Study on the mechanism of miR-142-3p regulation of estrogen receptor 1 in gestational diabetes mellitus with preeclampsia / 中华内分泌外科杂志

Objective:To investigate the significance and regulatory mechanism of miR-142-3p and ER1 in serum and placenta of pregnant women with gestational diabetes mellitus (GDM) complicated with preeclampsia (PE) in the occurrence and development of disease.Methods:A total of 198 pregnant women admitted from Jun. 2019 to Jun. 2020 were selected as the study subjects, including 66 pregnant women with GDM (GDM group) , 60 pregnant women with GDM complicated with PE (GDM+PE group) and 72 normal pregnant women (control group) . Clinical indicators were detected and pregnancy outcome data were collected. The relative expression levels of miR-142 -3p and ER1 mRNA in serum and placental tissues of study subjects were determined by quantitative real-time polymerase link assay. The expression of ER1 protein in the placenta was detected by Western blot. Human choriotrophoblast cells HTR-8/SVneo were treated with miR-142-3p.Results:The expression levels of miR-142-3p in serum and placenta tissues in GDM+PE group were significantly lower than those in GDM+PE group and control group ( P<0.05) . The mRNA expression of ER1 in serum and placenta in GDM+PE group was significantly higher than that in GDM+PE group and control group ( P<0.05) . There was a significant negative correlation between the relative expression levels of miR-142-3p and ER1 mRNA in serum and placental tissues of pregnant women in the GDM+PE group ( r=-0.589 and -0.643, P=0.006 and < 0.001) .After transfection of HTR-8/SVneo cells with miR-142-3p, ER1 mRNA expression in the mimic group was 1.09±0.14,significantly lower than that of NC group (2.14±0.52) , inhibitor group (3.69±0.88) and inhibitor NC group (2.26±0.43) ( P<0.001) . The expression of DNMT1 in inhibitor group was significantly higher than that in the other three groups ( P<0.001) . Conclusion:In patients with GDM complicated with PE, miR-142-3p levels are reduced and ER1 levels are increased, which may be involved in the occurrence and progression of the disease.

Inokosterone Is A Potential Drug Target of Estrogen Receptor 1 in Rheumatoid Arthritis Patients: Analysis from Active Ingredient of Cyathula Officinalis / 中国结合医学杂志

OBJECTIVE@#To elucidate the active compounds and the molecular mechanism of Cyathula Officinalis as a drug treatment for rheumatoid arthritis (RA).@*METHODS@#The target genes of active ingredients from Cyathula Officinalis were obtained from bioinformatics analysis tool for the molecular mechanism of traditional Chinese medicine. The protein-protein interaction between the target genes were analyzed using STRING and Genemania. The transcriptome of RA patients compared to healthy people (GSE121894) were analyzed using R program package Limma. The relative expression of the target genes was obtained from the RNA-seq datasets. The molecular docking analyses were processed based on the molecular model of estrogen receptor 1 (ESR1) binding with estradiol (PDB ID:1A52). The binding details were analyzed by SYBYL.@*RESULTS@#Inokosterone, ecdysterone, and cyaterone were the 3 active ingredients from Cyathula Officinalis that bind to target genes. Of all the significantly changed genes from RA patients, ESR1, ADORA1, and ANXA1 were significantly increased in mRNA samples of RA patients.@*CONCLUSION@#ESR1, the transcription factor that binds inokosterone in the molecular binding analysis, is the target protein of Cyathula Officinalis.

Association of Estrogen Receptor 1 Genetic Polymorphisms with Recurrent Spontaneous Abortion Risk / 中华医学杂志(英文版)

Background@#Estrogen is one of the most important reproductive steroidal hormones and plays a critical role in the maintenance of pregnancy, and its function is mediated by estrogen receptor 1(ESR1). The polymorphisms of ESR1 were involved in recurrent spontaneous abortion (RSA); however, the association between ESR1 polymorphisms and RSA remains controversial. The present meta-analysis was aimed to clarify the association between ESR1 PvuII (-397C/T, rs2234693) and XbaI (-351A/G, rs9340799) polymorphisms and the risk of RSA.@*Methods@#All the included articles were retrieved from PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Med Online Database up to January 3, 2018. Data were processed in the Stata 12.0 software. The odds ratios (OR s) and 95% confidence intervals (95% CI s) were calculated using fixed-effects models (FEM)/random-effects models (REM).@*Results@#Seven case-control studies with 836 cases and 1164 controls were included in the study. Generally, the ESR1 polymorphisms were not associated with RSA in any of the genetic analysis models. However, it was found that as rs9340799 polymorphism was related to increased risk of RSA in non-Asian group in the homozygous genetic model (OR = 2.40, 95% CI = 1.05-5.50, P = 0.039). Moreover, in Asian group, rs9340799 polymorphism was found to be related to decreased RSA risk in both the heterozygous model (OR = 0.53, 95% CI = 0.33-0.85, P = 0.009) and the dominant genetic model (OR = 0.55, 95% CI = 0.30-0.98, P = 0.042).@*Conclusions@#Generally, there was no significant association between the polymorphisms of ESR1 and the risk of RSA. However, subgroup analysis indicated that ESR1 rs9340799 polymorphism was related to increased RSA risk in the non-Asian group while associated with decreased RSA risk in Asian group.

