CN109700790A - A kind of anti aging effect drug Butein targeting AQP3 - Google Patents
A kind of anti aging effect drug Butein targeting AQP3 Download PDFInfo
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- CN109700790A CN109700790A CN201811622071.XA CN201811622071A CN109700790A CN 109700790 A CN109700790 A CN 109700790A CN 201811622071 A CN201811622071 A CN 201811622071A CN 109700790 A CN109700790 A CN 109700790A
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Abstract
The invention belongs to antiaging agent applied technical fields, disclose a kind of preparation method for targeting AQP3 anti aging effect drug and its external preparation.The targeting AQP3 anti aging effect drug is butein.Butein (butein) is plant polyphenol, with antioxidation, local topical formulation can make drug go directly focal zone, improve curative effect of medication, the destruction that not only can avoid " first pass effect " and gastrointestinal tract of oral administration, can also reduce the generation of adverse reaction；Gel preparation has extraordinary stretchability and comfort, helps the infiltration of drug and delay in skin.The present invention predicts the small molecule compound Butein for capableing of selectively targeted AQP3 by database, and can have certain curative effect and no apparent skin side-effects in terms of skin anti-aging by targeting AQP3, and its local topical gel is constructed according to the physicochemical property of Butein.
Description
Technical field
The invention belongs to antiaging agent applied technical field more particularly to a kind of anti aging effect drugs for targeting AQP3
Butein。
Background technique
Currently, the prior art commonly used in the trade is such that skin is the most intuitive as showing during body aging
One of organ, not only reflects the health and aging state of body, but also greatly affected the mental health of people, Ren Renguan
Note.The cutaneous manifestations of aging are cutis laxa, wrinkle increases, Skin barrier destruction, Regeneration and Repair ability decline, wound healing is prolonged
Late etc..The mechanism of skin aging is simultaneously indefinite, and oxidative stress is most widely accepted one of mechanism.Regular treatment skin at present
The drug of aging is very deficient, and it is a kind of to only have 0.05% all-trans retinoic acid of external application by the FDA drug ratified.Therefore, energy is developed
The drug of effective delay skin aging is very necessary.Aquaporin 3 (AQP3) is to express water the most abundant in a kind of skin
Channel protein can transport the small-molecule substances such as water, glycerol and urea.In skin, AQP3 can from circulation by endogenous glycerol,
Triglyceride etc. in sebaceous glands brings epidermis into, while short water loop is formed in epidermal cell, to guarantee that epidermis continues
Water content, epidermal barrier function, water preservation in play a significant role.The hydration energy of Skin Cell can be made by increasing AQP3
Power, the turn-over capacity of glycerol improve, and wait agings performance so as to improve skin surface is coarse, can be used as the effect target of antiaging agent
Point.
With the exponential growth of all kinds of groups of data, various countries also establish various dedicated in storage group data
Heart database such as GEO, TCGA, EMBL etc., but the database in terms of disease-compound association analysis, it is also less both at home and abroad, and
Lack value for clinical application, such as DGIdb and TCMSP.The clinical biochemical letter of Chinese People's Liberation Army General Hospital Lu Xuechun professor
Xi Xue team, after 20 years, independent research was domestic first dedicated for the research of clinical biochemical informatics and Transformation Application
" EpiMed " apparent precisely treatment predicting platform is that current world authority is utilized to organize the total data for learning database plus autonomous survey
Chinese medicine target spot data, human normal tissue data and refractory/rare patient that sequence obtains combine certainly on the basis of organizing data
The association analysis platform that " the yin-yang and five elements association algorithm " of main design is established.EpiMed is existing to contain more than 2000 kinds of diseases, 8000
The secondary data of a variety of Western medicine and compound and 1000 kinds of traditional Chinese medicines.Existing a variety of antioxidants such as vitamin C, beta carotene
Deng being all added into anti aging effect in skin care item.However external application is only had by the FDA drug ratified for treating skin aging at present
0.05% all-trans retinoic acid is a kind of.
