CN113332375A - Application of traditional Chinese medicine composition in preparation of GPER1 receptor agonist medicine - Google Patents

Application of traditional Chinese medicine composition in preparation of GPER1 receptor agonist medicine Download PDF

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CN113332375A
CN113332375A CN202010099175.8A CN202010099175A CN113332375A CN 113332375 A CN113332375 A CN 113332375A CN 202010099175 A CN202010099175 A CN 202010099175A CN 113332375 A CN113332375 A CN 113332375A
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parts
fructus
traditional chinese
chinese medicine
medicine composition
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贾振华
吴相君
黄丹
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Shijiazhuang Yiling Pharmaceutical Co Ltd
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Shijiazhuang Yiling Pharmaceutical Co Ltd
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Abstract

The invention discloses application of a traditional Chinese medicine composition as a GPER1 receptor agonist medicine. The traditional Chinese medicine composition is prepared from the following raw material medicines in parts by weight: 150-350 parts of semen cuscutae, 100-200 parts of fructus lycii, 30-60 parts of fructus schisandrae, 20-50 parts of fructus cnidii, 20-50 parts of fructus rosae laevigatae, 20-50 parts of semen allii tuberosi, 20-50 parts of morinda officinalis, 20-50 parts of cistanche, 30-60 parts of radix rehmanniae recen, 20-50 parts of radix cyathulae, 40-100 parts of herba epimedii, 20-50 parts of raspberry, 15-35 parts of ginseng, 10-25 parts of cornu cervi pantotrichum, 15-35 parts of hippocampus and 15-35 parts of fructus toosendan. The traditional Chinese medicine composition has the same property as the positive medicine G1, and is GPER1 receptor agonist, so the traditional Chinese medicine composition can play the role of the receptor agonist, participate in gene expression of various cancer cells, activate various hormones and mediate various biological functions.

Description

Application of traditional Chinese medicine composition in preparation of GPER1 receptor agonist medicine
Technical Field
The invention relates to a new application of a traditional Chinese medicine composition, in particular to an application of the traditional Chinese medicine composition in preparing a medicine used as a GPER1 receptor agonist.
Background
The G protein coupled estrogen receptor (GPER1) is an estrogen membrane receptor which is discovered and attracted extensive attention in recent years, and unlike the classical estrogen nuclear receptor, the G protein coupled estrogen receptor can mediate the rapid non-genome effect of estrogen or indirectly participate in the regulation of gene transcription, and then influence the expression of downstream signal molecules to play the regulation role. The receptor is a transmembrane protein composed of 375 amino acids, and belongs to a G protein coupled receptor family.
GPER1 is widely distributed among the tissue cells of many systems, such as the reproductive system, circulatory system, nervous system, immune system, urinary system, and the like. Another study demonstrated that GPER1 is overexpressed in a variety of cancer tissues, including breast, endometrial, ovarian, prostate, and lung cancers. GPER1 was originally cloned from vascular endothelial cells, and its vascular expression and function play a crucial role in the development of atherosclerosis in postmenopausal women. There is currently no definitive discussion about the subcellular localization of gprer 1, and there are studies suggesting that gprer 1 is localized on the cell membrane; it is also believed that GPER1 is localized to the endoplasmic reticulum and golgi apparatus in the cytoplasm. At present, a great deal of research proves that GPER1 can mediate the rapid non-genomic effect of estrogen, regulate the expression of genes and mediate the biological function of estrogen by activating EGFR, cAMP and the like. Numerous studies have demonstrated that the involvement of agonist G1 is required for gprer 1 to mediate the rapid biological effects of estrogen. Administration of the highly selective GPER1 agonist G1 significantly reduced vascular inflammation while simultaneously reducing atherosclerotic plaque formation. G1 has the ability to inhibit tumor cell proliferation, and can be used as medicine for treating ovarian cancer and breast cancer.
