KR101788299B1 - Composition containing protocatechuic acid for improving pregnancy - Google Patents
Composition containing protocatechuic acid for improving pregnancy Download PDFInfo
- Publication number
- KR101788299B1 KR101788299B1 KR1020160012900A KR20160012900A KR101788299B1 KR 101788299 B1 KR101788299 B1 KR 101788299B1 KR 1020160012900 A KR1020160012900 A KR 1020160012900A KR 20160012900 A KR20160012900 A KR 20160012900A KR 101788299 B1 KR101788299 B1 KR 101788299B1
- Authority
- KR
- South Korea
- Prior art keywords
- female infertility
- protocatechuic acid
- infertility
- originating
- origin
- Prior art date
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- 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
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2200/00—Function of food ingredients
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Abstract
The present invention provides a composition for promoting pregnancy or a composition for the prevention or treatment of gynecological infertility comprising protocatechuic acid as an active ingredient. The protocatechuic acid of the present invention increases the expression of LIF associated with the implantation in the endometrial cells and has an excellent effect of effectively inducing the implantation of the embryo by increasing the binding force between the endometrial cells and the fetal-derived trophoblast, Can be useful in fields related to pharmaceuticals and functional foods that can prevent and treat gynecological infertility including causal infertility.
Description
The present invention provides a composition for promoting pregnancy or a composition for the prevention or treatment of gynecological infertility comprising protocatechuic acid as an active ingredient.
In recent years, in conjunction with an aging society, infertility is increasing as maternal age increases. In addition, due to environmental pollution caused by industrialization and the advancement of women into society, the stress of women is increasing, and the pregnancy rate is significantly lowered. Common causes of female infertility include ovulation disorders, transfer of fertilized eggs, and implantation disorders. Infertility due to obstructive ovarian failure and transfer of embryos is largely solved through in vitro fertilization (IVF), but sterilization due to implantation disorder has yet to be clarified. Normal pregnancy progresses in the order of fertilization, implantation and fetal development. Quality of fertilized eggs and receptivity of endometrium are very important factors in embryo implantation. The major factors controlling the endometrium's water solubility include growth factors such as cytokine such as leukemia inhibitory factor (LIF), insulin-like growth factor-2 and interleukin-11 (IL-11) is important (Hum Rep Update, 12 (6): 731-746). Among them, the expression of LIF, an interleukin-6 (IL-6) family cytokine, is known to be a key factor controlling the implantation process. In particular, in mice deficient in LIF, there are reports of defects in the adhesion process between the embryo and the endometrium and conception and pregnancy (Nature 359 (6390): 76-79; Endocrinology 150 6): 2915-2923). In addition, it has been reported that inhibition of LIF function by using an antagonist for LIF does not result in implantation (PNAS 104 (49): 19357-19362). LIF is known to be the most important factor in the implantation process have.
Protocatechuic acid (Protocatechuic acid) is the first isolate from Magnolia and Lilium sp., And is also present in Magnolia and other plants. Protocatechuic acid has been reported to ameliorate neuropsychiatric dysfunction induced by chronic intermittent hypoxia (Sci. Rep. 5: 14507) and to protect the brain's mitochondrial function in diabetic rat models (Appl Physiol Nutr Metab. 40 10): 1078-81). There is also a report that protocatechuic acid inhibits oxidized LDL-induced apoptosis in macrophages (Oxid Med Cell Longev. 2015: 351827) and is effective in antiinflammatory and neuroprotective actions (Neurochem Res 40 (8): 1655-60, Free Radic Biol Med. 84: 331-43). However, there has been no previous report that protocatechuic acid is effective for the prevention or treatment of infertility and for pregnancy.
The present inventors have found that protocatechuic acid increases the expression of LIF, a key cytokine related to the implantation in endometrial cells, in inducing fertilization of embryos and effective in promoting pregnancy. Thus, the endometrial cells and embryo- The present invention has been accomplished by confirming that the present invention is effective in promoting pregnancy and promoting ovarian non-implantation in female infertility by increasing cell binding.
It is an object of the present invention to provide a composition for promoting pregnancy comprising protocatechuic acid as an active ingredient.
It is also an object of the present invention to provide a composition for the prevention or treatment of gynecological infertility comprising protocatechuic acid as an active ingredient.
In order to solve the above problems, the present invention provides a pharmaceutical composition for promoting pregnancy comprising protocatechuic acid as an active ingredient.
In addition, the present invention provides a food composition for promoting pregnancy comprising protocatechuic acid as an active ingredient.