In conclusion problem of the existing technology is: being only had at present by the FDA drug ratified for treating skin aging
0.05% all-trans retinoic acid of external application is a kind of.Be difficult to find at present it is a kind of in terms of anti-aging with positive effect, Ke Yiyong
In the new drug of clinical antidotal therapy, therefore the new drug for finding a kind of anti-aging is imperative, and the present invention is screened by big data
A new drug for having apparent anti-aging effects in cellular level and animal body out provides new for clinic antidotal therapy
Drug candidate.
Summary of the invention
In view of the problems of the existing technology, the present invention provides a kind of targeting AQP3 anti aging effect drugs.
The invention is realized in this way a kind of targeting AQP3 anti aging effect drug, the targeting AQP3 anti aging effect
Drug is butein；Its structural formula are as follows:
Another object of the present invention is to provide a kind of detection for verifying the targeting AQP3 anti aging effect drug is different
For Butein acute drug on a cellular level to the action method of the expression of AQP3 and Aging marker, the detection is different
Butein acute drug includes: to the action method of the expression of AQP3 and Aging marker on a cellular level
1) cell culture
The primary fibroblast of cell culture people, cell monolayer are seeded in containing in 10% fetal calf serum, DMEM culture solution,
Containing 1 × 105U L-1Penicillin and 100mg × L-1Streptomysin is cultivated in 37 DEG C, 5% carbon dioxide incubator；
2) influence of the Butein of the detection various concentration of quantitative fluorescent PCR to the mRNA level in-site of AQP3；
3) beta galactosidase staining kit is catalyzed using X-Gal as substrate in the beta galactosidase of senescence-specific
Under can generate navy blue product, be readily observed under optical microscopy become blue expression beta galactosidase cell or
Tissue；The cell cultivated in 6 orifice plates is absorbed cell culture fluid, is washed 1 time with PBS or HBSS, and 1ml beta galactosidase is added
Fixer is dyed, room temperature is fixed, and counts the ratio for catching cytochrome.
Another object of the present invention is to provide a kind of AQP3 for verifying the targeting AQP3 anti aging effect drug to express,
The animal model of Aging marker, AQP3 expression, Aging marker the different Butein concentration of animal model
After screening external-use gel and bare substrate Gel Treatment control group and mouse aging, to the work of AQP3 expression and Aging marker
With；With screening external-use gel and the control of bare substrate Gel Treatment and mouse aging 3 months, mouse skin is taken to carry out AQP3 table
It reaches, the detection of Aging marker.
In conclusion advantages of the present invention and good effect are as follows: the present invention is sieved by target spot of this water ion channel AQP3
Select a kind of small molecule compound Butein in terms of anti-aging with obvious effect；Butein (butein) is that plant is more
Phenol has antioxidation, and local topical formulation can make drug go directly focal zone, improve curative effect of medication, not only can avoid taking orally
The destruction of " first pass effect " and gastrointestinal tract of administration, can also reduce the generation of adverse reaction, gel preparation has extraordinary painting exhibition
Property and comfort, help the infiltration and delay in skin of drug, the present invention is the exploitation of targeting AQP3 drug and sieve later
Choosing provides data and method is supported；The present invention predicts the small molecule for capableing of selectively targeted AQP3 by database EpiMed
Object Butein is closed, and there can be remarkable result in terms of skin anti-aging by targeting AQP3, while without apparent skin
Side effect.
Detailed description of the invention
Fig. 1 be various concentration provided in an embodiment of the present invention Butein processing people primary fibroblast after AQP3
The horizontal variation of mRNA, * * P < 0.01vs Control.
Fig. 2 be various concentration provided in an embodiment of the present invention Butein processing people primary fibroblast after P16
The horizontal variation of mRNA, * * P < 0.01vs Control.
Fig. 3 be various concentration provided in an embodiment of the present invention Butein processing people primary fibroblast after β-GAL
The positive rate of dyeing, * * P < 0.01vs Control.
Fig. 4 is back of mice skin change after external-use gel and bare substrate Gel Treatment March provided in an embodiment of the present invention
Change.
Fig. 5 is that the horizontal of AQP3 mRNA becomes after the Butein of various concentration provided in an embodiment of the present invention smears mouse
Change, * * P < 0.01vs Control.