Disclosure of Invention
The invention provides an application of a traditional Chinese medicine composition in preparation of a medicine used as a GPER1 receptor agonist, and a control test proves that the traditional Chinese medicine composition has the same property with a positive medicine G1 and is a GPER1 receptor agonist, so that the traditional Chinese medicine composition can play a role of the receptor agonist, participate in gene expression of various cancer cells, activate various hormones and mediate various biological functions. The traditional Chinese medicine composition is prepared from the following raw material medicines in parts by weight: 150-350 parts of semen cuscutae, 100-200 parts of fructus lycii, 30-60 parts of fructus schisandrae, 20-50 parts of fructus cnidii, 20-50 parts of fructus rosae laevigatae, 20-50 parts of semen allii tuberosi, 20-50 parts of morinda officinalis, 20-50 parts of cistanche, 30-60 parts of radix rehmanniae recen, 20-50 parts of radix cyathulae, 40-100 parts of herba epimedii, 20-50 parts of raspberry, 15-35 parts of ginseng, 10-25 parts of cornu cervi pantotrichum, 15-35 parts of hippocampus and 15-35 parts of fructus toosendan.
The preferred traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: 150 parts of semen cuscutae, 200 parts of fructus lycii, 30 parts of fructus schizandrae, 50 parts of fructus cnidii, 20 parts of fructus rosae laevigatae, 20 parts of semen allii tuberose, 50 parts of morinda officinalis, 20 parts of herba cistanche, 30 parts of radix rehmanniae recen, 50 parts of radix cyathulae, 40 parts of herba epimedii, 50 parts of raspberry, 15 parts of ginseng, 25 parts of cornu cervi pantotrichum, 15 parts of hippocampus and 35 parts of fructus toosendan.
The preferred traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: 350 parts of semen cuscutae, 100 parts of fructus lycii, 60 parts of fructus schizandrae, 20 parts of fructus cnidii, 50 parts of fructus rosae laevigatae, 50 parts of semen allii tuberose, 20 parts of morinda officinalis, 50 parts of herba cistanche, 60 parts of radix rehmanniae recen, 20 parts of radix cyathulae, 100 parts of herba epimedii, 20 parts of raspberry, 35 parts of ginseng, 10 parts of cornu cervi pantotrichum, 35 parts of hippocampus and 15 parts of fructus toosendan.
The preferred traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: 250 parts of semen cuscutae, 138 parts of fructus lycii, 46 parts of fructus schizandrae, 35 parts of fructus cnidii, 35 parts of fructus rosae laevigatae, 35 parts of semen allii tuberose, 35 parts of morinda officinalis, 35 parts of herba cistanche, 46 parts of radix rehmanniae recen, 35 parts of radix cyathulae, 70 parts of herba epimedii, 35 parts of raspberry, 25 parts of ginseng, 16 parts of cornu cervi pantotrichum, 21 parts of hippocampus and 23 parts of fructus toosendan.
The preferred traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: 250 parts of dodder, 150 parts of medlar, 45 parts of schisandra chinensis, 30 parts of fructus cnidii, 30 parts of cherokee rose fruit, 30 parts of semen allii tuberosi, 30 parts of morinda officinalis, 30 parts of cistanche, 45 parts of radix rehmanniae recen, 30 parts of medicinal cyathula root, 70 parts of epimedium, 30 parts of raspberry, 20 parts of ginseng, 19 parts of pilose antler, 20 parts of hippocampus and 20 parts of szechwan chinaberry fruit.
The medicament of the invention is in the form of decoction, capsules, tablets, granules, powder or pills.
In order to achieve the purpose of the invention, the traditional Chinese medicine composition is prepared into various pharmaceutical dosage forms, theoretically, the traditional Chinese medicine composition can be prepared into any dosage form according to a general preparation method, and the traditional Chinese medicine composition is preferably decoction, capsules, tablets, granules, powder or pills according to the applicable objects and indications. In order to make the above dosage forms possible, pharmaceutically acceptable excipients, such as: fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, bases, and the like. The filler comprises: starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, etc.; the disintegrating agent comprises: starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, crospolyvinylpyrrolidone, low-substituted hydroxypropylcellulose, croscarmellose sodium, etc.; the lubricant comprises: magnesium stearate, sodium lauryl sulfate, talc, silica, and the like; the suspending agent comprises: polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methylcellulose, and the like; the adhesive comprises starch slurry, polyvinylpyrrolidone, hydroxypropyl methylcellulose, etc.; the sweetener comprises: saccharin sodium, aspartame, sucrose, sodium cyclamate, glycyrrhetinic acid, and the like; the flavoring agent comprises: sweeteners and various essences; the preservative comprises: parabens, benzoic acid, sodium benzoate, sorbic acid and its salts, benzalkonium bromide, chloroacetidine acetate, eucalyptus oil, etc.; the matrix comprises: PEG6000, PEG4000, insect wax, etc.
