CN116077501A - Application of quinazoline derivative in preparation of anti-aging products - Google Patents
Application of quinazoline derivative in preparation of anti-aging products Download PDFInfo
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- CN116077501A CN116077501A CN202310073432.4A CN202310073432A CN116077501A CN 116077501 A CN116077501 A CN 116077501A CN 202310073432 A CN202310073432 A CN 202310073432A CN 116077501 A CN116077501 A CN 116077501A
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- aging
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- pharmaceutically acceptable
- terazosin
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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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/38—Other non-alcoholic beverages
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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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
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
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- 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
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- 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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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The invention belongs to the technical field of medicines, functional foods and cosmetics, and particularly relates to application of quinazoline derivatives in preparation of products for resisting aging, especially reducing or preventing skin aging, cell aging or photoaging in mammals, wherein the quinazoline derivatives comprise a 4-amino-6, 7-dimethyl quinazoline ring structure. Preferably, the quinazoline derivative is selected from prazosin, terazosin, doxazosin or alfuzosin or pharmaceutically acceptable salts thereof. The product of the invention can be a medicine, a functional food, a beverage, a nutritional supplement or a cosmetic, so the product of the invention has wide application market.
Description
Technical Field
The invention belongs to the technical fields of medicines, functional foods and cosmetics, and particularly relates to application of quinazoline derivatives in preparation of products for resisting aging (especially reducing or preventing skin aging, cell aging or photoaging) in mammals.
Background
Cells, tissues and organs in an organism age gradually with age, thereby making the organism appear as a multisystemic integral aging. Cell aging is one of the most important in vivo mechanisms associated with aging. Aging cells impair tissue function through irreparable cellular damage caused by natural aging, thereby limiting longevity. Replicative senescence is the main cause of cell senescence, observed after about 60 rounds of cell division in culture, which is the result of progressive erosion of telomeres after each division. This progressive erosion results in telomere dysfunction and irreversible cell cycle arrest.
The most intuitive manifestation of the aging process is skin aging, which is the largest organ of the human body, accounting for 15% of the body weight, and adults have a skin area of about 2 square meters. The skin is anatomically divided into three layers altogether: epidermal layer, dermis layer, subcutaneous layer. The epidermis layer is the outermost barrier of the skin, and keratinocytes are the most predominant cell type of the epidermis layer, and it also contains langerhans cells, T cells, merkel cells, etc. The major cell type of the dermis is fibroblast.
The skin has important barrier function, defends invasion of harmful microorganisms and toxins, protects the body from ultraviolet radiation, and the impermeable stratum corneum blocks loss of moisture. In addition, the skin has the biological functions of immunoregulation, thermoregulation, vitamin D synthesis, secretion and excretion, and the like. However, the skin is in a complex external environment and is subject to aging by various external stimuli. Skin aging is a multifactorial process that affects its tissue morphology and biological function, and is caused by a variety of factors including intrinsic factors such as age, genetics, hormones, etc., and extrinsic factors such as uv exposure, environmental pollution, etc. Skin aging is accompanied by obvious signs such as thinning and drying of the skin, fine wrinkles, reduced elasticity, pigmentation, whitening of the hair, and hair loss.
Keratinocytes of the epidermis are one of the primary target cells of ultraviolet irradiation. Keratinocytes are subject to cell senescence or cell death, which are affected by different uv intensities. Fibroblast cells of the dermis are primarily affected by UVA in the uv and can undergo cell senescence or death. Much evidence suggests that aging keratinocytes and fibroblasts accumulate in naturally aging and photoaged skin, resulting in aging-related skin changes, including thinning, drying out, fine lines, reduced elasticity, abnormal pigmentation, and the like. Thus, reducing the accumulation of skin aging cells will delay the phenotype associated with skin aging.
Although the anti-aging products on the market are various at present, the effect of most products is poor and satisfactory, so that research and development of novel anti-aging methods and strategies and search of novel anti-aging active ingredients have important social significance and commercial value.
Disclosure of Invention
In order to overcome the defects of the prior art and enrich the prior art, the invention provides a method for delaying aging, and particularly relates to application of quinazoline derivatives in preparation of anti-aging products in mammals.
