KR102127290B1 - Composition comprising fibroblast growth factor 2(FGF2) for improving pregnancy - Google Patents

Abstract

The present invention relates to a composition comprising FGF2 (Fibroblast growth factor 2) as an active ingredient, and more specifically, a pharmaceutical composition and food composition for promoting pregnancy, comprising FGF2 as an active ingredient, infertility comprising FGF2 as an active ingredient It relates to a pharmaceutical composition and a food composition for the prevention or treatment of.
The composition comprising FGF2 according to the present invention as an active ingredient is a material in the body that can minimize toxicity or side effects in the body compared to chemical compounds, and activates the expression of proteins in the PI3K/AKT and MAPK signaling pathways. By improving the proliferation of endothelial cells and reducing the expression of endoplasmic reticulum stress-inducing proteins, implantation efficiency can be greatly increased. have.

Description

Composition comprising fibroblast growth factor 2 (FGF2) for improving pregnancy}

The present invention relates to a composition comprising FGF2 (Fibroblast growth factor 2) as an active ingredient, and more specifically, a pharmaceutical composition and food composition for promoting pregnancy, comprising FGF2 as an active ingredient, infertility comprising FGF2 as an active ingredient It relates to a pharmaceutical composition and a food composition for the prevention or treatment of.

In recent years, with the aging society, infertility is increasing as the age of mothers giving birth increases. In addition, as the stress of women increases due to environmental pollution caused by industrialization and women's social advancement, the pregnancy rate is greatly reduced. Commonly known causes of female infertility include ovulation disorder, fertilized egg transport disorder, and implantation disorder. Infertility problems due to ovulation disorders and transfer disorders of fertilized eggs are mostly solved through IVF, but there is no clear solution to infertility due to implantation disorders.

In order to maintain a successful pregnancy, embryo development, endometrial development, implantation, placenta formation, hormone regulation, exchange of nutrients and gases between the mother and the fetus are required (Spencer TE et al, Reproduction, 128(6):657 -668, 2004).

In the early stages of pregnancy, the fetus undergoes morphological changes in the form of filaments in the spherical blastocyst to implant into the endometrium, forming a successful non-invasive placenta (Bazer FW and Johnson GA, Differentiation, 2014).

During the peri-implantation period, estrogen secreted from the product is prevented by prostaglandin F 2α secretion, thereby preventing luteolysis and remodeling the endometrial tissue to form the uterine environment for implantation (Bazer FW and Johnson GA, Differentiation, 87(1-2):52-65, 2014).

Implantation is an early pregnancy phenomenon in which fertilized blastocyst, which is being developed as an embryo, is attached to the endometrial layer of the mother, the endometrial layer of the mother induced decidualization and the cell nutritional membrane cells of the embryo. (cytotrophoblast) and cell fusion (cell fusion) by the formation of happotrophic membrane cells (syncytiotrophoblast) to form an idea.

On the other hand, cell death due to endoplasmic reticulum stress in female reproductive organs acts as a factor that interferes with the development of abnormal reproductive organs and pregnancy. In particular, vesicular stress causes abnormal placental development in mice and delays fetal growth and gestational addiction and miscarriage in women. It is known to cause (Mizuuchi et al., J Pathol, 2016; Yung et al., Am J Pathol, 2008; Gao et al., Mol Biol Rep, 2012).

Therefore, for successful implantation, endometrial cells need to be sufficiently proliferated, differentiated, and developed, and there is a need to reduce vesicle stress.

Under the above-mentioned technical background, the present inventors tried to develop a substance capable of improving implantation efficiency and maintenance ability in early pregnancy by improving the proliferative properties of endometrial cells and reducing vesicle stress, as a result of fibroblasts. The growth factor 2 (Fibroblast growth factor 2, FGF2) activates PI3K/AKT and MAPK signaling pathways to improve the proliferation of endometrial cells and confirms the effect of reducing the expression of endoplasmic reticulum stress-inducing proteins and the present invention. Completed.

An object of the present invention is to provide a pharmaceutical composition for promoting pregnancy, comprising FGF2 (Fibroblast growth factor 2) as an active ingredient.

