CN118845805A - Application of notoginsenoside Ft1 in promoting ovarian follicle blood supply and preparing ovulation-assisting medicament - Google Patents
Application of notoginsenoside Ft1 in promoting ovarian follicle blood supply and preparing ovulation-assisting medicament Download PDFInfo
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Abstract
The invention provides an application of notoginsenoside Ft1 in promoting ovarian follicle blood supply and preparing an auxiliary ovulation-promoting medicament; the invention proves that the notoginsenoside Ft1 can effectively promote the blood supply of ovarian follicles, can obviously improve the ovulation quantity of female mice, and can promote the angiogenesis of the follicles; when the clinical verification test of mice is carried out by injecting the notoginsenoside Ft1, the pregnancy rate and the litter size of the mice treated by the notoginsenoside Ft1 are obviously higher than those of the control group.
Description
Technical Field
The invention relates to the field of medicines, in particular to application of notoginsenoside Ft1, derivatives thereof and structural analogues thereof in the auxiliary reproduction field.
Background
The ovaries are the reproductive organs of the female mammal core and bear the great mission of discharging mature ova and reproducing offspring. As endocrine organs, the ovaries maintain endocrine homeostasis by secreting E2, P4 and other hormones through granulosa cells and mesenchymal cells, and also respond to FSH and LH secreted by the pituitary gland and transported into the ovaries through blood vessels to promote granulosa cell proliferation and maintain normal development of follicles and formation of corpus luteum. Thus, a perfect and functional vascular system in the ovary is important for the maintenance of ovarian function.
The decrease in the number of follicles with age has been considered by past studies as a major cause of ovarian aging, but it is notable that even at the end of female fertility, around 40 years old, there are tens of thousands of follicles in the ovary, much more than the number of ova required for the final offspring. One of the reasons for failure to achieve fertility at this time is that the follicle's ability to respond to hormones is reduced, resulting in failure to develop to the pre-ovulatory follicular stage.
Active angiogenesis is one of the unique features of ovaries in adult organisms, and is also an important channel for regulating blood supply and hormone transport and finally regulating follicular development process. Therefore, promotion of ovarian angiogenesis in older females is expected to be a new strategy for improving ovarian aging. Meanwhile, since various angiogenesis diseases such as tumors, rheumatoid arthritis, diabetic retinopathy and the like can generate excessive angiogenesis, safe and effective medicaments for promoting angiogenesis still remain to be developed.
Along with the development of social economy, the human life rhythm is gradually accelerated, so that the female fertility age is gradually delayed. In addition, endocrine disorders caused by ovarian aging also present health hazards to the woman themselves. Meanwhile, the auxiliary reproductive strategy commonly used in clinic at present is in vitro fertilization, and for advanced women, the success rate is low, and the repeated ovum taking brings great pain to the body and mind of a patient, so that a new method for promoting the development of the follicle of the advanced women in vivo and improving the fertility is urgent to develop.
Notoginseng radix saponin Ft1 (Notoginsenoside Ft 1) was found in 2006 to be a novel saponin extracted from leaves of Notoginseng radix with CAS number 80418-24-2. The notoginsenoside Ft1 has the function of promoting endothelial cell proliferation more effectively than other saponins in pseudo-ginseng, such as notoginsenoside R1, ginsenoside Rb1 and Re. Studies show that Ft1 promotes angiogenesis by promoting transfer of hypoxia inducible factor Hif1α from cytoplasm to nucleus and promoting binding of Hif1α to Vegfa promoter, thereby increasing Vegfa transcription level. In addition, PI3K/AKT/mTOR and Raf/MEK/ERK signaling pathways are involved in Ft1 regulation of angiogenesis. The chemical formula is as follows:
。
Although the prior art has a certain research progress on the notoginsenoside Ft1, the application of the notoginsenoside Ft1 in preparing medicaments for treating the Parkinson disease is disclosed in CN 107625778A; CN115317496a discloses the application of ginsenoside Rg3, notoginsenoside Ft1 and their composition in preparing medicine for treating prostatic hyperplasia; CN115252631a discloses that notoginsenoside Fc and notoginsenoside Ft1 can be applied to the preparation of a medicament for treating diabetic nephropathy; CN108014118a discloses that notoginsenoside Ft1 is used as an active ingredient for preparing a TGR5 agonist, and is used for preparing a medicine or health food for preventing and/or treating diseases of abnormal glucose metabolism, abnormal lipid metabolism or/and abnormal insulin sensitivity; CN104771408a discloses the use of notoginsenoside Ft1, prodrug and pharmaceutically acceptable salt or plant extract containing notoginsenoside Ft1 in preparing medicament or health care product for preventing or treating ulcerative colitis; CN103908459a discloses that notoginsenoside Ft1 can be used for preventing and treating various hemorrhagic diseases such as platelet dysfunction and coagulation dysfunction; CN107625778a discloses the application of compound notoginsenoside Ft1 in the preparation of medicament for treating parkinson's disease PD. In the above prior art disclosures, although the therapeutic or adjuvant therapeutic effect of notoginsenoside Ft1 on various disease types and mechanisms is disclosed, the prior art has not studied notoginsenoside Ft1 on ovary and adjuvant reproduction, improving ovarian function. It is still unknown how notoginsenoside Ft1 affects the reproductive function of the ovaries and follicular development.