Specifically, the invention is realized through the following technical schemes:
the invention provides application of quinazoline derivatives in preparation of anti-aging products in mammals, wherein the quinazoline derivatives comprise 4-amino-6, 7-dimethyl quinazoline ring structures.
Alternatively, in the above application, the quinazoline derivative is selected from prazosin or a pharmaceutically acceptable salt thereof, terazosin or a pharmaceutically acceptable salt thereof, doxazosin or a pharmaceutically acceptable salt thereof, or alfuzosin or a pharmaceutically acceptable salt thereof.
Preferably, the quinazoline derivative is selected from terazosin or a pharmaceutically acceptable salt thereof.
More preferably, the pharmaceutically acceptable salt is a hydrochloride or mesylate salt.
Alternatively, in the above use, the anti-aging includes reducing or preventing skin aging, cell aging, or photoaging.
Alternatively, in the above use, the mammal is a primate.
Preferably, the mammal is a human.
Alternatively, in the above use, the product is an oral product or a topical product.
Alternatively, in the above use, the product is a pharmaceutical product, a functional food, a beverage, a nutritional supplement or a cosmetic product.
Alternatively, in the above use, the product is an oral solution, a liquid suspension, an injection, a tablet, a pill, a granule, a powder, a film, a capsule, a spray, an aerosol, a syrup, a beverage, a nutraceutical, a snack, an energy stick, a chewing gum, a candy, a mask, a cream, an essence, an emulsion, a toner, or a color cosmetic.
Alternatively, in the above-mentioned uses, auxiliary materials or excipients commonly used in medicines, functional foods, beverages, nutritional supplements or cosmetics are also contained in the product.
Alternatively, in the above use, the quinazoline derivative is used in an amount of from 0.5% to 20% by weight of the product.
Compared with the prior art, the invention has the following beneficial effects:
the quinazoline derivative containing the 4-amino-6, 7-dimethyl quinazoline ring structure can be used for relieving age-related natural skin aging and skin accelerated aging caused by external bad factors for the first time, and has no obvious side effect. In addition, the quinazoline derivative can be used for preparing food, health products, medicaments, compositions and cosmetics related to anti-aging, and has wide application market.
Drawings
Fig. 1: terazosin is not cytotoxic to skin keratinocytes (HACAT).
Fig. 2: terazosin is not cytotoxic to skin fibroblasts (HFF).
Fig. 3: terazosin has an inhibitory effect on ultraviolet-induced skin keratinocyte (HACAT) aging.
Fig. 4: terazosin has an inhibitory effect on ultraviolet-induced skin fibroblast (HFF) aging (β -gal staining).
Fig. 5: terazosin has an inhibitory effect on ultraviolet-induced skin fibroblast (HFF) aging (qPCR assay).
Fig. 6: terazosin has an inhibitory effect on ultraviolet-induced oxidative stress of skin fibroblasts (HFF).
Fig. 7: terazosin has an inhibitory effect on ultraviolet-induced skin keratinocyte (HACAT) death (CCK 8 assay).
Fig. 8: terazosin has an inhibitory effect on ultraviolet-induced skin keratinocyte (HACAT) death (ATP assay).
Detailed Description
In the above summary and detailed description, and in the claims, reference is made to specific features of the invention, and it is to be understood that all possible combinations comprising these specific features are disclosed in the present specification. For example, when a particular feature is disclosed in a particular aspect or embodiment of the invention or in a particular claim, that feature may also be used as far as possible and/or in combination with other particular aspects and embodiments of the invention.
Skin aging is a complex process. Macroscopically, skin aging manifests itself as fine lines, loss of elasticity, dullness or darkness of the skin, and reduced thickness of the epidermis and dermis. Microcosmically, typical features of skin aging include epidermal atrophy, reduced basal keratinocyte mitosis rate, reduced proliferative capacity, and cellular aging, atrophy of the dermal extracellular matrix, and altered connective tissue physiological properties.
The following briefly describes several active ingredients involved in the present invention:
prazosin (Prazosin) is also known as MAILINING and JIANGYAZING. Prazosin was the first selective alpha 1 receptor antagonist discovered at the end of the 60 s of the 20 th century and was clinically used to treat hypertension and congestive heart failure of various etiologies.