The present invention also provides a pharmaceutical composition for the prevention or treatment of gynecological infertility comprising protocatechuic acid as an active ingredient.
The present invention also provides a food composition for preventing or ameliorating gynecological infertility comprising protocatechuic acid as an active ingredient.
The protocatechuic acid of the present invention has an excellent effect of increasing the expression of LIF related to the implantation in the endometrial cells, increasing the binding force between the endometrial cells and the fetal-derived trophoblast and effectively inducing the implantation of the embryo. Accordingly, the protocatechuic acid according to the present invention can be usefully used in fields related to medicines and functional foods for prevention and treatment of gynecological infertility including oocyte non-implantation infertility.
Figure 1 shows the formula of protocatechuic acid.
FIG. 2 is a graph showing the results of confirming cytotoxicity according to the concentration of protocatechuic acid treatment. FIG.
FIG. 3 is a graph showing the results of RT-PCR for the increase in the expression of LIF mRNA according to the concentration of protocatechuic acid treatment.
FIG. 4 is a graph showing the result of Western blot analysis of the increase in the expression of LIF protein according to the treatment concentration of protocatechuic acid.
Fig. 5 is a graph showing the results (A) and (B) of counting the adhesion of the spermatids by fluorescent microscopy in Ishikawa cells treated with protocatechuic acid and in the untreated control group.
The present invention provides a composition for promoting pregnancy comprising protocatechuic acid as an active ingredient.
In the present invention, the term " protocatechuic acid "is a polyphenolic compound, which has been reported to have excellent antioxidative and antiinflammatory properties. Is a material having the formula C 7 H 6 O 4 and a molecular weight of 154, which is shown in FIG. 1 of the present invention.
The protocatechuic acid increases, but is not limited to, the expression of leukemia inhibitory factor (LIF).
The protocatechuic acid can be treated at a concentration of 1 to 600 μM, but preferably at a concentration of 30 to 60 μM. When protocatechuic acid is within the above-mentioned range, it is more preferable because it has no cytotoxicity.
In the present invention, "pregnancy" is a process in which the fertilized egg is implanted in the inner wall of the uterus, is supplied with nutrition from the mother, and develops into the fetus. The normal pregnancy process proceeds in the order of fertilization, implantation and fetal development.
The term "fertilization" means that an ovum ovulated in a female ovary meets with spermatozoa at the upper part of the oviduct to form an embryo. The ovum has the ability to stay alive for 1-2 days after ovulation and the sperm to remain alive for 2-3 days in the uterus, and the sperm survive for one week after being ejaculated. Sperm are spermatozoa that reach the ovary close to the
The "implantation" refers to a phenomenon in which an embryo in which a sperm and an egg are brought together at the upper part of the oviduct is moved to the uterus repeatedly and buried in the uterine wall in a bladder state. After the embryo is conceived, it is called pregnancy. Embryos implanted into the uterus are born after about nine months of age, while being fed from the uterine lining.
The composition comprises a pharmaceutical composition or a food composition.
The composition may contain protocatechuic acid alone, or may further contain a substance effective for promoting pregnancy as an active ingredient. In addition to the active ingredient, the composition may contain additional ingredients, Acceptable or nutritionally acceptable carrier, excipient, diluent or subcomponent.
More specifically, the pharmaceutical composition for promoting pregnancy comprising the above-mentioned protocatechuic acid may further contain, in addition to the above-mentioned active ingredients, a nutritional supplement, a vitamin, an electrolyte, a flavoring agent, a colorant, a thickening agent, a pectic acid and a salt thereof, , Protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like.
Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, Calcium stearate, mineral oil, calcium carbonate, dextrin, propyleneglycol, liquid paraffin, sodium carboxymethylcellulose, sodium carboxymethylcellulose, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, And physiological saline, but is not limited thereto. The components may be added to the active ingredient, i.e., protocatechuic acid, either independently or in combination.
The composition according to the present invention can be used alone for promoting pregnancy, or in combination with surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.
The composition according to the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) according to a desired method, and the dosage may be appropriately selected according to the weight, age, sex, The range varies depending on the condition, diet, time of administration, method of administration, excretion rate and severity of the disease. The daily dose of protocatechuic acid of the present invention is 0.01 to 10000 mg / kg, preferably 1 to 20 mg / kg, and is preferably administered once to three times a day.