Another object of the present invention is to provide a food composition for promoting pregnancy, which includes FGF2 (Fibroblast growth factor 2) as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating infertility, which includes FGF2 (Fibroblast growth factor 2) as an active ingredient.

Another object of the present invention is to provide a food composition for preventing or improving infertility comprising FGF2 (Fibroblast growth factor 2) as an active ingredient.

Another object of the present invention is to provide a method of improving the proliferation ability of endometrial cells using the composition.

The present invention provides a pharmaceutical composition for promoting pregnancy comprising FGF2 (Fibroblast growth factor 2) as an active ingredient.

The present invention also provides a food composition for promoting pregnancy comprising FGF2 (Fibroblast growth factor 2) as an active ingredient.

The present invention also provides a pharmaceutical composition for the prevention or treatment of infertility comprising FGF2 (Fibroblast growth factor 2) as an active ingredient.

The present invention also provides a food composition for preventing or improving infertility comprising FGF2 (Fibroblast growth factor 2) as an active ingredient.

The present invention also provides a method of improving the proliferation ability of endometrial cells using the composition.

The composition comprising FGF2 according to the present invention as an active ingredient is a material in the body that can minimize toxicity or side effects in the body compared to chemical compounds, and activates the expression of proteins in the PI3K/AKT and MAPK signaling pathways. By improving the proliferation of endothelial cells and reducing the expression of endoplasmic reticulum stress-inducing proteins, implantation efficiency can be greatly increased, and thus, it can be usefully used in the field of medicines and functional foods that can help prevent and treat fertility and pregnancy infertility. have.

Figure 1 shows the results of analyzing the effect of FGF2 on the cell proliferation of endometrial epithelial cells in cattle.
Figure 2 shows the results of analyzing the cell cycle change pattern of endometrial epithelial cells in cattle by FGF2 treatment.
Figure 3 shows the results of analyzing the expression pattern of the signal transduction regulation in the endometrial epithelial cells of cattle according to the dose-dependent administration of FGF2.
Figure 4 shows the results of analyzing the expression pattern of the signal transduction regulatory phosphatase by a mixed composition of PI3K, MAPK inhibitor and FGF2.
Figure 5 shows the results of analyzing the effect on the proliferation of endometrial epithelial cells during FGF treatment after treatment with fibroblast growth factor receptor inhibitors.
Figure 6 shows the results of analyzing the effect of FGF2 treatment on endoplasmic reticulum stress in bovine endometrial epithelial cells.
FIG. 7 shows the mechanism of action of FGF2 related to the proliferation of bovine endometrial epithelial cells and the effect of relieving vesicle stress.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which the present invention pertains. In general, the nomenclature used herein is well known and commonly used in the art.

In the present invention, the mechanism of action of FGF2 related to the proliferation of endometrial epithelial cells and the effect of relieving endoplasmic reticulum was revealed (FIG. 7 ).

The present invention provides a composition for promoting pregnancy comprising FGF2 (Fibroblast growth factor 2) as an active ingredient.

The composition includes both pharmaceutical and food compositions.

As used herein, the term "composition" is considered to include any product that is made directly or indirectly by the combination of a particular component, as well as products that contain a particular component.

In the present invention, "pregnancy" is a process in which the fertilized egg implants on the inner wall of the uterus and receives nutrition from the mother and develops into a fetus, and the normal pregnancy process proceeds in the order of fertilization, implantation and fetal development.

The "fertilization" means that when an egg ovulated from a female ovary meets a sperm at the top of the oviduct, a fertilized egg is formed. The egg survives 1-2 days after ovulation, and sperm survives 2-3 days in the womb and has the ability to fertilize, and sperm may survive until 1 week after ejaculation. Since the sperm reaches the ovary along the oviduct 2 to 3 hours after ejaculation, in general, when the sperm reaches the upper part of the oviduct first and then the egg ovulated from the ovary reaches here, only one of several sperm combines with the oocyte To form.