Disclosure of Invention
In view of the above, the present invention aims to provide a new application of notoginsenoside Ft1 (C 47H80O17), specifically, an application of notoginsenoside Ft1 as an agent for improving blood supply of ovary, improving ovulation efficiency, and/or improving ovarian function, improving female reproductive health and female fertility. The chemical formula of the notoginsenoside Ft1 is as follows:
。
The invention provides an application of notoginsenoside Ft1 in preparing medicines for improving ovarian function, female fertility and female health; in a preferred embodiment, the improving ovarian function comprises: promote the angiogenesis of ovarian follicles and enhance the blood supply of ovaries.
In another specific embodiment, said increasing fertility comprises increasing pregnancy rate of an older female and birth rate of a offspring.
The invention also aims to provide the application of the notoginsenoside Ft1 in the preparation of related methods of the assisted ovulation-promoting drugs, and in a preferred embodiment, the assisted ovulation-promoting drugs comprise increasing the number of oocytes after superovulation.
In some embodiments of the invention, pseudo-ginseng saponin Ft1 is taken as an experimental object, and is verified to have the effects of enhancing the supply of ovarian blood vessels, improving the functions of the ovaries of senior females and improving fertility. Meanwhile, it is verified that the notoginsenoside Ft1 can assist in ovulation promotion and improve the ovulation efficiency. The Panax notoginsenosides do not have the above-mentioned functions.
Specifically, the technical scheme provided by the invention comprises the following steps: provides an application of notoginsenoside Ft1 in preparing medicines for improving ovarian function, female fertility and female reproductive health. Further, improving fertility includes increasing the ovulation rate of young females and increasing the pregnancy rate and litter size of older females.
In another aspect, the invention provides the use of notoginsenoside Ft1 in the manufacture of a medicament for promoting ovarian fertility in adolescent or senior mammals, preferably in mice or primates, preferably in mice, rats or humans.
On the other hand, the invention provides the application of the notoginsenoside Ft1 in preparing the fertility-improving medicaments, and preferably, the fertility improvement particularly improves the pregnancy rate of the senior females and the birth rate of offspring.
In another aspect, the invention provides the use of notoginsenoside Ft1 in the manufacture of a medicament for improving ovarian function, improving female fertility and/or improving female health, preferably female reproductive health, preferably improving female fertility and reducing fertility-related disorders/afflictions.
In another aspect, there is provided the use of notoginsenoside Ft1 in the preparation of a formulation for enhancing ovarian blood supply.
In another aspect, the application of notoginsenoside Ft1 in preparing ovulation-promoting auxiliary medicines is provided.
Preferably, the ovulation-assisted stimulation comprises increasing the number of oocytes after superovulation and natural ovulation in elderly females.
More preferably, the formulation or medicament for use in the above application further comprises a pharmaceutically acceptable carrier. Preferably, the formulation or medicament in the above application further comprises pharmaceutically acceptable excipients selected from one or more of diluents, lubricants, wetting agents, emulsifiers, preservatives, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the recipient, suspending agents, solubilising agents, thickening agents, stabilizing agents, sweeteners and fragrances. Pharmaceutically acceptable excipients, including carriers or excipients, are also included.
Preferably, in the above pharmaceutical product or pharmaceutical composition and application, the notoginsenoside Ft1 is used as the only active pharmaceutical ingredient.
The beneficial effects of the invention are as follows:
1) The novel application of the natural micromolecular compound notoginsenoside Ft1 is found for the first time, in particular to the application of enhancing the blood supply of ovaries, improving the aging of the ovaries, improving the pregnancy rate of the elderly females and the birth rate of the offspring thereof, and improving the health of females.