According to one embodiment of the present invention, the protocatechuic acid increases the expression of leukemia inhibitory factor (LIF), thereby increasing the binding force between endometrial cells and fetal-derived trophoblast cells and effectively inducing embryo implantation .
In addition, the present invention provides a food composition for promoting pregnancy comprising protocatechuic acid as an active ingredient.
The composition according to the present invention may be included in a health food for the purpose of promoting pregnancy. When the active ingredient of the present invention is used as a food additive, the composition isolated from the synthesis or the extract may be added as it is, And can be suitably used according to a conventional method. The amount of the active ingredient to be mixed may be appropriately adjusted depending on the intended use (prevention, health or therapeutic treatment).
There is no particular limitation on the kind of the food. Examples of foods to which the above substances can be added include meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, drinks, tea, , Alcoholic beverages and vitamin complexes, and includes all health foods in a conventional sense.
Various additives such as flavors or natural carbohydrates can be used as the food-aid additive of the present invention. The above-mentioned natural carbohydrates are sugar saccharides such as monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like.
In addition to the above, the composition according to the present invention may further contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid concentrating agents, pH adjusting agents, stabilizers, preservatives, , A carbonating agent used in carbonated drinks, and the like. In addition, the composition according to the present invention may contain flesh for the production of natural fruit juice, fruit juice beverage and vegetable beverage. These components may be used independently or in combination.
The present invention also provides a composition for preventing or treating feminine infertility comprising protocatechuic acid as an active ingredient.
The composition comprises a pharmaceutical composition or a food composition.
The female infertility is related to nonimplantation of ovum, female infertility associated with anovulation associated with anovulation, female infertility of tubal origin, Tubal occlusion, Tubal stenosis, Female infertility of the uterine origin, Infertility of the uterus, Infertility of the uterus, Infertility associated with male factors, female infertility associated with cervical origins, female infertility associated with male factors, and other factors related to congenital anomaly of uterus. At least one selected from the group consisting of female infertility of other origin and unspecified female infertility (unspecified) However, not limited to this.
In the present invention, the above-mentioned "Nonimplantation of ovum" is a representative cause of female infertility. During fertilization, the embryo moves while dividing cells into the uterus, and when it reaches the blastocyst stage, it is buried in the endometrium and seated. However, when embryos are not thick enough to be implanted or stiff due to damage, it is difficult to obtain implants, and abortion is often caused by lack of space due to adhesion of the uterine wall. Endometrial hyperplasia due to intrauterine inflammation caused by spontaneous abortion, mastectomy, abortion, endometritis, pelvic tuberculosis and intrauterine device, or uterine myopathy, Or if the uterine endometrium is incomplete due to congenital abnormal uterine hormone secretion. The oocyte implantation has been identified as the major cause of artificial insemination and failure of in vitro procedures.
Since the pharmaceutical composition or the food composition includes the pharmaceutical preparation or the food preparation containing the above-mentioned protocatechuic acid as an active ingredient, the contents overlapping with the composition of the present invention described above can be used in the present specification The description thereof is omitted in order to avoid excessive complexity.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the invention as defined by the appended claims. It will be obvious to you.
Example One. Protocatechus Cytotoxicity Assessment
The toxicity of protocatechuic acid to cells was confirmed by MTT (3- (4,5-dimethylthiazole-2-yl) -2,5-diphenyltetrazoli-umbromide) analysis.
Specifically, protocatechuic acid having the formula of Fig. 1 was treated at the concentration of 0, 10, 30, 50, 100 and 500 μM for 24 hours in the endometrial cell line Ishikawa cell. The MTT solution (2 mg / ml) was reacted at 37 ° C for 4 hours in a CO 2 incubator and the supernatant was removed. Live cells were reduced by intracellular redox enzyme, and purple dyes (Formazan) were dissolved in DMSO and measured at 540 nm wavelength with a microplate reader. Live cells were expressed as percentage compared to the control group. The results are shown in Fig.
As shown in FIG. 2, it was confirmed that even when the protocatechuic acid was treated to a concentration of 500 μM, no significant cytotoxicity was confirmed. Therefore, the concentrations below 50 μM without toxicity were used in the experiments below.
Example 2. Protocatechus Leukemia inhibitory factor (leukemia inhibitory factor; LIF ) mRNA Confirmation of expression of
The expression level of LIF mRNA according to the treatment concentration of protocatechuic acid was confirmed by RT-PCR.