Terazosin (Terazosin) is a long-acting antihypertensive developed by Abbott corporation in the united states in the 80 th century, and has the effect of blocking the peripheral postsynaptic α1-adrenoreceptors, thereby causing vasodilation and reducing peripheral vascular resistance to lower blood pressure. The product has the advantages of little influence on cardiac output, no reflective heartbeat acceleration, no reduction of renal blood flow or glomerular filtration, etc. Since the alpha 1-adrenergic receptor blocks to relax bladder neck, prostate and prostate envelope smooth muscle and reduce urethral resistance and pressure and bladder resistance, thereby reducing urethral symptoms, the terazosin hydrochloride is also a first-line medicament for treating benign prostatic hyperplasia lower urinary tract symptoms of men at present.
Doxazosin (Doxazosin) is an alpha 1 selective alpha blocker that inhibits the binding of norepinephrine (released from sympathetic nerve endings) to alpha-1 receptors on vascular smooth muscle cell membranes. The primary effect of this inhibition is to relax vascular smooth muscle tone (vasodilation), which reduces peripheral vascular resistance, resulting in a decrease in blood pressure. Clinically used for treating hypertension and urinary retention associated with Benign Prostatic Hyperplasia (BPH).
Alfuzosin (Alfuzosin) has effects similar to those of prazosin and papaverine, and has effects of blocking the protruding posterior membrane alpha 1 receptor and directly dilating vascular smooth muscle, so that the Alfuzosin (Alfuzosin) has good blood pressure lowering effect. The reflex heart rate is not accelerated when the blood pressure is reduced. Can block alpha 1 receptor in trigone, urethra and prostate capsule, reduce urine flow resistance, and improve urination. Can be used for treating hypertension and some functional symptoms of benign prostatic hyperplasia.
Those skilled in the art recognize that even if the sign or condition is not completely eradicated or prevented, its symptoms and/or effects are partially ameliorated or reduced in the subject, the amount can still be considered "effective".
The term "pharmaceutically acceptable" refers to those compositions or agents, materials or combinations of compositions and/or dosage forms thereof which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and are acceptable either pharmaceutically, physiologically, dietetically, and/or nutritionally.
The term "mammal" refers to any animal to which the uses and products of the present disclosure may be applied or administered. Animals may suffer from afflictions or other diseases, but the animals do not need to be ill to benefit from the uses and products of the present disclosure. Thus, any animal can utilize the disclosed products or be a recipient of the disclosed uses. "mammal" includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, particularly humans. Although the animal subject is preferably a human, the methods and compositions of the invention are equally applicable to veterinary medicine.
The invention will be further illustrated with reference to specific examples. It should be understood that the detailed description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the invention.
The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or equipment used were conventional products available for purchase through regular channels, with no manufacturer noted.
The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the examples described below, unless otherwise specified, are all commercially available products.
Example 1: safety evaluation of terazosin on skin-related cells
The safety of terazosin was evaluated in skin keratinocytes HACAT and fibroblasts HFF (both of which were purchased from Qiao Xin boat biotechnology limited in the Shanghai).
The complete culture medium of both cells is DMEM+10% FBS+0.5% green streptomycin mixed solution, and the culture condition is 37 deg.C and 5% CO 2 . Two cells were individually plated into 96-well cell culture plates for evaluation, with an initial plating cell number of 0.8-1.2 ten thousand cells per well. HACAT and HFF cells were treated with different concentrations of terazosin for 48 hours after 24 hours post plating, respectively, after which survival of the cells was examined using CCK8 (the same institute of chemistry).
As shown in FIGS. 1-2, the results showed that neither 300. Mu.M, 100. Mu.M, 30. Mu.M, nor 10. Mu.M terazosin had an effect on the survival of both cells (One-way ANOVA, dunnett's multiple comparisons test, neither group was statistically significant). The result shows that the terazosin has no toxicity to skin cells under the condition of higher concentration, and has high safety.