The preparation method of the capsule comprises the following steps:
a. weighing fructus Cnidii, semen Cuscutae, fructus Schisandrae chinensis, and herba Epimedii at a certain proportion, adding 6-10 times of 70% ethanol, reflux extracting for 1-3 times, each for 1-3 hr, filtering, mixing filtrates, recovering ethanol under reduced pressure to obtain ethanol extract;
b. mixing the medicinal material residues after the alcohol extraction in the step a with wolfberry fruit, radix rehmanniae recen, raspberry, cherokee rose fruit, Chinese chive seed, morinda officinalis and szechwan chinaberry fruit in proportion, adding 7-12 times of water, decocting for 1-3 times each time for 1-3 hours, filtering, mixing the filtrates, mixing with the alcohol extract obtained in the step a, and concentrating under reduced pressure until the relative density is 1.25-1.30 measured at 60 ℃ to obtain an extract;
c. weighing the ginseng, the pilose antler, the sea horse, the cistanche salsa and the medicinal cyathula root according to the proportion, crushing into fine powder, uniformly mixing with the extract obtained in the step b, drying at the temperature of 60-70 ℃, crushing, sieving and filling into capsules.
Detailed Description
Example 1: preparation of capsules
The formula is as follows: 250g of dodder, 138g of medlar, 46g of schisandra chinensis, 35g of fructus cnidii, 35g of cherokee rose, 35g of semen allii tuberosi, 35g of morinda officinalis, 35g of cistanche, 46g of radix rehmanniae recen, 35g of medicinal cyathula root, 70g of epimedium herb, 35g of raspberry, 25g of ginseng, 16g of pilose antler, 21g of hippocampus and 23g of szechwan chinaberry fruit.
The preparation method comprises the following steps:
a. weighing fructus Cnidii, semen Cuscutae, fructus Schisandrae chinensis, and herba Epimedii at a certain proportion, adding 3208ml70% ethanol, reflux extracting for 3 times, each for 2 hr, filtering, mixing filtrates, recovering ethanol under reduced pressure to obtain ethanol extract;
b. mixing the medicinal material residues after the alcohol extraction in the step a with wolfberry fruit, radix rehmanniae recen, raspberry, cherokee rose fruit, Chinese chive seed, morinda officinalis and szechwan chinaberry fruit in a certain proportion, adding 6732ml of water for decoction for 2 times, each time for 2 hours, filtering, mixing the filtrates, mixing with the alcohol extract obtained in the step a, and concentrating under reduced pressure until the relative density is 1.28 when the temperature is 60 ℃ to obtain an extract;
c. weighing the ginseng, the pilose antler, the sea horse, the cistanche and the medicinal cyathula root according to the proportion, crushing into fine powder, uniformly mixing with the extract obtained in the step b, drying at 60-70 ℃, crushing, sieving, and filling into capsules to obtain 757 capsules.
Example 2: preparation of tablets
The formula is as follows: 250g of dodder, 150g of medlar, 45g of schisandra chinensis, 30g of fructus cnidii, 30g of cherokee rose, 30g of semen allii tuberosi, 30g of morinda officinalis, 30g of cistanche, 45g of radix rehmanniae recen, 30g of medicinal cyathula root, 70g of epimedium herb, 30g of raspberry, 20g of ginseng, 19g of antler, 20g of hippocampus and 20g of szechwan chinaberry fruit.