The "implantation" refers to a phenomenon in which the fertilized egg formed by the meeting of the sperm and the egg at the upper part of the oviduct is transferred to the uterus while repeating the difficulty and buried in the inner wall of the uterus in the state of blastocyst. After the conception of the fertilized egg is called pregnancy. The fertilized egg implanted in the uterus is born after being raised for about 9 months while being supplied with nutrients from the inner wall of the uterus.

According to an embodiment of the present invention, the FGF2 has an effect of increasing the implantation efficiency by improving the proliferation ability of endometrial epithelial cells by activating PI3K/AKT and MAPK signaling mechanisms.

At this time, the endometrial epithelial cells may be cells derived from mammals, and the mammals are rodents (eg, mice, rats, hamsters, gerbils, and guinea pigs), right heads (eg, cows, Sheep, pigs, goats, deer, giraffes and antelopes, mechanics (e.g. horses, donkeys, rhinos and tapirs), carnivores (e.g. dogs, cats, tigers, wolves, foxes, lions, cheetahs, leopards) , Raccoons, badgers, puma, jaguar and wildcat), lepidoptera (rabbits and crying rabbits), carnivores (e.g. hedgehogs, moles and solenoids) and primates (e.g. chimpanzees, orangutans, gorillas, bonobonos) , Japanese macaque, rhesus macaque).

According to an embodiment of the present invention, the FGF2 has an effect of increasing the implantation efficiency by reducing the expression of the endoplasmic reticulum stress-inducing protein.

At this time, the endoplasmic reticulum stress-inducing protein is not necessarily limited thereto, but may be one or more selected from the group consisting of IRE1α, ATF6α, p-PERK, p-eIF2α and GRP78.

The composition may include FGF2 alone, or may further include a substance having a substance that is effective in promoting pregnancy as an active ingredient, and in addition to the active ingredient, additional ingredients according to the formulation, method of use, and purpose of use, that is, pharmaceuticals It may further include a scientifically acceptable or nutritionally acceptable carrier, excipient, diluent or accessory ingredient.

More specifically, the pharmaceutical composition for promoting pregnancy comprising the FGF2 is a nutrient, vitamin, electrolyte, flavor, colorant, neutralizer, pectic acid and salts thereof, alginic acid and salts thereof, organic acid, and protection in addition to the active ingredient It may further contain a sex colloidal thickener, pH adjusting agent, stabilizer, preservative, glycerin, alcohol, carbonic acid used in carbonated beverages, and the like.

The carrier, excipients, and diluents can be used in common, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, Calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, calcium carbonate, dextrin, propylene glycol, liquid paraffin And one or more selected from the group consisting of physiological saline, but is not limited thereto. The components may be added to the active ingredient, FGF2, independently or in combination.

The composition according to the present invention may be used alone for promoting pregnancy, or may be used in combination with surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.

The composition according to the present invention can be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is the patient's weight, age, sex, health The range varies depending on the condition, diet, administration time, administration method, excretion rate, and severity of the disease. The daily dose of FGF2 of the present invention is 001 to 10000 mg/kg, preferably 1 to 20 mg/kg, and is preferably administered in divided doses once to three times a day.

In addition, the present invention provides a food composition for promoting pregnancy comprising FGF2 as an active ingredient.

The composition according to the present invention may be included in a health functional food for the purpose of promoting pregnancy, and when the active ingredient of the present invention is used as a food additive, the one separated from the synthetic or extract is added as it is or along with other food or food ingredients. It can be used and can be suitably used according to conventional methods. In addition, the mixing amount of the active ingredient may be appropriately adjusted according to the purpose of use (prevention, health or therapeutic treatment).

There are no particular restrictions on the type of food. Examples of foods to which the above substances can be added are meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other dairy products including noodles, gums, ice creams, various soups, beverages, teas, and drinks. , Alcoholic beverages and vitamin complexes, and includes both healthy foods and health functional foods in the usual sense.

The food supplement additive of the present invention may use various flavoring agents or natural carbohydrates. The above-mentioned natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, sugar alcohols such as xylitol, sorbitol, and erthritol. Natural sweeteners such as Martin and Stevia extract, and synthetic sweeteners such as saccharin and aspartame can be used.

