Use of mevalonic acid in the manufacture of a medicament for improving early embryonic development of aged oocytes

Abstract

The present invention provides a use of mevalonic acid in the manufacture of a drug for improving early embryonic development of aged oocytes, which belongs to the field of biomedicine technology. Through experimental research, the present invention has found that mevalonic acid can be used to improve the fertilization rate, two-cell formation rate and good-quality blastocyst formation rate of aged oocytes, thereby improving the development process of early embryos, providing a new idea and method for infertility treatment.

Description

[Technical field]

[0001] The present invention belongs to the field of biomedicine technology, specifically, to the use of mevalonic acid in the manufacture of a medicament for improving early embryonic development of aged oocytes. [Background technology]

[0002] The medical definition of infertility is the failure to conceive without any contraceptive measures for more than a year, with a normal sex life, and no successful pregnancy. Infertility is mainly divided into primary infertility and secondary infertility. Primary infertility is when a couple has never conceived, and secondary infertility is when a couple has conceived once and then becomes infertile again. Infertility is a common problem, affecting at least 10-15% of couples of childbearing age. The main causes of infertility are ovulation disorders, semen abnormalities, fallopian tube abnormalities, unexplained infertility, endometriosis and other immunological infertility, in that order. Other causes include cervical factors such as cervical stenosis, which accounts for more than 5% of all cervical factors. The main causes of female infertility are ovulation disorders, fallopian tube factors, and endometrial receptivity abnormalities. The main causes of male infertility are sperm abnormalities and ejaculation disorders. Compared to younger women, women over 35 years of age have a lower quality of oocytes, and a higher risk of infertility, miscarriage, and stillbirth. In particular, the clinical pregnancy rate of in vitro fertilization (IVF) is less than 20% for women over 40 years old. The decline in oocyte quality and the decline in fertilization rate and good-quality blastocyst formation rate in older women are the main causes of the decline in pregnancy rate and increase in miscarriage. Currently, there is a lack of effective methods to improve the oocyte fertilization rate and good-quality blastocyst formation rate in older patients.

[0003] The mevalonate pathway is a metabolic pathway that synthesizes cholesterol and isoprenoids using acetyl A as a raw material, and plays an important role in human health and disease. Cholesterol itself can not only control the fluidity of cell membranes and regulate gene transcription, but also synthesize steroid hormones as a precursor molecule. In addition, the mevalonate pathway contains a series of important metabolic intermediates, such as farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP), which modify proteins by isoprenylation and exert important regulatory effects on cellular functions. Furthermore, recent studies have shown that mevalonic acid (MVA), an important metabolic intermediate of the mevalonate pathway, not only serves as a precursor for the synthesis of cholesterol and isoprenoids, but also activates the IGF1-R and mTOR signaling pathways and performs epigenetic modifications via histone function. Patent CN202110273233.9 discloses the use of geranylgeraniol (GGOH) or farnesol (FOH) in improving the quality and meiotic progression of aged ovarian oocytes, which can improve the meiotic progression of aged oocytes, but GGOH needs to be dissolved in an organic solvent, which may increase the risk of in vitro culture medium addition.

[0004] Mevalonate supplementation can improve intracellular cholesterol content, increase protein isoprenylation modification, and improve epigenetic modifications, but the improving effects of mevalonate on the fertilization and embryo development process of aged oocytes have not yet been reported. Summary of the Invention [Problem to be solved by the invention]

[0005] In view of the above deficiencies, the present invention provides the use of mevalonic acid (MVA) in the manufacture of a drug for improving the early embryonic development of aged oocytes. Through experiments, the present invention has discovered that mevalonic acid has the effect of improving the fertilization rate, two-cell formation rate, and good-quality blastocyst formation rate of aged oocytes, improving the developmental process of early embryos, and proposing a new approach and method for infertility treatment. [Means for solving the problem]

[0006] In order to achieve the above object of the invention, the following technical proposal of the present invention is proposed.

[0007] According to one aspect, the present invention provides the use of mevalonic acid in the manufacture of a medicament for improving early embryonic development of aged oocytes.

[0008] Specifically, the chemical formula of mevalonic acid is: As shown in JPEG2025512571000002.jpg3159.

[0009] According to another aspect, the present invention provides the use of mevalonic acid in the manufacture of a medicament for improving the fertilization rate, the two-cell formation rate and / or the good quality blastocyst formation rate of aged oocytes.

[0010] Specifically, the chemical formula of mevalonic acid is: As shown in JPEG2025512571000003.jpg3159.

[0011] According to another aspect, the present invention provides a drug for improving early embryonic development of an aged oocyte, the drug comprising mevalonic acid.

[0012] Specifically, the chemical formula of mevalonic acid is: As shown in JPEG2025512571000004.jpg3159.

[0013] Specifically, the concentration of the mevalonic acid is 10 to 100 μmol / L, and preferably 50 μmol / L.

[0014] In particular, the medicament further comprises an optional pharma- ceutically acceptable carrier.