Specifically, protocatechuic acid was treated with Ishikawa cells at concentrations of 0, 10, 30 and 50 μM and cultured for 24 hours. Then, the RNAs of the cells treated at the respective concentrations were extracted and primers specific for LIF were used. The sequence of the primer was 5'-GGCCCGGACACCCATAGACG-3 '(SEQ ID NO: 1) in the forward direction and 5'-CCACGCGCCATCCAGGTAAA-3' (SEQ ID NO: 2) in the reverse direction. The primer sequence used for amplification of- 3 '(SEQ ID NO: 3) and 5'-TCCTTCTGCATCCTGTCGGCA-3' (SEQ ID NO: 4) in the reverse direction. CDNA was synthesized by total RNA, oligo-dT primer and M-MLV reverse transcriptase at 42 ° C for 1 hour. The cDNA was amplified by 30 cycles of denaturation at 95 ° C. for 30 seconds, annealing at 60 ° C. for 30 seconds, and extension at 72 ° C. for 30 seconds using the primers described above. And the amount of mRNA expression was confirmed by polymerase chain reaction. The amplified DNA was electrophoretically photographed under ultraviolet light (UV) and the intensity of the band was measured using a densitometry. In addition, the ratio of the expression level of LIF mRNA and the expression level of alpha-actin mRNA as a control standard was confirmed. The results are shown in Fig.
As shown in FIG. 3, when the endometrial cells were treated with protocatechuic acid at a concentration of 50 μM, the expression of LIF mRNA was 2.05 times Respectively.
Therefore, it was confirmed that the expression of LIF mRNA was increased in a concentration-dependent manner of protocatechuic acid .
Example 3. Protocatechus Depending on treatment concentration LIF Identification of Protein Expression
The expression of LIF protein was confirmed by western blotting according to the treatment concentration of protocatechuic acid.
Specifically, protocatechuic acid was treated with Ishikawa cells at a concentration of 0, 10, 30 and 50 μM and cultured for 24 hours. Proteins were extracted from the cells and electrophoresed by SDS-PAGE. Subsequently, the separated proteins were transferred to a nitrocellulose membrane by electrophoresis and then sequentially bound to LIF-specific antibodies (SantaCruz) and secondary antibodies to which HRP (Horseradish peroxidase) had been added ECL (enhanced chemiluminescence) solution. The intensity of the band was measured using a densitometer and the ratio of the expression amount of LIF protein and the expression amount of GAPDH protein as a representative standard was confirmed. The results are shown in Fig.
As shown in FIG. 4, when 10, 30 and 50 μM of protocatechuic acid was treated in endometrium cells, LIF protein expression was increased to about 2.00, 2.71 and 3.27 times as compared with the control group, respectively.
Thus, it was confirmed that the expression of LIF protein was increased in a concentration-dependent manner in protocatechuic acid.
Example 4. Protocatechuic acid Of the JAR cells to the treated cells Attachment Confirm
The adherent ability of the fetal - derived trophoblast cell line to the Ishikawa cell line derived from endometrium treated with protocatechuic acid was confirmed.
Specifically, human endometrial cell line Ishikawa cells were cultured in a single layer to make 80% confluence, then treated with protocatechuic acid to a concentration of 50 μM, and cultured for 48 hours to obtain 100% Respectively. Subsequently, the pre-cultured fetal-derived cell line was removed from the culture dish, and the cell was stained well to be a single cell and stained with CellTracker ™ Green CMFDA (5-chloromethylfluorescein diacetate), a cell permeable green fluorescent substance . Thereafter, the cells were sprinkled on a single layer of Ishikawa cells and cultured in an incubator at 37 캜 for 30 minutes while stirring at a speed of about 60 rpm. The cultured cells were washed twice with phosphate buffered saline (PBS) to remove unattached cells, and the adhered cells were fixed with 3.7% formalin solution. When confirmed by fluorescence microscopy, the number of cells that fluoresce by CMFDA is the number of sperm cells attached to the Ishikawa cells on the floor, and the number of the sperm cells was measured (Fig. 5 (A)). Thereafter, the total number of cells counted in photographs of five or more different regions was compared with a control group not treated with protocatechuic acid, and then the average and standard deviation of the values repeated three times were determined (see (B )). The results are shown in Fig.
As shown in Figs. 5 (A) and 5 (B), it was confirmed that the adherence of autologous cells to Ishikawa cells treated with protocatechuic acid was significantly higher than that of the control group not treated with protocatechuate Respectively.
Hereinafter, the pharmaceutical composition of the present invention and the preparation example of the food composition will be described, but the present invention is not intended to be limited but is specifically described.