Effect of G Protein Coupled Estrogen Receptor 1 on Angiotensin Ⅱ-induced Hypertrophy of Cultured Neonatal Rat Cardiomyocytes / 中国循环杂志

Objectives: To observe the effect of activated G-protein coupled estrogen receptor 1 (GPER1) on Angiotensin II (AngII)-induced hypertrophy of cultured neonatal rat cardiomyocytes and explore related mechanisms. Methods: Primary cardiomyocytes derived from 2-to 3-day-old neonatal rats were cultured in vitro. Tandem mass tags (TMT) protein mass spectrometry was used to examine protein expressions; relevant bioinformatics analysis was performed to screen the possible regulatory mechanisms. Cardiomyocytes were divided into 6 groups: (1)Blank control group, (2) AngII group, (3)AngII+G1 (GPER1 activator) group, (4)AngII+G1+G15 (GPER1 inhibitor) group, (5)AngII+G1+U0126 (extracellular ERK inhibitor) group and (6)AngII+G1+MK2206 (AKT inhibitor) group (n=3 for each group). Cardiomyocytes GPER1 expressions, mRNA levels of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), protein levels of ERK, AKT with their interactions, autophagy-related proteins LC3II and LC3I were compared among different groups;impact of GPER1 on cardiomyocytes apoptosis was detected by flowcytometry. Results: AngII induced cardiomyocytes hypertrophy and upregulation of ANP and BNP mRNA levels in a dose-dependent manner (P<0.05). GPER1 expression could be detected on cardiomyocytes by Immunofluorescence technique. qRT-PCR results showed that GPER1 was activated by the specific activator G1 and mRNA expressions of ANP and BNP were inhibited in a dose-dependent manner by the specific activator G1 (P<0.05); mRNA levels of ANP and BNP were re-elevated in AngII+G1+G15 group (P<0.05). Western blotting results showed that protein expression of p-ERK and p-AKT was significantly higher in AngII group and AngII+G1 group than in blank control group (P<0.05), significantly reduced in AngII+G1+G15 group compared with AngII+G1 group (P<0.05); decreased expressions of p-ERK, p-AKT and mRNA levels of ANP,BNP were also detected in AngII+G1+MK2206 group (P<0.05). G1 induced protein expression was similar between AngII+G1 group and AngII+G1+U0126 group. Flowcytometry results indicated that cardiomyocytes apoptosis was similar between AngII+G1 group and AngII group (P>0.05). Ratio of LC3II/LC3I was significantly higher and autophagy levels were significantly enhanced in AngII group than in blank control group (P<0.01), these changes could be significantly reversed in AngII +G1 group (P<0.01 vs. AngII). Conclusions: Activation of GPER1 could inhibit neonatal cardiomyocytes hypertrophy, this effect might be related to AKT and ERK signaling pathway and cell autophagy.

Increased Serum G Protein-coupled Estrogen Receptor 1 Levels and Its Diagnostic Value in Drug Naïve Patients with Major Depressive Disorder