Example 2: antagonism of terazosin against skin aging
Ultraviolet (UV) irradiation using an ultraviolet aging oven (Shanghai kiosks) induced HACAT and HFF cell senescence. The complete culture medium of both cells is DMEM+10% FBS+0.5% double antibody, and the culture condition is 37 ℃ and 5% CO 2 . Two cells were individually plated into 96-well cell culture plates for evaluation, with an initial plating cell number of 0.8-1.2 ten thousand cells per well. After 24 hours of plating, UV irradiation (UV-A95%, UV-B5%, UV-A1.5W/m) 2 ) After 20 minutes, cells were treated with 10 μm terazosin. After 48 hours, cell senescence was stained with beta-galactosidase staining (Sigma, senescent histochemical staining kit) and quantified by photographing, and the proportion of positively stained cells was counted.
As shown in fig. 3-4, the results show that UV irradiation can cause a significant increase in the proportion of HACAT cells positive for β -galactosidase staining (One-way ANOVA, dunnett' smultiple comparisons test, p=0.0012; P <0.05, <0.01, <0.001, <0.0001, < P) indicating that UV irradiation can trigger cell senescence; following Terazosin (TZ) treatment, the proportion of cells positive for beta-galactosidase staining was significantly reduced (One-way ANOVA, dunnett's multiple comparisons test, p=0.0039). UV irradiation can cause a significant increase in the proportion of beta-galactosidase staining positive HFF cells (One-way ANOVA, dunnett's multiple comparisons test, p < 0.0001), indicating that UV irradiation can trigger cell senescence; following Terazosin (TZ) treatment, the proportion of cells positive for beta-galactosidase staining was significantly reduced (One-way ANOVA, dunnett's multiple comparisons test, p=0.0007). These results indicate that: terazosin is capable of significantly inhibiting both keratinocyte and fibroblast senescence caused by UV irradiation.
To further quantify cellular senescence, a real-time fluorescent quantitative PCR (qPCR) method was used to detect P21, one of the markers of cellular senescence. Primer information is shown in table 1 below:
table 1: primer information table for qPCR detection of P21
| β-actin F | GCGCGGCTACAGCTTCA |
| β-actin R | CTTAATGTCACGCACGATTTCC |
| P21F | GGCGGGCTGCATCCA |
| P21R | AGTGGTGTCTCGGTGACAAAGTC |
Complete medium of HFF cells is DMEM+10% FBS+0.5% diabody, and culture conditions are 37 ℃ and 5% CO 2 . Cells were plated into 6-well plates at 30 ten thousand cells per well. After 24 hours of plating, UV irradiation (UV-A95%, UV-B5%, UV-A1.5W/m) 2 ) After 20 minutes, HFF fibroblasts were treated with 10. Mu.M terazosin. After 48 hours, total RNA from cells was extracted (TRIZOL method) and an equivalent amount of RNA was reverse transcribed into cDNA (Nuo-NZAN HiScript II 1st Strand cDNA Synthesis Kit). The level of transcription of P21 was detected using qPCR method.
As shown in fig. 5, the results show that UV irradiation can significantly increase P21 levels in HFF cells (One-way ANOVA, dunnett's multiple comparisons test, P < 0.0001), and that transcript levels of P21 can be significantly reduced after treatment with Terazosin (TZ) (One-way ANOVA, dunnett's multiple comparisons test, P < 0.0001). The results further demonstrate that: terazosin is capable of significantly inhibiting fibroblast senescence caused by UV irradiation.
Example 3: terazosin drop has antioxidation effect
Oxidative stress plays an extremely important role in the aging process. Thus, example 3 detects intracellular reactive oxygen levels under UV radiation induced senescence conditions using ROS probes (Invitrogen, image-iT TM LIVE Green Reactive Oxygen Species Detection Kit) to reflect the relative amount of ROS in the cell by measuring the fluorescent intensity of the ROS probe.
As shown in FIG. 6, the HFF cells were completely cultured in DMEM+10% FBS+0.5% diabody at 37℃under 5% CO 2 . Cells were plated into 6-well plates at 30 ten thousand cells per well. After 24 hours of plating, UV irradiation (UV-A95%, UV-B5%, UV-A1.5W/m) 2 ) After 20 minutes, HFF fibroblasts were treated with 10. Mu.M terazosin. After 24 hours, the intracellular active oxygen levels were measured. The results show that the intracellular ROS content increases significantly after UV irradiation of fibroblast HFF (One-way ANOVA, dunnett's multiple comparisons test, p)<0.0001 The administration of 10 μm Terazosin (TZ) treated cells significantly reduced the excess ROS generated in the process (One-way ANOVA, dunnett's multiple comparisons test, p=0.0065). This result shows that: terazosin may protect against cellular aging by antioxidant.