Formulation example 1. Preparation of pharmaceutical compositions
1-1. Sanje Produce
Protocatechuic acid 20 mg
The above components are mixed and filled in airtight bags to prepare powders.
1-2. Manufacture of tablets
Protocatechuic acid 10 mg
After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.
1-3. Preparation of capsules
Protocatechuic acid 10 mg
Lactose 14.8 mg
Magnesium stearate 0.2 mg
The above components are mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.
1-4. Injection preparation
Protocatechuic acid 10 mg
180 mg mannitol
Sterile sterilized water for injection 2974 mg
Na2HPO42H2O 26 mg
(2 ml) per 1 ampoule in accordance with the usual injection preparation method.
1-5. Liquid Produce
Protocatechuic acid 20 mg
10 g per isomer
5 g mannitol
Purified water quantity
Each component was added and dissolved in purified water according to the usual liquid preparation method, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and purified water was added thereto. The whole was added with purified water to adjust the total volume to 100 ml, And sterilized to prepare a liquid preparation.
Formulation example 2. Preparation of food composition
2-1. Health food manufacturing
100 mg of protocatechuic acid, a proper amount of vitamin mixture, 70 g of vitamin A acetate, 1.0 mg of vitamin E, 0.13 mg of vitamin B1, 0.15 mg of vitamin B2, 0.2 mg of vitamin B6, 0.2 g of vitamin B12, 10 mg of vitamin C, 1.7 mg, folate 50 g, calcium pantothenate 0.5 mg, an appropriate amount of inorganic mixture, ferrous sulfate 1.75 mg, zinc oxide 0.82 mg, magnesium carbonate 25.3 mg, potassium phosphate monohydrate 15 mg, dibasic calcium phosphate 55 mg, potassium citrate 90 mg , Calcium carbonate (100 mg) and magnesium chloride (24.8 mg), granules were prepared, and a health food was prepared according to a conventional method. At this time, although the composition ratio of the vitamin and mineral mixture is relatively mixed with the ingredient suitable for health food, it may be arbitrarily modified.
2-2. Health drink manufacturing
According to the conventional health drink manufacturing method, 100 mg of protocatechuic acid, 15 g of vitamin C, 100 g of vitamin E (powder), 19.75 g of iron lactate, 3.5 g of zinc oxide, 3.5 g of nicotinic acid amide, 0.2 g of vitamin A, 0.3 g of vitamin B2 and a predetermined amount of water were mixed and heated at 85 DEG C for about 1 hour with stirring. The resulting solution was filtered and sterilized in a 2 L container to be sterilized by sealing, and then stored in a refrigerator to prepare a health drink. At this time, although the composition ratio of the ingredients suitable for the beverage is comparatively mixed, the mixture ratio may be arbitrarily varied according to the demand, the demanded country, the intended use, and the regional or national preference.
<110> Pusan National University Industry-University Cooperation Foundation <120> Composition containing protocatechuic acid for improving pregnancy <130> 1-263 <160> 4 <170> Kopatentin 2.0 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> forward primer for LIF <400> 1 ggcccggaca cccatagacg 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> reverse primer for LIF <400> 2 ccacgcgcca tccaggtaaa 20 <210> 3 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> forward primer for alpha-actin <400> 3 caagagatgg ccacggctgc t 21 <210> 4 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> reverse primer for alpha-actin <400> 4 tccttctgca tcctgtcggc a 21
Claims (8)
Wherein said protocatechuic acid increases the expression level of a leukemia inhibitory factor (LIF) to increase adherence of endometrial cells and fetal-derived drug-derived membrane cells to a pharmaceutical composition for the prevention or treatment of gynecological infertility .
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| CN103462946A (en) | 2013-09-18 | 2013-12-25 | 三峡大学 | New applications of protocatechuic acid in preparing medicaments |
| CN105250246A (en) | 2015-09-18 | 2016-01-20 | 华北理工大学 | Application of protocatechualdehyde in treatment of male infertility and in-vitro treatment of sperms |
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| CN103462946A (en) | 2013-09-18 | 2013-12-25 | 三峡大学 | New applications of protocatechuic acid in preparing medicaments |
| CN105250246A (en) | 2015-09-18 | 2016-01-20 | 华北理工大学 | Application of protocatechualdehyde in treatment of male infertility and in-vitro treatment of sperms |
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| ZHONGGUO ZHONG YAO ZA ZHI. 2010 DEC;35(24):3362-7. |
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