The preparation method comprises the following steps:
a. weighing fructus Cnidii, semen Cuscutae, fructus Schisandrae chinensis, and herba Epimedii at a certain proportion, adding 2765ml70% ethanol, reflux extracting for 3 times, each for 1 hr, filtering, mixing filtrates, and recovering ethanol under reduced pressure to obtain ethanol extract;
b. mixing the medicinal material residues after the alcohol extraction in the step a with wolfberry fruit, radix rehmanniae recen, raspberry, cherokee rose fruit, Chinese chive seed, morinda officinalis and szechwan chinaberry fruit in a certain proportion, adding 5110ml of water for decocting for 1 time and 3 hours, filtering, mixing the filtrates, mixing with the alcohol extraction extract obtained in the step a, and concentrating under reduced pressure until the relative density is 1.30 measured at 60 ℃ to obtain an extract;
c. weighing the ginseng, the pilose antler, the sea horse, the cistanche and the medicinal cyathula root according to the proportion, crushing into fine powder, uniformly mixing with the extract obtained in the step b, drying at 60-70 ℃, crushing, sieving, adding 1% of magnesium stearate, and tabletting to obtain 760 tablets.
Example 3: preparation of pills
The formula is as follows: 350g of dodder, 100g of medlar, 60g of schisandra chinensis, 20g of fructus cnidii, 50g of cherokee rose fruit, 50g of Chinese chive seed, 20g of morinda officinalis, 50g of cistanche, 60g of radix rehmanniae recen, 20g of medicinal cyathula root, 100g of epimedium herb, 20g of raspberry, 35g of ginseng, 10g of pilose antler, 35g of hippocampus and 15g of szechwan chinaberry fruit.
The preparation method comprises the following steps:
a. weighing fructus Cnidii, semen Cuscutae, fructus Schisandrae chinensis, and herba Epimedii at a certain proportion, adding 5300ml70% ethanol, reflux extracting for 1 time and 3 hr, filtering, mixing filtrates, recovering ethanol under reduced pressure to remove ethanol smell to obtain ethanol extract;
b. mixing the medicinal material residues after the alcohol extraction in the step a with wolfberry fruit, radix rehmanniae recen, raspberry, cherokee rose fruit, Chinese chive seed, morinda officinalis and szechwan chinaberry fruit in a proportion, adding 10140ml of water for decoction for 3 times, each time for 1 hour, filtering, mixing the filtrates, mixing with the alcohol extraction extract obtained in the step a, and concentrating under reduced pressure until the relative density is 1.25 measured at 60 ℃ to obtain an extract;
c. weighing Ginseng radix, cornu Cervi Pantotrichum, Hippocampus, Cistanchis herba, and radix Cyathulae at a certain proportion, pulverizing into fine powder, mixing with the extract obtained in step b, drying at 60-70 deg.C, pulverizing, sieving, and making into pill, 320 g.
Example 4: preparation of granules
The formula is as follows: 150g of dodder, 200g of medlar, 30g of schisandra chinensis, 50g of fructus cnidii, 20g of cherokee rose fruit, 20g of Chinese chive seed, 50g of morinda officinalis, 20g of cistanche, 30g of radix rehmanniae recen, 50g of medicinal cyathula root, 40g of epimedium, 50g of raspberry, 15g of ginseng, 25g of pilose antler, 15g of hippocampus and 35g of szechwan chinaberry fruit.
The preparation method comprises the following steps:
a. weighing fructus Cnidii, semen Cuscutae, fructus Schisandrae chinensis, and herba Epimedii at a certain proportion, adding 2430ml70% ethanol, reflux extracting for 2 times, each for 1.5 hr, filtering, mixing filtrates, recovering ethanol under reduced pressure to obtain ethanol extract;
b. mixing the residue of the medicinal materials extracted by the alcohol in the step a with the other medicinal materials in a proportion, adding 8800ml of water, decocting for 3 times, 1 hour each time, filtering, mixing the filtrates, mixing with the alcohol extract obtained in the step a, and concentrating under reduced pressure until the relative density is 1.29 measured at 60 ℃ to obtain an extract;
c. and c, uniformly mixing the extract obtained in the step b with 300g of dextrin and 200g of sucrose powder, drying at 60-70 ℃, crushing, sieving and granulating to obtain 700g of granules.
