CN117949669A - Application of nuclear receptor coactivator 4 as target spot in screening and preparing medicine for treating polycystic ovary syndrome ovulation disorder - Google Patents
Application of nuclear receptor coactivator 4 as target spot in screening and preparing medicine for treating polycystic ovary syndrome ovulation disorder Download PDFInfo
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Abstract
The invention provides application of a nuclear receptor coactivator 4 serving as a target spot in screening and preparing a medicine for treating polycystic ovary syndrome ovulation disorder. The invention also provides application of the reagent for detecting the nuclear receptor coactivator 4 in preparing a kit for diagnosing the ovulation disorder of polycystic ovary syndrome. The invention also provides application of the nuclear receptor coactivator 4 in preparing a marker for diagnosing the ovulation disorder of polycystic ovary syndrome. The invention also provides application of the nuclear receptor coactivator 4 serving as a diagnostic marker in preparing a kit for diagnosing the ovulation disorder of polycystic ovary syndrome. The invention also provides an interfering RNA, the nucleotide sequence of which is 5'-GACCUUAUUUAUCAGCUUATT-3'. The present invention has found that NCOA4 can improve ERK1/2 phosphorylation inhibition by androgens and C/EBP beta expression reduction.
Description
Technical Field
The invention belongs to the field of biological medicine, and relates to a nuclear receptor coactivator 4, in particular to an application of the nuclear receptor coactivator 4 serving as a target spot in screening and preparing a medicine for treating polycystic ovary syndrome ovulation disorder.
Background
Polycystic ovary syndrome (polycystic ovary syndrome, PCOS) is the most important cause of anovulatory infertility in women, and is the most common reproductive endocrine disease in women of childbearing age, and the number of patients in China is over 5000 ten thousand. PCOS changes to a major clinical feature with dilute ovulation or anovulation, clinically or biochemically hyperandrogenism, polycystic ovary-like, leading to female infertility. The pathogenesis of the anovulatory disorder of PCOS is currently unknown, and the treatment of infertility caused by PCOS is still a difficult problem in clinic.
PCOS has extremely high heterogeneity, and PCOS patients with fertility will mainly adopt treatments such as lifestyle adjustment, but the effect is still poor, and many patients still cannot spontaneously ovulate after treatment. These patients with anovulatory PCOS then need ovulation-promoting and assisted reproductive therapy, but conventional ovulation-promoting therapy is still less effective in PCOS patients. The existing ovum has low maturity, low fertilization rate, high abortion rate and high incidence rate of the syndrome of ovarian hyperstimulation with complications, and causes no small burden on the psychology and socioeconomic of patients. There is therefore a great need to search for therapeutic targets for the mechanism of occurrence of the ovulation failure of PCOS.
Gene ID of nuclear receptor coactivator 4 (nuclear receptor coactivator, NCOA4) was 8031 (https:// www.ncbi.nlm.nih.gov/gene/. Also known as androgen receptor co-regulator 70, can enhance androgen receptor (androgen receptor, AR) transcriptional activity. Previous studies have found its involvement in the development and progression of prostate cancer. High androgens are the core cause of PCOS, and elevated ovarian local androgen concentrations in PCOS patients are the primary cause of anovulatory disorders in PCOS patients. Studies have shown that elevated ovarian local androgen concentrations in PCOS patients cause increased ovarian granulosa cell death, leading to follicular developmental disorders, and thus to ovarian polycystic changes in PCOS patients. Iron autophagy is a newly discovered apoptosis in recent years, and the invention discovers that the level of iron autophagy in the ovary of a PCOS patient is increased and is consistent with the results of the previous study.
Disclosure of Invention
Aiming at the technical problems in the prior art, the invention provides application of the nuclear receptor coactivator 4 as a target spot in screening and preparing medicines for treating the ovulation disorder of polycystic ovary syndrome, and the application of the nuclear receptor coactivator 4 as the target spot in screening and preparing medicines for treating the ovulation disorder of polycystic ovary syndrome can solve the technical problem that the medicines in the prior art have poor effect in treating the ovulation disorder of polycystic ovary syndrome.
The invention provides application of a nuclear receptor coactivator 4 serving as a target spot in screening and preparing a medicine for treating polycystic ovary syndrome ovulation disorder, wherein the gene ID of the nuclear receptor coactivator 4 is 8031.
The invention also provides application of the reagent for detecting the nuclear receptor coactivator 4 in preparing a kit for diagnosing the ovulation disorder of polycystic ovary syndrome.
The invention also provides application of the nuclear receptor coactivator 4 in preparing a marker for diagnosing the ovulation disorder of polycystic ovary syndrome.
The invention also provides application of the nuclear receptor coactivator 4 serving as a diagnostic marker in preparing a kit for diagnosing the ovulation disorder of polycystic ovary syndrome.
The invention also provides an interfering RNA, the nucleotide sequence of which is 5'-GACCUUAUUUAUCAGCUUATT-3' (shown as SEQ ID NO. 1).