2) The invention also discloses application of notoginsenoside Ft1 in preparing an ovulation-promoting auxiliary drug.
Drawings
FIG. 1 shows that notoginsenoside Ft1 promotes follicular angiogenesis of aged mice, and is mainly characterized in that in the process of in vitro culture of follicles, after notoginsenoside Ft1 (50 mu M) is added, the growth speed of follicular blood vessels is obviously accelerated within 24 hours, the blood vessel network construction is more dense, and the total notoginsenoside cannot promote follicular blood vessel network construction;
FIG. 2 shows that notoginsenoside Ft1 promotes follicular vascular permeability of aged mice, and is mainly shown by that in vivo injection of notoginsenoside Ft1 (50 mg/kg. BW) is carried out for one week, after tail vein injection of Evans blue for 15 minutes, the mice follicular is separated, the notoginsenoside Ft1 can significantly promote follicular vascular permeability, and the follicular vascular permeability is not significantly changed after total arasaponin treatment;
FIG. 3 shows that notoginsenoside Ft1 improves gonadotrophin ovulation promoting efficiency, and is mainly expressed as follows: after injection of notoginsenoside Ft1 (50 mg/kg.BW) into mice before puberty, superovulation treatment is carried out, the ovulation quantity of the mice is remarkably increased (A and B), the weight of the mice is not obviously changed (C), and the total notoginsenoside can not increase the ovulation quantity of the mice;
FIG. 4 shows that notoginsenoside Ft1 significantly improves fertility in aged mice, and is mainly represented by that in vivo injection of notoginsenoside Ft1 (50 mg/kg. BW) for one week, after 5 days of cage combination with male rats with normal fertility, pregnancy rate is increased (A), offspring birth number is increased (B), and pregnancy rate and offspring birth number of mice after total notoginsen treatment are not significantly different from those of control groups (A and B).
Detailed Description
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
The application of the notoginsenoside Ft1 provided by the invention in improving the ovarian aging, improving the pregnancy rate of the elderly females and the birth rate of offspring thereof and improving the female health and the application of the notoginsenoside Ft1 in preparing ovulation-promoting auxiliary medicines are further described below.
Example 1: pseudo-ginseng saponin Ft1 for promoting ovarian angiogenesis
Reagent 1: DMSO (DMSO)
Reagent 2: notoginseng radix total saponins
Reagent 3: notoginseng radix saponin Ft1 (powder)
The reagent can be used for respectively packaging the total arasaponin, the arasaponin Ft1 and the organic solvent, and when in use, the total arasaponin and the arasaponin Ft1 are dissolved in the DMSO of the organic solvent to prepare the working solution with the concentration of 1mM, and the working solution is placed in a refrigerator with the temperature of minus 20 ℃ to be packaged and stored in a dark place, and when in specific application, 50 mu M is adopted.
The experimental procedure was as follows:
1) Dividing the experimental mice into three groups, namely a control group, a total arasaponin group and a arasaponin Ft1 group, wherein 10 follicles of a 12-month-old Tek-Creer T2 and mTmG female mice are separated from each other;
2) The working reagent is taken out from a refrigerator at the temperature of minus 20 ℃ and placed at room temperature for being fully dissolved for use;
3) 50 mu M of notoginsenoside Ft1, notoginsenoside and DMSO with the same amount are respectively added into culture solutions of notoginsenoside group, notoginsenoside Ft1 group and control group follicles for continuous culture in vitro for 24 hours and real-time imaging;
4) After imaging, the vascular area of the follicle was calculated every 4 hours by ImageJ software and a follicular blood vessel growth rate curve was obtained within 24 hours, and as a result, as shown in fig. 1, notoginsenoside Ft1 significantly accelerated the growth rate of the follicular blood vessel, whereas total notoginsenoside did not have this effect.
The method shows that the ovarian follicle angiogenesis can be obviously promoted after the treatment of a proper amount of notoginsenoside Ft 1. While the total saponins of pseudo-ginseng do not have the function of promoting ovarian follicle angiogenesis under the same concentration.
Example 2: notoginseng radix saponin Ft1 for improving ovary blood supply
Reagent 1: DMSO (DMSO)
Reagent 2: notoginseng radix total saponin (powder)
Reagent 3: notoginseng radix saponin Ft1 (powder)
The reagent can be used for respectively packaging the notoginsenoside Ft1 and the organic solvent, and when in use, the notoginsenoside Ft1 is dissolved in the DMSO of the organic solvent to prepare working solution with the concentration of 20-40 mg/ml, and the working solution is placed in a refrigerator with the temperature of minus 20 ℃ to be packaged and stored in a dark place, and when in specific application, 10 mg/ml is adopted.