Example 5: preparation of powder
The formula is as follows: 250g of dodder, 150g of medlar, 45g of schisandra chinensis, 30g of fructus cnidii, 30g of cherokee rose, 30g of semen allii tuberosi, 30g of morinda officinalis, 30g of cistanche, 45g of radix rehmanniae recen, 30g of medicinal cyathula root, 70g of epimedium herb, 30g of raspberry, 20g of ginseng, 19g of antler, 20g of hippocampus and 20g of szechwan chinaberry fruit.
The preparation method comprises the following steps: weighing the traditional Chinese medicinal materials in the formula according to the proportion, mixing and crushing the traditional Chinese medicinal materials into fine powder to obtain 823g of powder.
Example 6: preparation of decoction
The formula is as follows: 250g of dodder, 150g of medlar, 45g of schisandra chinensis, 30g of fructus cnidii, 30g of cherokee rose, 30g of semen allii tuberosi, 30g of morinda officinalis, 30g of cistanche, 45g of radix rehmanniae recen, 30g of medicinal cyathula root, 70g of epimedium herb, 30g of raspberry, 20g of ginseng, 19g of antler, 20g of hippocampus and 20g of szechwan chinaberry fruit.
The preparation method comprises the following steps: weighing traditional Chinese medicinal materials in a formula according to a certain proportion, adding water until the traditional Chinese medicinal materials are submerged, soaking for 15 minutes, heating until the water is boiled, continuing decocting for 30 minutes with slow fire, filtering, adding water again until the medicinal materials are submerged, decocting for 30 minutes again, filtering, and combining the filtrates to obtain 4320g decoction.
Description of the drawings:
FIG. 1: performing immunohistochemical staining on aorta endothelium GPER1, and performing immunohistochemical staining on a Control group (Control), a Model group (Model), a positive Control group (G1), a high-dose group (HD-BZ) of the pharmaceutical composition of the invention and a low-dose group (LD-BZ) of the pharmaceutical composition of the invention;
FIG. 2: performing immunohistochemical staining quantification on the aorta endothelium GPER1, and performing quantitative analysis on a Control group (Control), a Model group (Model), a positive Control group (G1), a high-dose group (HD-BZ) of the pharmaceutical composition of the invention and a low-dose group (LD-BZ) of the pharmaceutical composition of the invention;
FIG. 3: western blot analysis of protein level of GPER1, taking GAPDH as an internal reference Control, a Control group (Control), a Model group (Model), a positive Control group (G1), a high-dose group (HD-BZ) of the pharmaceutical composition of the invention and a low-dose group (LD-BZ) of the pharmaceutical composition of the invention;
FIG. 4: quantitative analysis of protein level of GPER1, taking GAPDH as an internal reference Control, a Control group (Control), a Model group (Model), a positive Control group (G1), a high dose group (HD-BZ) of the pharmaceutical composition of the invention and a low dose group (LD-BZ) of the pharmaceutical composition of the invention.
To confirm the effect of the Chinese medicinal composition of the present invention, the contents of the capsules obtained in example 1 were tested as follows:
1. animal grouping and Experimental design
Female homozygote ApoE-/-60 mice and 15 female C57BL/6J mice, both 6-8 weeks old, were purchased from Jiangsu Jiejiaokang Biotech Ltd. The animal feeding conditions are 22 deg.C, 12h/12h light and dark circadian rhythm, no food limit and water limit. 3 days after adaptive feeding, ApoE-/-Mice received bilateral ovariectomy (surgical menopausal model), and C57BL/6J mice were given sham surgery. After 1 week, ApoE-/Mice were randomized into 4 groups (n = 15/group): model group (Model) (high fat diet +0.5% sodium carbonate cellulose (CMC) gavage), GPER1 agonist G1 group (high fat diet + G10.2ug/d subcutaneous injection), the inventive pharmaceutical composition high dose group (HD-BZ) (high fat diet + inventive pharmaceutical composition 2.8G/kg/d gavage), the inventive pharmaceutical composition low dose group (LD-BZ) (high fat diet + inventive pharmaceutical composition 1.4G/kg/d gavage), and 15C 57BL/6J mice were Control group (Control) (normal diet + CMC gavage). Normal diet (standard diet) was purchased from mohr feed limited (M10001, Chengdu), high fat diet (no phytoestrogen, 40% fat, 1.25% cholesterol, 0.5% bile acid) was purchased from Research diet ltd (D12109C, new jersey, usa).