The invention also provides application of the interfering RNA in preparation of a medicament for treating polycystic ovary syndrome ovulation disorder.
The present invention has found that androgen induced NCOA4 expression in ovarian granulosa cells is elevated resulting in reduced expression of iron storage protein (FERRITIN HEAVY CHAIN, FTH 1) and iron death major inhibitor glutathione peroxidase (glutathione peroxidase, GPX 4). Furthermore, the present study also found that NCOA4 can improve ERK1/2 phosphorylation inhibition by androgens and C/EBP beta expression reduction. In animal experiments, the NCOA4 is further verified to be blocked, so that the phenomena of reduction of the number of ovarian corpus luteum, reduction of ovulation number and reduction of ovum quality of PCOS rats can be improved. The research finds an important signal path aiming at the onset of the PCOS ovulation disorder, finds an important molecular target NCOA4 in the PCOS pathogenesis, and can be used as a future therapeutic target of the PCOS ovulation disorder.
Compared with the prior art, the invention has the technical effects of being positive and obvious. The invention provides a more accurate target NCOA4 in the pathogenesis of the ovulation disorder of polycystic ovary syndrome, and provides a new view for research and treatment of the pathogenesis of PCOS in the future by targeting the high androgen pathogenicity mediated by NCOA4 and the iron autophagy signal path regulated by NCOA4 to possibly reverse the pathogenesis of the ovulation disorder of polycystic ovary syndrome.
Drawings
Fig. 1: the NCOA4 protein expression level in the ovary granular cells of the PCOS patient is increased, and the FTH1 and GPX4 protein expression level is reduced. (A) non-PCOS patients and PCOS patients ovarian granulosa cells NCOA4, FTH1 and GPX4 protein expression profiles represent the figures. (B) NCOA4 statistical plot. (C) FTH1 statistical plot. (D) GPX4 statistical map. * P <0.05 and P <0.01, P <0.001.
Fig. 2: in primordial ovarian granulosa cells, inhibition of NCOA4 ameliorates the effect of androgens on the expression of iron autophagy-related proteins. (A) The NCOA4, FTH1 and GPX4 protein expression levels are detected after androgens DHT with different concentrations are added. (B) After NCOA4 is knocked down, androgen DHT is added to detect the expression level of the FTH1 and GPX4 proteins.
FIG. 3 inhibition of NCOA4 in primordial granulosa cells improves the effect of androgens on ovulation-related genes. (A) After knock-down of NCOA4, the expression of p-ERK/ERK protein levels was detected after addition of androgen DHT. (B) Protein expression levels of C/EBP beta after androgen DHT addition after knock-down of NCOA 4.
Figure 4. Rats were improved in ovulation barrier function following local injection of pcos rat ovaries to knock down lentiviruses. The ovarian morphology (A), the number of ovarian corpus luteum (B), the number of ovulation (C) and the quality of ova (D).
Detailed Description
Example 1
In one embodiment of the invention, the agent that inhibits or down-regulates the amount of expression of NCOA4 is an interfering RNA (siRNA) of NCOA4, the interfering RNA having the sequence:
5’-GACCUUAUUUAUCAGCUUA-3’。
The above sequence is obtained by the following method:
1. By scanning the nucleotide sequence of NCOA4 gene (Gene ID: 8031) so that its 3' -end is dTdT; searching a first AA sequence from 75bp downstream of the promoter, and taking 19 bases after the sequence as a target sequence;
1. the resulting sequence was analyzed to give a GC content of about 50%.
2. The obtained sequences were compared with NCBI gene database using BLAST.
3. TT is added at the 3' end to increase the stability of siRNA, and the sequence of the obtained interference RNA is as follows:
4.5'-gaccuuauuuaucagcuuatt-3' (SEQ ID NO. 1). (the first to eighth "t" in the attached sequence listing represent uracil in the RNA sequence, and the ninth and tenth t represent thymine in the DNA sequence).
Example 2
PCOS patients (n=12) and non-PCOS patients (n=12) aged 20-35 years old who received IVF-ET treatment in a reproductive medicine center, all subjects used a flexible antagonist regimen to superovulate and ova were collected 36 hours after hCG triggering. The PCOS patients who were enrolled according to the standards set by cartap revised in 2004 (at least 2 out of 3).
Example 3
Western Blot detection of protein expression the tissues were lysed on ice using protein lysate (RIPA extracted cell total protein), protein concentration was determined using BCA protein quantification kit, 30. Mu.g of the samples were separated by SDS-PAGE electrophoresis, the proteins were transferred to PVDF membrane, blocked with 5% skim milk-TBST on a room temperature shaker for 2 hours, primary antibody was applied to a shaker at 4℃overnight, secondary antibody incubated at room temperature for 1 hour, and ECL luminophore stimulated fluorescence. Chemiluminescent exposure was performed in G-BOX. The following antibodies were used :anti-p-ERK(CST),total-ERK(CST),anti-C/EBPβ(Santa cruz),anti-GAPDH(Proteintech).FTH1(Abcam),GPX4(Abcam),GAPDH(Proteintech).