In addition to the above, the composition according to the present invention includes various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal focusing agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohol , Carbonic acid used in carbonated beverages, and the like. In addition, the composition according to the present invention may contain flesh for the preparation of natural fruit juices, fruit juice drinks and vegetable drinks. These ingredients can be used independently or in combination.

In addition, the present invention provides a composition for preventing or treating infertility comprising FGF2 as an active ingredient.

The composition includes a pharmaceutical composition or a food composition.

The infertility may be female infertility.

The female infertility is associated with non-implantation of the ovum, female infertility associated with anovulation, female infertility of tubal origin, and congenital abnormalities in the uterine tube (Associated with congenital anomaly of tube), Tubal block, Tubal occlusion, Tubal stenosis, Female infertility of uterine origin, Associated with congenital anomaly of uterus, Female infertility of cervical origin, Female infertility associated with male factors, and other factors It may be one or more selected from the group consisting of Female infertility of other origin and Female infertility, unspecified, but is not limited thereto.

In the present invention, the "Nonimplantation of ovum" is a representative cause of female infertility. When implanting, the fertilized egg moves through the cell division, enters the uterus, and when it reaches the blastocyst stage, it is buried in the endometrium, so it becomes implanted when the thickness of the endometrium to be implanted by the embryo is insufficient or due to damage. It is difficult and is often miscarried when there is insufficient space due to adhesion of the uterine wall. Endometrial adhesion due to intrauterine inflammation caused by natural abortion, mooring abortion, abortion, endometritis, pelvic tuberculosis, and intrauterine devices, or immunological hypersensitivity to endometrial deformity or endometrium due to uterine fibroid polyps If this occurs or the endometrial formation is incomplete due to congenital uterine malformation hormone secretion, implantation disorder occurs. Implantation of oocytes has been cited as the biggest cause of artificial insemination and in vitro failure.

Since the pharmaceutical composition or food composition includes a pharmaceutical formulation or a food formulation comprising FGF2 as an active ingredient, the contents overlapped with the above-described composition of the present invention may be excessively described by the description of the duplicate contents. The description is omitted to avoid complexity.

The present invention also provides a method of improving the proliferation ability of endometrial cells using the composition comprising the FGF2.

The present invention also provides a method of alleviating endoplasmic reticulum stress by using a composition comprising the FGF2.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as limited by these examples. Therefore, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Example

<Experiment method>

Laboratory animals and cell culture

The bovine endometrial cell line (BEND) was purchased from the American Type Culture Collection and used to derive from the normal endometrium of cows on day 14 of the estrus cycle. For monolayer culture of bovine endometrial cells, 10% fetal bovine serum (FBS) and 10% horse serum, 0.034 in medium mixed 1:1 with Ham's F12 and Eagle's minimal essential medium g/L D-valine was used by mixing together. For each assay, endometrial cells of bovine cultured in vitro were cultured in starvation for 24 hours under serum exclusion conditions, and then cultured in a medium to which various FGF2 was added.

Experimental material

Candidate composition, FGF2, was purchased from R&D systems and used to confirm the signaling mechanism by FGF2, phospho-AKT, ERK1/2, P70S6K, JNK, S6, P38, Cyclin D1 protein and total-AKT, ERK1/ 2, P70S6K, JNK, S6, P38, Cyclin D1 protein was purchased from Cell Signaling Techonology. In addition, to investigate the effects of inhibiting the target signaling process, PI3K inhibitor wortmannin was purchased from Cell Signaling Technology, ERK1/2 inhibitor U0126, and JNK inhibitor SP600125 was purchased from Enzo Life Science.

Cell proliferation analysis

Endometrial cells were cultured by dispensing endometrial cells in a 96-well plate at 3×10 ³ cells/well, followed by starvation by incubating with serum-free DME/F12 1:1 medium for 24 hours, and then treating useful substances for 48 hours. And incubated for 2 hours by adding 10 μM BrdU, treated with fixdenat solution for 30 minutes at room temperature, treated with Anti-BrdU-POD solution for 90 minutes, washed 3 times with 1X wash buffer, and then put substrate ( Cell Proliferation Cell proliferation was confirmed using ELISA, BrdU kit, Cat No. 11647229001, Roche) Epoch microplate reader (BioTek) equipment.

