Estrogen Receptor 1 Research Articles

Potential molecular mechanism of the Xiexin capsule in the intervention of dyslipidemia based on bioinformatics and molecular docking.

Objective: bioinformatic methods and molecular docking technology were used to predict the active components, targets, and related biological pathways of the Xiexin capsule in the intervention for dyslipidemia, exploring its mechanism. Methods: the active components and targets of the Xiexin capsule were screened by the TCMSP (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform )database. Genecards (The Human Gene Database), OMIM (Online Mendelian Inheritance in Man), PharmGkb (Pharmacogenomics Knowledge Base database), TTD (Therapeutic Target Database), and Drugbank platforms were used to search the disease targets of dyslipidemia. The Cytoscape 3.8.0 software was used to construct the 'component-target' network diagram, and the STRING (functional protein association networks) platform was used to analyze protein-protein interaction (PPI). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomics (KEGG) enrichment analyses were performed by R language data packets to predict the mechanism of action. The AutoDockVina and PyMol software were used to dock the key active components in the Xiexin capsule and the core proteins in PPI. Results: a total of 66 effective components were screened, involving 114 targets; 87 key active compounds were screened from the 'drug-component-target' diagram. The PPI network mainly involved core proteins such as PTGS2 (prostaglandin-endoperoxide synthase 2), PTGS1 (prostaglandin-endoperoxide synthase 1), and HSP90AA1 (heat shock protein 90 alpha family class A member 1). GO and KEGG enrichment analysis results of common targets mainly involved hormone-mediated signaling pathway, steroid hormone response, lipid transport and metabolism, regulation of cholesterol storage, cyclooxygenase pathway, and other biological pathways, as well asMM PPAR (peroxisome proliferators-activated receptor) signaling pathway, IL-17 (interleukin 17) signaling pathway, PI3K-Akt (protein kinase b) signaling pathway, FcεRI signaling pathway, and other related pathways. Molecular docking verification showed that quercetin had the best binding with the core target protein HSP90AA1, and HSP90AA1 was the target protein with the best binding activity for the key chemical components in Xiexin capsules. Conclusion: the main chemical components in the Xiexin capsules may participate in the regulation of PPAR and other signaling pathways by regulating key genes such as ESR1 (estrogen receptor 1), MAPK14 (mitogen-activated protein kinase 14), and HSP90AA1, to exert the pharmacological effect of the intervention on dyslipidemia.

Clarifying differences in gene expression profile of umbilical cord vein and bone marrow-derived mesenchymal stem cells; a comparative in silico study

BackgroundMesenchymal stem cells (MSCs) represent a promising therapeutic approach due to their capacity for self-renewal, immunomodulatory properties, and tissue regenerative potential. The immunomodulatory properties of MSCs have opened up the use of these versatile cells for treating immune- and inflammation-mediated disease entities. In addition, MSCs have emerged as a perspective for anti-cancer therapy, showing a tendency to accumulate at tumor sites. In the present study, we analyzed two MSC types, human bone marrow-derived MSC (hBM-MSCs) and human umbilical cord-derived MSC (hUC-MSCs), with the same passage numbers and before their exposure to any stimulating environment to compare their immunomodulation and migration abilities. MethodsVarious pro- and anti-inflammatory factors expressed by hBM-MSCs and hUC-MSCs in non-stimulating environments were screened out and compared. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) analysis were accomplished to determine functional annotation of the robust differentially expressed genes. Moreover, hub genes were identified using protein-protein interaction (PPI) network analysis. ResultsOur findings revealed that hUC-MSCs can express higher levels of pro- and anti-inflammatory factors compared to hBM-MSCs. Additionally, 1305 upregulated genes for hUC-MSCs and 1969 upregulated genes for hBM-MSCs were identified. We found that the limited number of hBM-MSCs upregulated genes were associated with some cancers and immune system diseases, yet the significant numbers of hUC-MSCs upregulated genes were mainly involved in pathways of neurodegeneration and cancers. Among all hub genes, estrogen receptor 1 (ESR1) and JUN achieved the highest scores in hBM-MSCs and hUC-MSCs, respectively. ConclusionsThe novel data obtained from our study have declared the presence of a wide range of robust upregulated genes in hUC-MSCs, particularly JUN as a proto-oncogene, which can contribute to some life-threatening diseases.

ASSOCIATION OF NOVEL POLYMORPHISM OF ESR2 GENE (G40100A) WITH PRODUCTION TRAITS OF BROWN LOCAL IRAQI CHICKEN

The estrogen receptor 2 (ESR2) plays a crucial role in the growth and development of follicles and ovulation in chickens. The aim of this study was detect the association of estrogen receptor 2(ESR2) gene polymorphisms with the production performance of brown local Iraqi chicken. A total of 104 hens from the F4th generation of local chicken selected for high egg yield were used. The novel SNP(G40100A) transition within third prime untranslated region (3 prime UTR) of ESR2 gene. Three genotypes were found: Wild(GG), Heterozygous(GA), and Homozygous(AA) through (PCR-DAN sequencing). Chi-square analysis showed no significant in genotypic and allelic frequencies for SNP which were agreement with Hardy-Weinberg equilibrium. The genotypes GG and GA were significantly superior with age at sexual maturity compared to AA genotype. The genotype GA was significantly associated with hen day egg production (HDEP) at 30 weeks compared to genotype AA, as well as the genotype GA highest significant variance was reported comparing with the GG genotype in HDEP at 45 and 60 weeks, thus, the study recommends to exploit this ESR2 gene polymorphism (G40100A) as promising marker in breeding program via, the selection of individuals carrying the genotype GA, characterized by the high egg production.