Fig. 6 is that the horizontal of P16 mRNA becomes after the Butein of various concentration provided in an embodiment of the present invention smears mouse
Change, * * P < 0.01vs Control.
Fig. 7 is that the horizontal of P21 mRNA becomes after the Butein of various concentration provided in an embodiment of the present invention smears mouse
Change, * * P < 0.01vs Control.
Specific embodiment
In order to make the objectives, technical solutions, and advantages of the present invention clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
The present invention is the prediction by database, and logical by the targeting water ion that experiment confirms that Butein can be specific
Road AQP3 lowers the relevant index of aging, have in terms of skin anti-aging must effect, and have no apparent skin pair and make
With providing new drug candidate for clinically antidotal therapy.
Application principle of the invention is explained in detail with reference to the accompanying drawing.
Targeting AQP3 anti aging effect drug provided in an embodiment of the present invention is Butein (butein)；Its structural formula are as follows:
Application effect of the invention is explained in detail below with reference to embodiment.
The people of (0.1,0.5,1,2,5 μM) of Butein processing control and the aging of various concentration of the embodiment of the present invention is at fibre
Cell is tieed up, cell is collected and carries out the detection of AQP3 mRNA, Aging marker.As the result is shown through various concentration drug-treated
Afterwards, while the mRNA level in-site of AQP3 rises, aging relevant index P16 decline, after β-GAL dyeing positive cell rate also under
Drop, and there is concentration dependent in certain concentration range, illustrate the aging level decline of cell after Butein processing, and be
By increasing this access of AQP3.
Embodiment 1
With the human fibroblasts of (0.1,0.5,1,2,5 μM) of Butein processing control and aging of various concentration, collect
Cell and the detection for carrying out AQP3 expression, Aging marker.
1) cell culture
The primary fibroblast of cell culture people, cell monolayer are seeded in containing in 10% fetal calf serum, DMEM culture solution
(contain 1 × 105U L-1Penicillin and 100mg × L-1Streptomysin), it is cultivated in 37 DEG C, 5% carbon dioxide incubator；
2) influence of the Butein of the detection various concentration of quantitative fluorescent PCR to the mRNA level in-site of AQP3 and P16, such as Fig. 1
With shown in Fig. 2；
3) β-GAL is dyed and is counted, as shown in Figure 3；
Beta galactosidase staining kit is using X-Gal as substrate, under the beta galactosidase catalysis of senescence-specific
Navy blue product can be generated, the cell or group for becoming the expression beta galactosidase of blue are readily observed under optical microscopy
It knits.The cell cultivated in 6 orifice plates is absorbed cell culture fluid, is washed 1 time with PBS or HBSS, and 1ml beta galactosidase dye is added
Color fixing liquid, room temperature are fixed, and count the ratio for catching cytochrome.
Embodiment 2
Respectively with the Butein screening external-use gel of various concentration and the control of bare substrate Gel Treatment and mouse aging 3
Month, take mouse skin to carry out AQP3 expression, the detection of Aging marker.Mouse is handled through various concentration Butein as the result is shown
After skin of back, back of mice skin is compact compared with the control group, and fold weakens, and while the mRNA level in-site rising of AQP3,
Aging relevant index P16, P21 decline, has concentration dependent in certain concentration range, illustrates thin after Butein is handled
The aging level of born of the same parents declines, and is by increasing this access of AQP3.
1) mouse is raised and carries out drug-treated, as shown in Figure 4；
2) detection of quantitative fluorescent PCR, as shown in Figure 5-Figure 7.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Made any modifications, equivalent replacements, and improvements etc., should all be included in the protection scope of the present invention within mind and principle.