2. Results
The pharmaceutical composition of the invention is used for treating Ovx/ApoE-/-Effect of mouse aortic GPER1 expression
Immunohistochemistry and Western blotting results show that the expression level of GPER1 in the model group is obviously reduced compared with that in the control group. The positive control drug G1 treatment increases the GPER1 level, the pharmaceutical composition of the invention also increases the GPER1 protein level, and is dose-dependent, and the pharmaceutical composition of the invention has better effect at high dose.
The present study shows that the pharmaceutical compositions of the present invention are agonists of the GPER1 receptor. Therefore, the pharmaceutical composition provided by the invention, as a GPER1 receptor agonist, can remarkably reduce vascular inflammation and simultaneously reduce the formation of atherosclerotic plaques; has the ability of inhibiting tumor cell proliferation, and can be used for treating ovarian cancer and breast cancer, and endometriosis.

Claims (10)

1. The application of a traditional Chinese medicine composition in a medicament as a GPER1 receptor agonist is characterized in that the traditional Chinese medicine composition is prepared from the following raw material medicines in parts by weight: 150-350 parts of semen cuscutae, 100-200 parts of fructus lycii, 30-60 parts of fructus schisandrae, 20-50 parts of fructus cnidii, 20-50 parts of fructus rosae laevigatae, 20-50 parts of semen allii tuberosi, 20-50 parts of morinda officinalis, 20-50 parts of cistanche, 30-60 parts of radix rehmanniae recen, 20-50 parts of radix cyathulae, 40-100 parts of herba epimedii, 20-50 parts of raspberry, 15-35 parts of ginseng, 10-25 parts of cornu cervi pantotrichum, 15-35 parts of hippocampus and 15-35 parts of fructus toosendan.
2. The application of claim 1, wherein the traditional Chinese medicine composition is prepared from the following raw material medicines in parts by weight: 150 parts of semen cuscutae, 200 parts of fructus lycii, 30 parts of fructus schizandrae, 50 parts of fructus cnidii, 20 parts of fructus rosae laevigatae, 20 parts of semen allii tuberose, 50 parts of morinda officinalis, 20 parts of herba cistanche, 30 parts of radix rehmanniae recen, 50 parts of radix cyathulae, 40 parts of herba epimedii, 50 parts of raspberry, 15 parts of ginseng, 25 parts of cornu cervi pantotrichum, 15 parts of hippocampus and 35 parts of fructus toosendan.
3. The application of claim 1, wherein the traditional Chinese medicine composition is prepared from the following raw material medicines in parts by weight: 350 parts of semen cuscutae, 100 parts of fructus lycii, 60 parts of fructus schizandrae, 20 parts of fructus cnidii, 50 parts of fructus rosae laevigatae, 50 parts of semen allii tuberose, 20 parts of morinda officinalis, 50 parts of herba cistanche, 60 parts of radix rehmanniae recen, 20 parts of radix cyathulae, 100 parts of herba epimedii, 20 parts of raspberry, 35 parts of ginseng, 10 parts of cornu cervi pantotrichum, 35 parts of hippocampus and 15 parts of fructus toosendan.
4. The application of claim 1, wherein the traditional Chinese medicine composition is prepared from the following raw material medicines in parts by weight: 250 parts of semen cuscutae, 138 parts of fructus lycii, 46 parts of fructus schizandrae, 35 parts of fructus cnidii, 35 parts of fructus rosae laevigatae, 35 parts of semen allii tuberose, 35 parts of morinda officinalis, 35 parts of herba cistanche, 46 parts of radix rehmanniae recen, 35 parts of radix cyathulae, 70 parts of herba epimedii, 35 parts of raspberry, 25 parts of ginseng, 16 parts of cornu cervi pantotrichum, 21 parts of hippocampus and 23 parts of fructus toosendan.