Example 4
After the human primordial granulosa cells are extracted, the expression of iron autophagy-related proteins NCOA4, FTH1 and GPX4 in the primordial granulosa cells of two groups of patients is detected by Western Blot.
As a result, it was found that iron autophagy carrier protein NCOA4 was increased in ovarian granulosa cells of PCOS patients as compared with the control group, and that iron-storing protein FTH1 and iron autophagy inhibiting protein GPX4 were decreased as compared with the control group, as shown in FIG. 1. The PCOS patient is indicated that the autophagy level of the ovarian granulosa cells of the PCOS patient is obviously increased compared with the control group.
Example 5
After ovary granulosa cells are extracted and plated, androgens with different concentrations are added for culturing for 24 hours, and protein expression of iron autophagy related proteins NCOA4, FTH1 and GPX4 in the granulosa cells is detected. The iron autophagy carrier protein NCOA4 in the ovarian granulosa cells after androgen addition is found to be increased compared with a control group, and the iron-storing protein FTH1 and the iron autophagy inhibiting protein GPX4 are found to be reduced compared with the control group, so that the androgen can induce the ovarian primordial granulosa cells to generate autophagy. Knocking down NCOA4 by liposome transfection si-NCOA4, adding androgen DHT, and detecting expression of NCOA4, FTH1 and GPX4 again. The result shows that the iron autophagy carrier protein NCOA4 is reduced compared with the simple addition of an androgen group, and the iron storage protein FTH1 and the iron autophagy inhibiting protein GPX4 are increased compared with the simple addition of the androgen group, so that the knocking down of NCOA4 can block the iron autophagy of the ovarian primordial granulosa cells caused by the androgen. As shown in fig. 2.
Example 6
The liposome is transfected with si-NCOA4 to knock down NCOA4, and the ERK signal channel of an ovulation-related channel and the expression condition of C/EBP beta are detected after androgen DHT is added, so that the phosphorylation ERK of the ovulation-related channel is inhibited, and the expression of C/EBP beta is reduced compared with that of a control group. Knocking down NCOA4 can improve this. As shown in fig. 3.
Example 7
Female SD rats of 3 weeks of age are divided into three groups: control group, PCOS module and PCOS+ siNOCA4 module. PCOS building blocks were subcutaneously injected with DHEA (6 mg/100g body weight) for 21 days. After PCOS+ siNOCA4 model rats were batched, a cut of about 1cm was made at the projection of the ovary surface on the back of the rats, and small interfering viruses (containing small interfering RNAs of 5'-GACCUUAUUUAUCAGCUUATT-3' (SEQ ID NO. 1)) were injected into the envelope gap of the ovary using a microinjector, and simultaneously DHEA (6 mg/100g body weight) was injected subcutaneously.
Vaginal smear is carried out every day 8 days before the molding is finished to observe estrus cycle so as to judge whether the molding is successful or not and then the mold is killed. The morphology of the ovaries of each group of rats was observed after the sacrifice, and the number of ovaries was found to be significantly reduced in the PCOS group of rats compared to the control group, but significantly increased after siNOCA4 treatment. Meanwhile, the ovulation-promoting experiment is carried out on the rats, and after the successful modeling, the pregnant horse serum (PERGNANT MARE serum gonadotropin, PMSG) is injected into the abdominal cavity of the rats for 300IU/kg body weight. Rats were intraperitoneally injected with hCG300IU/kg body weight 48 hours after PMSG injection. The ova were collected and expelled from the oviducts 16 hours after hCG injection.
The number of ovulations was found to be significantly reduced in rats in the PCOS group and the quality of ova was significantly reduced compared to the control group. The ovulation number and the ovum quality of the PCOS+ siNOCA4 model group rats are obviously improved compared with those of the PCOS group rats. As shown in fig. 4.
The statistical method of the embodiment comprises the steps of adopting single-factor variance analysis to test whether the mean difference of each group has statistical significance; the test level was p <0.05. SPSS19.0 statistical software was used for data statistics and analysis.
Claims (6)
1. The application of the nuclear receptor coactivator 4 as a target spot in screening and preparing medicaments for treating the ovulation disorder of polycystic ovary syndrome.
2. The application of the reagent for detecting the nuclear receptor coactivator 4 in preparing a kit for diagnosing the ovulation disorder of polycystic ovary syndrome.
3. Use of nuclear receptor coactivator 4 for the preparation of a marker for diagnosing ovulation disorders of polycystic ovary syndrome.
4. Application of nuclear receptor coactivator 4 as diagnostic marker in preparing kit for diagnosing polycystic ovary syndrome ovulation disorder.
5. An interfering RNA having a nucleotide sequence 5'-GACCUUAUUUAUCAGCUUATT-3'.
6. Use of an interfering RNA of claim 5 in the manufacture of a medicament for the treatment of polycystic ovary syndrome with ovulation disorder.
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