Immunofluorescence

3×10 ⁴ endometrial epithelial cells with 300 μl of serum-free Ham's F12 and Eagle's minimal essential medium 1:1 mixed medium containing 10% FBS (catalog number: 100350, SPL Life Science, Republic of Korea) ), and then cultured for 24 hours FBS starvation, treated with 50 ng of fibroblast growth factor 2 for 60 minutes, and then fixed with cells for 10 minutes with methanol, PCNA diluted 1:200, p- Cyclin D1 antibody was treated and rabbit IgG was treated as a control group and incubated at 4°C for 16 hours. Subsequently, after washing twice with PBS containing 0.1% BSA (bovine serum albumin), the secondary antibody was goat anti-rabbit IgG Alexa 488 (catalog number: A-11008, Invitrogen, Carlsbad, CA, USA) Was diluted 1:200 in antibody dilution buffer and incubated at room temperature for 1 hour. The endometrial epithelial cells were washed with 0.1% BSA-PBS, and then DAPI staining was additionally performed to simultaneously observe the target protein in the cell as well as the nucleus. After the experiment was completed, cells were observed and photographed using a confocal microscope of LSM710 (Carl Zeiss, Thornwood, NY, USA).

Protein expression analysis (Western Blot)

Proteins were quantified by Bradford protein assay (Bio-Rad, Hercules, CA, USA) by treating endometrial epithelial cells with a mixture of FGF2 or a cell signaling inhibitor and then extracting the whole protein from the cells. Subsequently, the extracted protein was denatured at 95°C for 5 minutes, electrophoresis was performed using a 10% SDS/PAGE gel, and then transferred to a nitrocellulose membrane, followed by incubation of the primary and secondary antibodies, followed by chemiluminescence detection (SuperSignal West). Pico, Pierce, Rockford, IL, USA) using a ChemiDoc EQ system using a reagent and a Quantity One software (Bio-Rad) instrument to confirm the expression of the target protein, normalizing the amount of phosphorylated protein with the total target protein amount Analysis.

Cell cycle analysis

The endometrial epithelial cells were cultured in a 6-well plate, followed by starvation for 24 hours with serum-free Ham's F12 and Eagle's minimal essential medium 1:1 mixed medium, and concentration-dependent FGF2 treatment to incubate for 48 hours. Collect by centrifugation, wash cells twice with 0.1% BSA-PBS, fix the cells for 24 hours at 4°C with 70% ethanol, then collect cells by centrifugation and wash cells twice with 0.1% BSA-PBS Give and stain with RNase A (Sigma-Aldrich) propidium iodide (PI; BD Biosciences, Franklin Lakes, NJ, USA) containing 100 μg/mL for 30 minutes, and then use a Cytometer (BD Biosciences) Fluorescence was measured, and changes in each cell cycle were observed.

Statistical analysis

The results of this experiment were calculated using the statistical program of SAS (statistical analysis system) and the standard error was calculated, and one-way ANOVA was performed. Significance tests were performed at the P <0.05 level.

<Results and Discussion>

FGF2 Endometrial epithelial cells Effect on cell proliferation

As a result of conducting a cell proliferation assay by treating FGF2 on bovine endometrial cells, it was confirmed that the proliferation of endometrial epithelial cells increased from 50 ng to 155% in proportion to the throughput of FGF2. It was confirmed that there is no. In addition, the cell proliferation factor PCNA was confirmed by staining endometrial epithelial cells by immunofluorescence technique, and it was confirmed that the expression was induced by FGF2 (FIG. 1).

FGF2 Endometrial epithelial cells Effect on cell cycle

As a result of performing cell cycle assay by treating 0-50 ng of FGF2 to determine how FGF2 affects the cell cycle of endometrial epithelial cells, the G2/M phase, which was 46.05% from 0 ng, was processed from 50 ng to 55.35%. It was increased in proportion to, and it was confirmed that the cell proliferation was accelerated. In addition, the cell cycle factor Cyclin D1 was confirmed by staining endometrial epithelial cells by immunofluorescence technique, and it was confirmed that the expression was induced by FGF2 (FIG. 2 ).