[0015] More specifically, the pharma- ceutically acceptable carrier includes, but is not limited to, a diluent, an excipient, a filler, a wetting agent, a disintegrant, a flavoring agent, and an adhesive. Effect of the Invention

[0016] Compared with the prior art, the positive and beneficial effects of the present invention are as follows:

[0017] 1. Through experimental research, the present invention has discovered that mevalonate can be used to improve the fertilization rate, two-cell formation rate and high-quality blastocyst formation rate of aged oocytes, thereby improving the development process of early embryos, providing a new concept and method for infertility treatment. [Brief description of the drawings]

[0018] [Figure 1] FIG. 1 shows the results of the fertilization medium supplemented with MVA improving the two-cell formation rate of aged oocytes. [Diagram 2] This shows the results that embryo medium containing MVA improves the rate of high-quality blastocyst formation from aged oocytes. [Diagram 3] FIG. 1 shows the results of safety evaluation of offspring mice after transfer of MVA-treated blastocysts. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The present invention will be described in more detail below with reference to specific examples. The following examples are not intended to limit the present invention, but are used as examples to illustrate the present invention. Unless otherwise specified, the experimental methods used in the following examples generally follow normal conditions for those experimental methods for which no specific conditions are specified in the examples, and the materials, reagents, etc. used in the following examples are all commercially available unless otherwise specified.

[0020] Example 1. Improvement of fertilization rate, two-cell and good-quality blastocyst formation rate of aged oocytes by mevalonic acid (MVA) 1) Fertilization medium containing 50 μmol / L MVA and embryo medium containing 50 μmol / L MVA were prepared under sterile conditions according to the following compositions.

[0021] Table 1 JPEG2025512571000005.jpg56156

[0022] Table 2 JPEG2025512571000006.jpg55156

[0023] 2) Epididymides were harvested from 8-week-old C57BL / 6 male mice, transferred to a capacitation drip (G-IVF Plus), sperm were released using microscissors, and capacitation was performed for 1 hour.

[0024] 3) 10-month-old C57BL / 6 female mice were intraperitoneally injected with 10 IU PMSG, and 48 h later, 10 IU HCG was intraperitoneally injected. 13 h later, the ovaries and oviducts were separated from the M2 medium, the ampulla of the oviduct was broken using a microscope forceps to release the cumulus mucus mass, and the mucus mass was transferred to fertilization medium containing 50 μmol / L MVA covered with mineral oil, and sperm were added. The mice were incubated at 37°C, 5% CO 2 The cells were cultured in an incubator.

[0025] 4) Four hours after fertilization in fertilization medium containing 50 μmol / L MVA, the sperm around the fertilized eggs were washed using a mouth pipette and then transferred to embryo medium containing 50 μmol / L MVA. The fertilization rate was calculated after 2 hours, and the two-cell formation rate was calculated after 14 hours. The results are shown in Figure 1.

[0026] 5) The development of the embryos was observed, and the rate of good quality blastocyst formation was statistically calculated after 84 hours of culture. The results are shown in Figure 2.

[0027] 6) After selecting and transferring good quality blastocysts, a safety evaluation was performed, and the results are shown in Figure 3.

[0028] As can be seen from Figure 1 and Figure 2, compared with the control group, the addition of mevalonic acid (MVA) to the fertilization medium and embryo medium could significantly improve the two-cell and good-quality blastocyst formation rates of aged oocytes. As can be seen from Figure 3, MVA treatment did not affect the offspring safety. Therefore, MVA can be used to manufacture drugs to improve the two-cell formation rate and good-quality blastocyst formation rate of aged oocytes.

[0029] The above examples are merely representative of several embodiments of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the patent scope of the present invention. It should be noted that those skilled in the art can make some modifications and improvements without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the attached claims.

Claims

1. Use of mevalonic acid in the manufacture of a medicament for improving early embryonic development of aged oocytes.

2. The chemical formula of mevalonic acid is:

2. The use according to claim 1, characterized in that it is as shown in

3. Use of mevalonic acid in the manufacture of a medicament for improving the fertilization rate, two-cell formation rate and / or good quality blastocyst formation rate of aged oocytes.

4. The chemical formula of mevalonic acid is:

4. The use according to claim 3, characterized in that it is as shown in

5. A drug for improving early embryonic development of aged oocytes, comprising mevalonic acid.

6. The chemical formula of mevalonic acid is: The drug according to claim 5, characterized in that it is as shown in

7. The drug according to claim 5, characterized in that the concentration of the mevalonic acid is 10 to 100 μmol / L.

8. The drug according to claim 7, characterized in that the concentration of the mevalonic acid is 50 μmol / L.

9. The drug of claim 5, further comprising an optional pharma- ceutically acceptable carrier.

10. The drug of claim 9, characterized in that the pharma- ceutically acceptable carrier includes, but is not limited to, diluents, excipients, fillers, wetting agents, disintegrants, flavoring agents and adhesives.

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