OBJECTIVE: The facts that depression is more prevalent in females than in males and females are exposed to depression more commonly during certain hormonal fluctuating periods indicate the role of sex hormones in physiopathology. Estrogen acts over estrogen receptors alpha and beta and recently identified G protein-coupled estrogen receptor 1 (GPER1). The present study aimed, for the first time, to evaluate serum GPER1 levels in drug-naïve major depressive disorder (MDD) patients. METHODS: The study included 56 newly diagnosed drug-naïve MDD patients aged between 18 and 50 years and 42 age- and gender-matched healthy volunteers. Medical history was obtained and physical examinations, laboratory tests, and the Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A) were performed. The serum GPER1 levels were measured. RESULTS: The HAM-D score was significantly higher in the MDD patients than in the controls. The GPER1 level was significantly higher in the MDD patients than in the controls. A positive correlation was found with GPER1 levels and depression scores. The receiver operating characteristic analysis revealed sensitivity, specificity, positive predictive value, and negative predictive value as 82.1%, 90.5%, 92.0%, and 79.2%, respectively, for the presence of depression, when the serum GPER1 value was ≥0.16. CONCLUSION: This study demonstrated significantly higher serum GPER1 levels in the MDD patients than in the controls, a positive correlation was found between GPER1 levels and depression scores and serum GPER1 level was valuable in predicting the presence of depression.

G-protein Coupled Estrogen Receptor 1 Expression in Primary Breast Cancers and Its Correlation with Clinicopathological Variables / 한국유방암학회지

PURPOSE: G-protein coupled estrogen receptor 1 (GPER) probably play important roles in the progression of breast cancer including endocrine therapeutic resistance. We evaluated GPER in primary breast cancers. METHODS: Immunohistochemistry was used to detect GPER in paraffin-embedded tissues of primary breast cancers from 423 patients and GPER expression was correlated with clinicopathological factors. RESULTS: GPER was expressed in 63.8% of specimens, coexpressed with estrogen receptor alpha (ERalpha) in 36.6% of tumors and was positive in 62.5% of the ERalpha-negative tumors. The expression of GPER had no relationship with the status of ERalpha, progesterone receptor and HER2. Although the expression of GPER was significantly inversely related with nodal status (p=0.045), no correlation between GPER expression and other clinicopathological variables (age, menstruation status, tumor size, stage, histologic grade, Nottingham Prognostic Index or pathological type) was found. CONCLUSION: GPER and ERalpha exhibited independent expression pattern of distribution in primary breast cancers. A long-term follow-up and a more definite molecular phenotype for ER are necessary in confirming studies.

Estrogen receptor 1, Glutathione S-transferase P1, Glutathione S-transferase M1, and Glutathione S-transferase T1 Genes with Dysmenorrhea in Korean Female Adolescents / 대한진단검사의학회지

BACKGROUND: Dysmenorrhea is the most common gynecologic complaint among adolescent females. We investigated the association between genetic polymorphisms and dysmenorrhea. METHODS: A total of 202 postmenarcheal Korean female adolescents 16-17 yr old participated in this study. Genotyping for glutathione S-transferase mu 1 (GSTM1), glutathione S-transferase theta 1 (GSTT1), glutathione S-transferase pi 1 (GSTP1), and estrogen receptor 1 (ESR1) was performed using PCR-based methods. RESULTS: The PP+Pp genotype of the ESR1 gene was more frequent than pp genotypes in subjects with dysmenorrhea than in subjects without dysmenorrhea (odds ratio=2.440; 95% confidence interval, 1.036-5.753; P=0.040) using an unadjusted univariate logistic regression analysis. The relationship between dysmenorrhea and ESR1 gene polymorphisms remained significant after adjustment for premenstrual syndrome, years elapsed after menarche, and family history of dysmenorrhea. No significant difference was observed between subjects with dysmenorrhea and subjects without dysmenorrhea for polymorphisms of GSTM1, GSTT1, and GSTP1 genes. CONCLUSIONS: Our results suggest that ESR1 gene polymorphisms may be associated with dysmenorrhea.

Estrogen receptor 1 gene polymorphisms in premenopausal women: interaction between genotype and smoking on lipid levels

Estrogen has multiple effects on lipid and lipoprotein metabolism. We investigated the association between the four common single nucleotide polymorphisms in the estrogen receptor 1 (ESR1) gene locus, -1989T>G, +261G>C, IVS1-397T>C and IVS1-351A>G, and lipid and lipoprotein levels in southern Brazilians. The sample consisted in 150 men and 187 premenopausal women. The women were considered premenopausal if they had regular menstrual bleeding within the previous 3 months and were 18-50 years of age. Exclusion criteria were pregnancy, secondary hyperlipidemia due to renal, hepatic or thyroid disease, and diabetes. Smoking status was self-reported; subjects were classified as never smoked and current smokers. DNA was amplified by PCR and was subsequently digested with the appropriate restriction enzymes. Statistical analysis was carried out for men and women separately. In the study population, major allele frequencies were _1989*T (0.83), +261*G (0.96), IVS1-397*T (0.58), and IVS1-351*A (0.65). Multiple linear regression analyses indicated that an interaction between +261G>C polymorphism and smoking was a significant factor affecting high-density lipoprotein cholesterol (HDL-C) levels (P = 0.028) in women. Nonsmoking women with genotype G/C of +261G>C polymorphism had mean HDL-C levels higher than those with G/G genotype (1.40 ± 0.33 vs 1.22 ± 0.26 mmol/L; P = 0.033). No significant associations with lipid and lipoprotein levels in women and men were detected for other polymorphisms. In conclusion, the +261G>C polymorphism might influence lipoprotein and lipid levels in premenopausal women, but these effects seem to be modulated by smoking, whereas in men ESR1 polymorphisms were not associated with high lipoprotein levels.