The experimental procedure was as follows:
1) Dividing the experimental mice into three groups, namely a control group, a total arasaponin group and a arasaponin Ft1 group, wherein each group comprises 5 ICR background female mice of 12 months old;
2) The working reagent is taken out from a refrigerator at the temperature of minus 20 ℃ and placed at room temperature for being fully dissolved for use;
3) The medicine is processed by intraperitoneal injection, the dosage is 50 mg/kg.BW, and the medicine is administered once a day for 1 week;
4) Following drug treatment, the health status of the experimental mice was determined by weighing the mice at regular intervals. When the weight of the tested mice is kept unchanged or the weight of the tested mice increases at a low speed, the condition of the tested mice is good, and if the weight of the tested mice is obviously reduced, the dosage of the drug can be moderately reduced;
5) After 1 week of drug treatment, mice were given tail vein injection of evans blue (0.05 mg/kg. Bw), ovaries were harvested after 15 minutes and individual follicles were isolated, the morphology of the follicles was recorded under a fluorescence microscope and the fluorescence intensity was counted, and the results showed that notoginsenoside Ft1 significantly improved blood supply to the follicles of aged mice, whereas total notoginsenoside did not have the above efficacy (fig. 2).
The results show that the blood supply of the follicles can be obviously improved after the treatment of a proper amount of notoginsenoside Ft1, so that the working efficiency of the medicines beneficial to follicular development such as gonadotrophin is improved, and further follicular development is promoted.
Example 3: pseudo-ginseng saponin Ft1 improves superovulation efficiency of young mice
Reagent 1: DMSO (DMSO)
Reagent 2: notoginseng radix total saponin (powder)
Reagent 3: notoginseng radix saponin Ft1 (powder)
The reagent can be used for respectively packaging the total arasaponin, the arasaponin Ft1 and the organic solvent, and when in use, the total arasaponin and the arasaponin Ft1 are dissolved in the DMSO of the organic solvent to prepare working solution with the concentration of 20-40 mg/ml, and the working solution is placed in a refrigerator with the temperature of minus 20 ℃ to be packaged and stored in a dark place, and when in specific application, 10 mg/ml is adopted.
The experimental procedure was as follows:
1) Dividing the experimental mice into three groups, namely a control group, a total arasaponin group and a arasaponin Ft1 group, wherein each group comprises 5 ICR background female mice in 23 days;
2) The working reagent is taken out from a refrigerator at the temperature of minus 20 ℃ and placed at room temperature for being fully dissolved for use;
3) The medicine is processed by intraperitoneal injection, the dosage is 50 mg/kg.BW, and the medicine is administered once a day for 1 week; after stopping the medicine, performing superovulation, namely, administration of gonadotrophin (0.5 IU/g), administration of human chorionic gonadotrophin (0.5 IU/g) after 46 hours, and collection of oviduct and ampulla oocyte of the mice after 16 hours for morphological detection and counting statistics;
4) The results showed that after mice were injected with notoginsenoside Ft1 (50 mg/kg. BW), the number of ovulations in the mice was increased by about 38.04% by superovulation treatment (FIGS. 3A, 3B, mean 20.25/31.75), and that there was no significant change in the weight of the mice (FIG. 3C), while after total notoginsenoside treatment, the number of ovulations in the mice was not significantly increased (FIGS. 3A, 3B, mean 20.25/23.00);
The results show that after the treatment of notoginsenoside Ft1, the ovulation number of the mice is remarkably increased, the follicular cell morphology is normal, the weight of the mice is not obviously different from that of a control group, and the total notoginsenoside has no effect.
The results show that the proper amount of notoginsenoside Ft1 can obviously improve the ovulation promoting efficiency of young mice.
Example 4: pseudo-ginseng saponin Ft1 for improving pregnancy rate and litter size of aged mice
Reagent 1: DMSO (DMSO)
Reagent 2: notoginseng radix total saponin (powder)
Reagent 3: notoginseng radix saponin Ft1 (powder)
The reagent can be used for respectively packaging the total arasaponin, the arasaponin Ft1 and the organic solvent, and when in use, the total arasaponin and the arasaponin Ft1 are dissolved in the DMSO of the organic solvent to prepare working solution with the concentration of 20-40 mg/ml, and the working solution is placed in a refrigerator with the temperature of minus 20 ℃ to be packaged and stored in a dark place, and when in specific application, 10 mg/ml is adopted.