Example 4: terazosin inhibits cell death by UV irradiation
Excessive uv irradiation causes death of skin cells, thereby inducing the associated aging phenotype. Example 4 in HACAT cells, higher intensity uv irradiation was used to induce cell death in HACAT cells. HACAT cells were plated into 96-well cell culture plates for evaluation, with an initial plating cell number of 0.8-1.2 ten thousand cells per well. After 24 hours of plating, UV irradiation (UV-A95%, UV-B5%, UV-A1.5W/m) 2 40 minutes), cells were treated with 10 μm terazosin. After 24 hours, cell viability was first assessed using CCK8 assay. As shown in FIG. 7, the results show that UV irradiation can cause nearly half of the cells to die (One-way ANOVA, dunnett's multiple comparisons test, p=0.0096), and that terazosin treatment can significantly reduce cell death caused by UV irradiationApoptosis (One-way ANOVA, dunnett's multiple comparisons test, p=0.05).
At the same time, ATP detection (Promega, cell
Luminescent Cell Viability Assay) to quantify cell survival. As shown in fig. 8, the results were similar to CCK8 results in that UV irradiation was able to cause nearly half of the cells to die (One-way ANOVA, dunnett's multiple comparisons test, p=0.0001), and terazosin treatment was able to significantly reduce the cell death caused by irradiation (One-way ANOVA, dunnett' smultiple comparisons test, p=0.0024).
It will be apparent to those skilled in the art that various modifications and variations can be made to the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention also include such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.
Claims (10)
1. Use of quinazoline derivatives in the preparation of a product for combating ageing in a mammal, characterised in that: the quinazoline derivative comprises a 4-amino-6, 7-dimethyl quinazoline ring structure.
2. Use according to claim 1, characterized in that: the quinazoline derivative is selected from prazosin or pharmaceutically acceptable salt thereof, terazosin or pharmaceutically acceptable salt thereof, doxazosin or pharmaceutically acceptable salt thereof or alfuzosin or pharmaceutically acceptable salt thereof.
3. Use according to claim 2, characterized in that: the pharmaceutically acceptable salt is hydrochloride or mesylate.
4. Use according to any one of claims 1 to 3, characterized in that: the anti-aging includes reducing or preventing skin aging, cellular aging, or photoaging.
5. Use according to any one of claims 1 to 4, characterized in that: the mammal is a primate, preferably the mammal is a human.
6. Use according to any one of claims 1 to 5, characterized in that: the product is an oral or topical product.
7. Use according to any one of claims 1 to 6, characterized in that: the product is a pharmaceutical product, a functional food, a beverage, a nutritional supplement or a cosmetic product.
8. Use according to any one of claims 1 to 7, characterized in that: the product is an oral solution, a liquid suspension, an injection, a tablet, a pill, a granule, a powder, a film, a capsule, a spray, an aerosol, a syrup, a beverage, a nutritional product, a snack, an energy bar, a chewing gum, a candy, a facial mask, a cream, an essence, an emulsion, a toner or a color cosmetic.
9. Use according to any one of claims 1 to 8, characterized in that: the product also contains auxiliary materials or excipients commonly used in medicines, functional foods, beverages, nutritional supplements or cosmetics.
10. Use according to any one of claims 1 to 9, characterized in that: the quinazoline derivatives are used in an amount of 0.5-20% by weight of the product.
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| US20060099568A1 (en) * | 2002-06-05 | 2006-05-11 | Ik-Soon Jang | Signals and molecular species involved in senescence |
| CN104887682A (en) * | 2015-06-18 | 2015-09-09 | 刘磊 | Application of terazosin type medicines |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20060099568A1 (en) * | 2002-06-05 | 2006-05-11 | Ik-Soon Jang | Signals and molecular species involved in senescence |
| CN104887682A (en) * | 2015-06-18 | 2015-09-09 | 刘磊 | Application of terazosin type medicines |
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