Association Study between 2 Single Nucleotide Polymorphisms in Estrogen Receptor 1 Gene and Korean Female Schizophrenic Patient

OBJECTIVES: Schizophrenia is equally distributed in both sexes. However, later-onset, milder psychopathology, and better outcome are associated with the females. This reason is thought to be partly due to the estrogen system. Recently, it was suggested that estrogen receptor 1(ESR1) gene polymorphisms might affect the expression of ESR1 and were associated with several psychiatric disorders. Thus, we investigated the association between two single nucleotide polymorphisms(SNPs) in the ESR1 gene and Korean schizophrenic patients in this study. METHODS: Genotype, allele, and haplotype frequencies of the two SNPs(rs 2234693 and rs 2228480) were analyzed between 218 Korean controls and 158 Korean schizophrenic patients. Also, age of onset and negative symptom scale scores according to genotypes were analyzed in the patients with schizophrenia. RESULTS: There was a significant difference in allele frequencies of rs 2234693 between the schizophrenic patients and the controls(p=0.03). Genotype distributions(p=0.03) and allele frequencies(p=0.01) of rs 2234693 were significantly different between the female schizophrenic patients and the female controls. The frequency of TC-CC genotypes compared with TT genotype in the female schizophrenic patients was significantly higher than that in the female controls(OR=2.36). The mean age of onset in the schizophrenic patients with TC-CC genotypes was significantly lower than that in the patients with TT genotype. The frequency of rs 2234693C-rs 2228480G haplotype in the female schizophrenic patients was relatively higher than that in the female controls. CONCLUSIONS: These results of our study support the possibility that the ESR1 gene polymorphisms might be involved in the susceptibility of females to schizophrenia and play a role in sex difference of schizophrenia.

Interaction between Estrogen Receptor 1 and the Epsilon 4 Allele of Apolipoprotein E in Korean Schizophrenic Patients / 신경정신의학

OBJECTIVES: Recent studies indicated that estrogen receptor 1 subtype(ESR1) genetic polymorphisms may affect the expression of ESR1, and are associated with Alzheimer's disease. This study was designed to investigate the interaction between ESR1 polymorphism and the epsilon4 allele of apolipoprotein E(ApoE) in Korean schizophrenic patients. METHODS: We studied 46 schizophrenic patients and 40 healthy controls. The ESR1 & ApoE polymorphisms were assessed by PCR-restriction fragment length polymorphism(RFLP) or reverse hybridization. RESULTS: The distribution of the genotype in schizophrenic patients with XX, Xx, xx, PP, Pp, pp were 7(15.2%), 20(43.5%), 19(41.3%), 10(21.7%), 19(41.3%), 17(37%), and the controls were 1(2.5%), 12(30%), 27(67.5%), 7(17.5%), 21(52.5%), and 12(30%). No significant differences for genotype distribution were revealed between controls and schizophrenic patients except Xba I genotype. The genotype frequency of schizophrenia with xx of ESR1 and epsilon4 of ApoE were 58.7%, 6.5% and that of the controls were 58.7%, and 15%, respectively. The ESR1 genotypes and ApoE were not associated with onset age, psychiatric symptoms, familial history, subtype(positive vs negative) of schizophrenic cases. In kappa-square, there is no significant difference between the two groups, and we are with an assum the interaction between the homogenous ESR1 xx genotype and the ApoE epsilon4 allele was not ob-served in schizophrenic patients. CONCLUSION: The ESR1 gene may not appears to interact with the ApoE epsilon4 genotype in determining schizophrenia susceptibility. There was no significant association between schizophrenia and ESR1 & ApoE gene polymorphism. But, Xba I genotype may be closer to schizophrenia than Pvu II genotype.