FGF2 Cattle following dose-dependent administration Endometrial epithelial cells Analysis of changes in my signal transmission mechanism

Phosphorylation pattern of AKT, ERK1/2, P70S6K, JNK, S6, P38, Cyclin D1 proteins, which are the main signaling mediators of PI3K and MAPK signaling processes by extracting endometrial epithelial cells protein administered with 0-50ng concentration of FGF2 As a result, it was confirmed that when FGF2 was incubated, it increased to 13-fold, 2-fold, 3-fold, 2.2-fold, 2.6-fold, 5.1-fold, and 1.8-fold, respectively, compared to the control group (FIG. 3).

Functional analysis of fibroblast growth factor 2 by regulation of PI3K/AKT and MAPK signaling mechanisms

In order to confirm the mode of regulation of PI3K and MAPK mechanisms by FGF2 in bovine endometrial epithelial cells, treatment with PI3K inhibitors wortmannin, ERK1/2 inhibitors U0126, and JNK inhibitor SP600125 with fibroblast growth factor 2 results from FGF2. It was confirmed that the cell proliferation of endometrial epithelial cells increased again. In addition, it was confirmed that phosphorylation of the activated AKT, ERK1/2, P70S6K, JNK, S6, and Cyclin D1 proteins decreases. Through these results, it was confirmed that FGF2 induces cell proliferation through PI3K and MAPK signaling pathways in bovine endometrial epithelial cells (FIG. 4 ).

Inhibition of the effect of fibroblast growth factor 2 through inhibition of fibroblast growth factor receptor

In order to confirm that the signaling mechanism in endometrial epithelial cells is due to the fibroblast growth factor receptor, BGJ398, an inhibitor of the fibroblast growth factor receptor, was treated with endometrial epithelial cells and then treated with 50 ng of FGF2, resulting in an increase in uterus by FGF2. It was confirmed that the cell proliferation of endometrial cells decreased again. In addition, the phosphorylation patterns of AKT, ERK1/2, P70S6K, JNK, S6, and Cyclin D1 proteins, the major signaling mediators before PI3K and MAPK signaling, were also increased compared to the control group when 50 ng of FGF2 was incubated alone, but BGJ398 When it was treated with, it was suppressed, and it was confirmed that FGF2 regulates the signaling pathway and cell proliferation in endometrial epithelial cells through the fibroblast growth factor receptor (FIG. 5).

FGF2 Endometrial epithelial cells Analysis of the effect on vesicle stress

As a result of treatment with tunicamycin, a endoplasmic reticulum stress inducer, for endometrial epithelial cells, cell proliferation of bovine endometrial epithelial cells was confirmed to decrease, and when treated with the tunicamycin and FGF2 mixture, It was confirmed that the cell proliferation was alleviated again. It was confirmed that the expression level of Cyclin D1 also decreased when treated with tunicamycin, but increased again when the mixture of tunicamycin and FGF2 was treated. Expression of non-fold protein-related proteins IRE1α, ATF6α, p-PERK, p-eIF2α, and GRP78 expressed when vesicle stress is induced increases when tunicamycin is treated alone, while tunicamycin and FGF2 mixtures are treated. It was confirmed to be relieved if it was done. Through this, it was confirmed that FGF2 reduces vesicle stress in bovine endometrial epithelial cells and inhibits apoptosis (FIG. 6 ).

Claims (10)

delete delete delete delete delete delete delete delete A method of improving the proliferation ability of endometrial cells derived from mammals other than humans by using a composition comprising FGF2 (Fibroblast growth factor 2) as an active ingredient. A vesicle stress-inducing protein selected from the group consisting of IRE1α, ATF6α, p-PERK, p-eIF2α and GRP78 in endometrial cells derived from mammals except humans using a composition containing FGF2 (Fibroblast growth factor 2) as an active ingredient. How to reduce the expression of.

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