CN115813899B - Application of mevalonate in preparation of medicines for improving early embryo development of senescent oocytes - Google Patents
Application of mevalonate in preparation of medicines for improving early embryo development of senescent oocytes Download PDFInfo
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A40/00—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production
- Y02A40/80—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production in fisheries management
- Y02A40/81—Aquaculture, e.g. of fish
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
The invention provides an application of mevalonate in preparing a medicament for improving early embryo development of senescent oocytes, and belongs to the technical field of biological medicines. The invention discovers that the mevalonate can be used for improving the fertilization rate, the two-cell formation rate and the high-quality blastula formation rate of the aging oocyte through experimental study, thereby improving the development process of early embryo and providing a new thought and method for infertility treatment.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of mevalonate in preparation of a medicament for improving early embryo development of senescent oocytes.
Background
The medical science of infertility is defined as that no contraceptive measures are taken for more than one year, and the sexual life is normal without successful pregnancy, and is mainly divided into primary infertility and secondary infertility. Primary infertility is never conception; secondary infertility is infertility after once pregnant. Infertility is a common problem affecting approximately at least 10-15% of women of childbearing age. The primary etiology diagnosis of infertility is in turn: ovulation disorders, semen abnormalities, fallopian tube abnormalities, infertility of unknown origin, endometriosis and other such immunological infertility. Further factors are cervical factors, including cervical stenosis, which accounts for more than 5% of all cervical factors. Female infertility mainly refers to ovulation disorder, oviduct factors, endometrial acceptance disorder, and male infertility mainly refers to spermatogenic disorder and seminal emission disorder. Compared with young women, the oocytes of women over 35 years old have reduced quality and are more prone to risks of infertility, abortion, stillbirth and the like. Particularly women over the age of 40, have a clinical pregnancy rate of less than 20% even with IVF (in vitro infants). The reduced quality of oocytes, the low fertilization rate and the low formation rate of high quality blastula in elderly females are the main reasons for the reduced pregnancy rate and the increased abortion. At present, an effective means for improving the fertilization rate and the high-quality blastula formation rate of oocytes of elderly patients is lacking.
The mevalonate pathway is a metabolic pathway for synthesizing cholesterol and isoprenoids from acetyl-coa, and plays a key role in human health and disease. Cholesterol itself can regulate cell membrane fluidity, regulate gene transcription, and synthesize steroid hormones as precursor molecules. Meanwhile, there are a series of important metabolic intermediates in the mevalonate pathway, such as farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP), which exert important regulatory effects on cell function by prenylation modification of proteins. In addition, recent studies have shown that Mevalonate (MVA), a key metabolic intermediate of the mevalonate pathway, can itself activate IGF1-R and mTOR signaling pathways and be epigenetic modified by mediating histone function, in addition to being a synthetic precursor to cholesterol and isoprenoids. Patent CN202110273233.9 discloses the use of geranylgeraniol (GGOH) or Farnesol (FOH) for improving the quality and meiosis process of senescent oocysts, which can improve the meiosis process of senescent oocysts, whereas GGOH needs to be dissolved in organic solvents, increasing the risk of in vitro medium addition.
The supplementation of mevalonate can improve intracellular cholesterol levels, increase protein prenylation modifications, and improve epigenetic modifications, however the effect of mevalonate on the improvement of fertilisation of senescent oocytes and embryo development processes has not been reported.
Disclosure of Invention
In order to overcome the defects, the invention provides application of mevalonate dihydroxy acid (MVA) in preparing medicines for improving early embryo development of senescent oocytes. Experiments show that the mevalonate can be used for improving the fertilization rate, the two-cell formation rate and the high-quality blastula formation rate of the aged oocyte, so that the development process of early embryo is improved, and a new thought and method are provided for infertility treatment.
In order to achieve the above object, the present invention has the following technical scheme:
in one aspect, the invention provides the use of mevalonate for the preparation of a medicament for improving early embryo development of senescent oocytes.
Specifically, the chemical formula of the mevalonate is shown as follows:
in another aspect, the invention provides the use of mevalonate for the preparation of a medicament for improving the fertilization rate, the two-cell formation rate and/or the high quality blastocyst formation rate of an senescent oocyte.
Specifically, the chemical formula of the mevalonate is shown as follows:
in yet another aspect, the invention provides a medicament for improving early embryo development of an aging oocyte, the medicament including mevalonate.
Specifically, the chemical formula of the mevalonate is shown as follows:
specifically, the concentration of the mevalonate is 10-100. Mu. Mol/L, preferably 50. Mu. Mol/L.
Specifically, the medicament further comprises an optional pharmaceutically acceptable carrier.
Further specifically, the pharmaceutically acceptable carrier includes, but is not limited to: diluents, excipients, fillers, wetting agents, disintegrants, flavoring agents and binders.
Compared with the prior art, the invention has the following positive and beneficial effects:
the invention discovers that the mevalonate can be used for improving the fertilization rate, the two-cell formation rate and the high-quality blastula formation rate of the aging oocyte through experimental study, thereby improving the development process of early embryo and providing a new thought and method for infertility treatment.
Drawings
Fig. 1: results of improving the two cell formation rate of senescent oocytes by adding a fertilization medium of MVA;
fig. 2: results of improving the high-quality blastula formation rate of senescent oocytes by adding an embryo culture medium of MVA;
fig. 3: results of safety evaluation of mice after blastocyst transplantation by MVA treatment.