5. The application of claim 1, wherein the traditional Chinese medicine composition is prepared from the following raw material medicines in parts by weight: 250 parts of dodder, 150 parts of medlar, 45 parts of schisandra chinensis, 30 parts of fructus cnidii, 30 parts of cherokee rose fruit, 30 parts of semen allii tuberosi, 30 parts of morinda officinalis, 30 parts of cistanche, 45 parts of radix rehmanniae recen, 30 parts of medicinal cyathula root, 70 parts of epimedium, 30 parts of raspberry, 20 parts of ginseng, 19 parts of pilose antler, 20 parts of hippocampus and 20 parts of szechwan chinaberry fruit.
6. The use according to any one of claims 1 to 5, wherein the medicament is in the form of a decoction, capsule, tablet, granule, powder or pill.
7. The process for preparing a capsule according to claim 6, comprising the steps of:
a. weighing fructus Cnidii, semen Cuscutae, fructus Schisandrae chinensis, and herba Epimedii at a certain proportion, adding 6-10 times of 70% ethanol, reflux extracting for 1-3 times, each for 1-3 hr, filtering, mixing filtrates, recovering ethanol under reduced pressure to obtain ethanol extract;
b. mixing the medicinal material residues after the alcohol extraction in the step a with wolfberry fruit, radix rehmanniae recen, raspberry, cherokee rose fruit, Chinese chive seed, morinda officinalis and szechwan chinaberry fruit in proportion, adding 7-12 times of water, decocting for 1-3 times each time for 1-3 hours, filtering, mixing the filtrates, mixing with the alcohol extract obtained in the step a, and concentrating under reduced pressure until the relative density is 1.25-1.30 measured at 60 ℃ to obtain an extract;
c. weighing the ginseng, the pilose antler, the sea horse, the cistanche salsa and the medicinal cyathula root according to the proportion, crushing into fine powder, uniformly mixing with the extract obtained in the step b, drying at the temperature of 60-70 ℃, crushing, sieving and filling into capsules.
8. The use according to any one of claims 1 to 5, characterized in that the use of the Chinese medicinal composition as a GPER1 receptor agonist medicament in the inhibition of ovarian and breast cancer cell proliferation.
9. The use according to any one of claims 1 to 5, characterized in that the Chinese medicinal composition is used as a GPER1 receptor agonist medicament in the treatment of endometriosis.
10. The use of any one of claims 1-5, wherein the use of the composition as a GPER1 receptor agonist medicament for the inhibition of ulcerative colitis.
CN202010099175.8A 2020-02-18 2020-02-18 Application of traditional Chinese medicine composition in preparation of GPER1 receptor agonist medicine Pending CN113332375A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101584797A (en) * 2008-05-22 2009-11-25 河北以岭医药研究院有限公司 Application of traditional Chinese medicine composition in preparing medicament for treating climacteric syndrome
CN103417799A (en) * 2012-05-22 2013-12-04 石家庄以岭药业股份有限公司 Applications of a traditional Chinese medicine composition in preparing medicines treating anaemia

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101584797A (en) * 2008-05-22 2009-11-25 河北以岭医药研究院有限公司 Application of traditional Chinese medicine composition in preparing medicament for treating climacteric syndrome
CN103417799A (en) * 2012-05-22 2013-12-04 石家庄以岭药业股份有限公司 Applications of a traditional Chinese medicine composition in preparing medicines treating anaemia

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
健客网: "八子补肾胶囊对性激素水平的影响是怎样的?", pages 1, Retrieved from the Internet <URL:https://www.jianke.com/a/20141231/1204040.html> *
黄苗苗等: "植物雌激素对子宫内膜异位症的治疗机制", 安徽医学, vol. 37, no. 1, pages 113 - 115 *

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