Claims (4)
1. a kind of targeting AQP3 anti aging effect drug, which is characterized in that the targeting AQP3 anti aging effect drug is palas
Cause；Its structural formula are as follows:
2. a kind of preparation method of the AQP3 anti aging effect drug of targeting as described in claim 1, which is characterized in that the targeting
The preparation method of AQP3 anti aging effect drug the following steps are included:
Screen gel-type vehicle according to characteristics such as the solubility of Butein drug, Determination of oil-water partition coefficient, PH stability, with cone penetration and
Percutaneous accumulation infiltration capacity is index screening gel-type vehicle content, determines drugloading rate with transdermal permeation in vitro, and basic herein
It is upper to select suitable permeation enhancers, moisturizer and preservative etc., Butein gel preparation is constructed, by containing comprising following weight percent
The component of amount is made:
The gel-type vehicle be selected from hypromellose, sodium carboxymethylcellulose, carbomer, hyaluronic acid, polyvinyl alcohol,
One of sodium alginate, sodium hyaluronate or methylcellulose or more than one, preferably hypromellose；Described is anti-
Rotten agent is selected from one of ethyl hydroxy benzoate, ethylparaben, sodium benzoate, benzalkonium bromide, anesin or sorbic acid or one
Kind or more；The moisturizer is selected from propylene glycol or glycerol；The alcoholic solvent is polyethylene glycol-400 or propylene glycol.
3. a kind of different Butein acute drugs of detection of targeting AQP3 anti aging effect drug described in verifying claim 1 are thin
To the action method of the expression of AQP3 and Aging marker in born of the same parents' level, which is characterized in that the different Butein of the detection are dense
Spend drug includes: to the action method of the expression of AQP3 and Aging marker on a cellular level
1) cell culture
The primary fibroblast of cell culture people, cell monolayer are seeded in containing in 10% fetal calf serum, DMEM culture solution, contain 1
×105U L-1Penicillin and 100mg × L-1Streptomysin is cultivated in 37 DEG C, 5% carbon dioxide incubator；
2) influence of the Butein of the detection various concentration of quantitative fluorescent PCR to the mRNA level in-site of AQP3；
3) beta galactosidase staining kit is using X-Gal as substrate, the meeting under the beta galactosidase catalysis of senescence-specific
Navy blue product is generated, the cell or group for becoming the expression beta galactosidase of blue are readily observed under optical microscopy
It knits；The cell cultivated in 6 orifice plates is absorbed cell culture fluid, is washed 1 time with PBS or HBSS, and 1ml beta galactosidase dye is added
Color fixing liquid, room temperature are fixed, and count the ratio for catching cytochrome.
4. a kind of verify the dynamic of the AQP3 expression, Aging marker for targeting AQP3 anti aging effect drug described in claim 1
Object model, which is characterized in that the AQP3 is expressed, outside screening of the animal model of Aging marker with different Butein concentration
Effect after gel and bare substrate Gel Treatment control group and mouse aging, to AQP3 expression and Aging marker；With
External-use gel and the control of bare substrate Gel Treatment and mouse aging 3 months are screened, mouse skin is taken to carry out AQP3 expression, aging
The detection of index of correlation.
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|---|---|---|---|
| CN201811622071.XA CN109700790A (en) | 2018-12-28 | 2018-12-28 | A kind of anti aging effect drug Butein targeting AQP3 |
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| CN201811622071.XA CN109700790A (en) | 2018-12-28 | 2018-12-28 | A kind of anti aging effect drug Butein targeting AQP3 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101015350A (en) * | 2007-01-12 | 2007-08-15 | 南京大渊美容保健有限公司 | Senescence delaying health care composition |
| US20090012080A1 (en) * | 2007-06-20 | 2009-01-08 | Sirtris Pharmaceuticals, Inc. | Sirtuin modulating compounds |
| CN104491003A (en) * | 2015-01-23 | 2015-04-08 | 天津市南开医院 | Jiawei Yupingfeng gel, preparation method and purpose thereof |
-
2018
- 2018-12-28 CN CN201811622071.XA patent/CN109700790A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101015350A (en) * | 2007-01-12 | 2007-08-15 | 南京大渊美容保健有限公司 | Senescence delaying health care composition |
| US20090012080A1 (en) * | 2007-06-20 | 2009-01-08 | Sirtris Pharmaceuticals, Inc. | Sirtuin modulating compounds |
| CN104491003A (en) * | 2015-01-23 | 2015-04-08 | 天津市南开医院 | Jiawei Yupingfeng gel, preparation method and purpose thereof |
Non-Patent Citations (1)
| Title |
|---|
| JASON G. WOOD等: "Sirtuin activators mimic caloric restriction and delay ageing in metazoan" * |
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