The experimental procedure was as follows:
1) Dividing the experimental mice into three groups, namely a control group of arasaponin group and a arasaponin Ft1 group, wherein each group comprises 5 ICR background female mice of 12 months old;
2) The working reagent is taken out from a refrigerator at the temperature of minus 20 ℃ and placed at room temperature for being fully dissolved for use;
3) The medicine is processed by the intraperitoneal injection, the administration dosage is 50 mg/kg.BW, and the administration is carried out once a day for 1 week; after stopping the drug, the mice are put in a cage with healthy male mice for 5 days (an oestrus period), and the pregnancy and farrowing conditions of the mice are monitored and recorded;
4) The results are shown in Table 1:
TABLE 1 pregnancy rate and litter size in mice after intraperitoneal injection treatment
Compared with the control group, the pregnancy rate and the litter size of the notoginsenoside Ft1 group mice are significantly increased, while the total notoginsenoside does not have the effect (fig. 4 and table 1). The average pregnancy rate was increased by about 81.48% (fig. 4A), the birth number of offspring was increased by about 255.56% (fig. 4B), and the pregnancy rate and the birth number of offspring were not significantly different from those of the control group after the treatment with total saponins of panax notoginseng.
Namely, the pregnancy rate and the litter size of the mice in the group of notoginsenoside Ft1 are obviously increased, and the total notoginsenoside does not have the effect.
The result shows that the appropriate amount of notoginsenoside Ft1 can obviously improve the reproductive capacity of the aged female mammal, improve the pregnancy rate and the birth number of offspring, and improve reproductive aging.
Conclusion of experiment: the invention adopts the notoginsenoside Ft1, the molecular structural formula of which is C 47H80O17, and through in vitro culture and in vivo injection, the treatment of the notoginsenoside Ft1 can obviously improve the ovulation quantity of female mice and promote the angiogenesis of follicles. The results prove that the notoginsenoside Ft1 is involved in the physiological process related to follicular angiogenesis and follicular development and ovulation.
Further selecting adolescent mice and senior mice, and performing related exploration on the influence of notoginsenoside Ft1 on the fertility of the ovary by adopting an intraperitoneal injection mode.
When clinical trials of mice were carried out using adolescent mice, the number of ovulations of mice treated with notoginsenoside Ft1 was found to be significantly higher than that of the control group. When the clinical verification test of mice is carried out by using the aged mice, the pregnancy rate and the litter size of the mice treated by the notoginsenoside Ft1 are obviously higher than those of the control group.
In the specific embodiment of the invention, the comparison test is related, and each test group has identical test environment, raw materials and the like except due differences.
Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention. While the processing strategies and their associated applications of the present invention have been described in terms of embodiments, it will be apparent to those skilled in the relevant art that the processing strategies and their associated applications of the present invention can be modified or appropriately adapted and combined to implement and utilize the techniques of the present invention without departing from the spirit, scope and scope of the invention.
The embodiments described above are only some, but not all, embodiments of the present invention, and other embodiments, which can be obtained by those skilled in the art without inventive effort, are within the scope of the present invention.
Claims (10)
1. Application of notoginsenoside Ft1 in preparing ovulation promoting auxiliary medicine is provided.
2. The use according to claim 1, characterized by the use of promoting ovulation in older females.
3. Use according to claim 1 or 2, characterized in that female pregnancy rate and offspring birth rate are promoted.
4. Use according to claim 1, wherein the ovulation aid is an increase in the number of post-superovulation oocyte discharges.
5. Application of notoginsenoside Ft1 in preparing medicine for promoting follicular angiogenesis and/or enhancing ovary blood supply is provided.
6. The use according to claim 5, wherein notoginsenoside Ft1 enhances female ovarian vascular supply, thereby improving advanced female ovarian function and fertility.
7. Application of notoginsenoside Ft1 in preparing medicine for improving ovary function, female fertility and female reproductive health is provided.
8. The use according to claim 7, wherein increasing fertility comprises increasing ovulation rate of young females and increasing pregnancy rate and litter size of older females.
9. The use according to any one of claims 1 to 8, wherein the medicament further comprises a pharmaceutically acceptable carrier.
10. The use of claim 9, wherein the medicament further comprises a pharmaceutically acceptable adjuvant.
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