicating that 5% and below tectorigenin does not irritate skin.
Table 1 skin irritation response score
TABLE 2 skin irritation intensity grading
TABLE 3 tectorigenin, tretinoin scoring skin irritation
Example 10Human body test of tectorigenin emulsion
The volunteers over 28 years old were randomly recruited to total 33, wherein 18 females and 15 males were treated with 1% tectorigenin emulsion on the face after cleansing the face in the morning and evening, and the use was continued for 30 days. And detecting the skin state by using the VISIA at regular intervals, cleaning the face with clean water before detection, airing for about 20 minutes, and starting detection after the skin is aired. The room where the instrument is located is not ventilated, no direct sunlight exists, the room temperature is 24-26 ℃, and the humidity is about 40%. Finally, scoring the statistical analysis of the data obtained, wherein score 3: the method is remarkably improved; 2, the method comprises the following steps: general improvement; 1, the method comprises the following steps: the improvement is not obvious; 0 point: no improvement was observed and the results are shown in FIG. 9.
As can be seen from fig. 9, the number of volunteers whose skin was improved was 32, the improvement rate was 96.96%, and the number of volunteers whose skin was significantly improved was 15, and the significantly improvement rate was 45.45%.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (8)
1. The application of the vitamin A acid receptor agonist compound with the structure shown in the formula (I-1), or the isotopic derivative, or the isomer, or the solvate, or the metabolite, or the drug carrier thereof in the cosmetic composition,
2. the use according to claim 1, wherein,
the cosmetic composition is in the form of at least one of a cream, emulsion, solution, suspension, gel, stick, lotion or powder.
3. The use according to claim 2, wherein,
the emulsion is an oil-in-water emulsion, a water-in-oil emulsion or a multiple emulsion.
4. The use according to claim 2, wherein,
the gel is water-containing gel, hydroalcoholic gel, alcoholic gel or oleyl alcohol gel.
5. The use according to claim 1, wherein,
the cosmetic composition further comprises an excipient which is a solvent, a thickener, a diluent, a surfactant, an antioxidant, a dye, a preservative, and a perfume.
6. The use according to claim 1, wherein,
the cosmetic composition is used for treating skin aging caused by photoaging and natural aging.
7. The use according to claim 1, wherein,
the natural aging includes oxidative aging of the skin and inflammatory aging of the skin.
8. The use according to claim 1, wherein,
the photoaging is caused by exposure of the skin to ultraviolet light.
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| CN112791003B (en) | 2022-11-04 |
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