Detailed Description
The present invention will be described in further detail with reference to the following examples, which are not intended to limit the present invention, but are merely illustrative of the present invention. The experimental methods used in the following examples are not specifically described, but the experimental methods in which specific conditions are not specified in the examples are generally carried out under conventional conditions, and the materials, reagents, etc. used in the following examples are commercially available unless otherwise specified.
EXAMPLE 1 Mevalonate (MVA) improves the fertilization rate of senescent oocytes, the rate of two-cell and quality blastocyst formation
1) Fertilization medium containing 50. Mu. Mol/L MVA and embryo medium containing 50. Mu. Mol/L MVA were prepared under aseptic conditions according to the following ingredients:
TABLE 1.50. Mu. Mol/L MVA fertilization Medium
TABLE 2 embryo culture Medium for 50. Mu. Mol/L MVA
2) C57BL/6 male epididymis of 8 weeks old is taken and transferred to a capacitation drop (G-IVF Plus), sperm is released by microscopic shearing, and capacitation is carried out for one hour;
3) Separating ovary and oviduct in M2 culture medium after 10IU PMSG is injected into 10IU PMSG from 10 month old C57BL/6 female mice intraperitoneally, 10IU HCG is injected into intraperitoneally after 48h, and M2 culture medium after 13h, tearing the oviduct expansion place by using micro forceps to release cumulus mucus, transferring the mucus to mineral oil covered fertilization culture medium containing 50 mu mol/L MVA, adding sperm, 37 ℃ and 5% CO 2 Culturing in an incubator;
4) After fertilization for 4 hours in fertilization medium containing 50. Mu. Mol/L MVA, sperm surrounding the fertilized eggs were washed off by using an oral pipette and transferred to embryo culture medium containing 50. Mu. Mol/L MVA, fertilization rate was counted after 2 hours, and two cell formation rate was counted after 14 hours, and the results are shown in FIG. 1.
5) The embryo development was observed, and after 84 hours of culture, the formation rate of high-quality blastula was counted, and the result is shown in FIG. 2.
6) Safety evaluation was performed after selection of high-quality blastula for transplantation, and the results are shown in fig. 3.
As can be seen from FIGS. 1 and 2, the addition of Mevalonate (MVA) to fertilization medium and embryo medium significantly improved the formation rate of senescent oocytes and quality blasts compared to the control group. As can be seen from fig. 3, MVA treatment has no impact on offspring security. Therefore, MVA can be used for preparing medicines for improving the two-cell formation rate of senescent oocytes and the formation rate of high-quality blasts.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (6)
1. The application of mevalonate in preparing a medicament for improving early embryo development of senescent oocytes is characterized in that the chemical formula of the mevalonate is shown as follows:
2. the use of mevalonate for the preparation of a medicament for improving the fertilization rate, the two-cell formation rate and/or the high-quality blastocyst formation rate of an aging oocyte, wherein the chemical formula of the mevalonate is as follows:
3. the use according to any one of claims 1 or 2, characterized in that: the concentration of the mevalonate is 10-100 mu mol/L.
4. A use according to claim 3, characterized in that: the concentration of the mevalonate is 50 mu mol/L.
5. The use according to any one of claims 1 or 2, characterized in that: the medicament further comprises an optional pharmaceutically acceptable carrier.
6. The use according to claim 5, characterized in that: such pharmaceutically acceptable carriers include, but are not limited to: diluents, excipients, fillers, wetting agents, disintegrants, flavoring agents and binders.
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| CN202211455548.6A CN115813899B (en) | 2022-11-21 | 2022-11-21 | Application of mevalonate in preparation of medicines for improving early embryo development of senescent oocytes |
| PCT/CN2023/105430 WO2024109089A1 (en) | 2022-11-21 | 2023-06-30 | Use of mevalonic acid in preparing medicament for improving early embryonic development of senescent oocytes |
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| CN202211455548.6A CN115813899B (en) | 2022-11-21 | 2022-11-21 | Application of mevalonate in preparation of medicines for improving early embryo development of senescent oocytes |
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| CN110205284A (en) * | 2019-05-27 | 2019-09-06 | 中国农业大学 | L-PROLINE is improving the application in egg mother cell early embryonic development and oxidation resistance |
| CN112675155A (en) * | 2021-03-15 | 2021-04-20 | 南京鼓楼医院 | Application of mevalonate metabolic intermediate product in preparation of medicine for improving aged ovarian oocyte quality and meiosis process |
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| DE10148266A1 (en) * | 2001-09-28 | 2003-04-17 | Beiersdorf Ag | Mevalonic acid or its lactone is used in cosmetics or dermatological compositions for treating UV skin damage or symptoms of skin-ageing |
| KR20220052965A (en) * | 2019-08-28 | 2022-04-28 | 다니스코 유에스 인크. | Skin care composition comprising mevalonolactone |
| CN115813899B (en) * | 2022-11-21 | 2023-06-16 | 南京鼓楼医院 | Application of mevalonate in preparation of medicines for improving early embryo development of senescent oocytes |
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| CN110205284A (en) * | 2019-05-27 | 2019-09-06 | 中国农业大学 | L-PROLINE is improving the application in egg mother cell early embryonic development and oxidation resistance |
| CN112675155A (en) * | 2021-03-15 | 2021-04-20 | 南京鼓楼医院 | Application of mevalonate metabolic intermediate product in preparation of medicine for improving aged ovarian oocyte quality and meiosis process |
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