POLIMORPHIC CHARACTERIZATION OF ESR1 AND FOXL2 GENES AND THE ASSOCIATION OF THEIR INTERACTION WITH PRODUCTIVE TRAITS OF BROWN LOCAL IRAQI CHICKENS

The estrogen receptor 1(ESR1) and fork-head box L2 (FOX L2) genes play a pivotal role in regulation of egg formation in poultry. this study aimed to investigate interaction between ESR1 and FOXL2 in the productive performance of brown local Iraqi chickens (BLIC). A total of 104 BLIC represented from the F4th generation of local chicken selected for high egg productions were used. Two novel single nucleotide polymorphism (SNPs), one of them in ESR1 (T57198C) intron 3, and another of FOX L2 (C919T) gene within encoding region were identified through PCR-DNA sequencing. Six haplotypes (H1=TTCC, H2=TTCT, H3=TCCC, H4=TCCT, H5=CCCC, H6=CCCT) were obtained due to interaction between these two SNPs. Chi-square analysis showed no significant in genotypic and allelic frequencies for each SNP which revealed that both genes were agreement with Hardy-Weinberg equilibrium. Association analysis of haplotypes with production traits revealed that individuals have H4 genotype achieved higher body weight at sexual maturity, at 60 weeks of age and egg weight at 45 and 60 weeks of age, whereas, the higher number of eggs were exhibited in individual with H6 from onset egg till 60 weeks of age. The two haplotypes; H4(TCCT) and H6(CCCT) showed better combination than others with respect to production performance. In conclusion, our findings provided new evidence that the two genes (ESR1 and FOXLl2) with special interaction may have potential effects on productive traits of chickens and beneficial effects in laying breeding programs.

Prenatal Exposure to Triclocarban Impairs ESR1 Signaling and Disrupts Epigenetic Status in Sex-Specific Ways as Well as Dysregulates the Expression of Neurogenesis- and Neurotransmitter-Related Genes in the Postnatal Mouse Brain.

Triclocarban is a highly effective and broadly used antimicrobial agent. Humans are continually exposed to triclocarban, but the safety of prenatal exposure to triclocarban in the context of neurodevelopment remains unknown. In this study, we demonstrated for the first time that mice that had been prenatally exposed to environmentally relevant doses of triclocarban had impaired estrogen receptor 1 (ESR1) signaling in the brain. These mice displayed decreased mRNA and protein expression levels of ESR1 as well as hypermethylation of the Esr1 gene in the cerebral cortex. Prenatal exposure to triclocarban also diminished the mRNA expression of Esr2, Gper1, Ahr, Arnt, Cyp19a1, Cyp1a1, and Atg7, and the protein levels of CAR, ARNT, and MAP1LC3AB in female brains and decreased the protein levels of BCL2, ARNT, and MAP1LC3AB in male brains. In addition, exposure to triclocarban caused sex-specific alterations in the methylation levels of global DNA and estrogen receptor genes. Microarray and enrichment analyses showed that, in males, triclocarban dysregulated mainly neurogenesis-related genes, whereas, in females, the compound dysregulated mainly neurotransmitter-related genes. In conclusion, our data identified triclocarban as a neurodevelopmental risk factor that particularly targets ESR1, affects apoptosis and autophagy, and in sex-specific ways disrupts the epigenetic status of brain tissue and dysregulates the postnatal expression of neurogenesis- and neurotransmitter-related genes.

Exploring anti-liver cancer targets and mechanisms of oxyresveratrol: in silico and verified findings

ABSTRACT The aim of current study was to exhume the potential targets and molecular mechanisms of oxyresveratrol, a structurally re-constructed resveratrol, for treating liver cancer through bioinformatics investigation and experimentative validation. To start with, the network pharmacology approach and molecular docking technology were used to uncover all candidate targets of oxyresveratrol to treat liver cancer, accompanied with identified anti-liver cancer targets including estrogen receptor 1 (ESR1), epidermal growth factor receptor (EGFR). In addition, more pharmacological mechanisms of oxyresveratrol against liver cancer were revealed in details. In experimental verification, the clinical samples of liver cancer showed elevated ESR1, EGFR mRNA expressions. The in-vitro data indicated that intracellular contents of ESR1, EGFR mRNAs in oxyresveratrol-treated liver cancer cells were reduced. Taken together, the bioinformatics and validated findings have highlighted detailed pharmacological targets and molecular mechanisms of oxyresveratrol for treating liver cancer. Following with experimental verification, the identified genes of ESR1, EGFR may function as potential screening anti-liver cancer markers.

Effects of FecB Mutation on Estrus, Ovulation, and Endocrine Characteristics in Small Tail Han Sheep.

The Booroola fecundity gene (FecB) has a mutation that was found to increase the ovulation rate and litter size in Booroola Merino sheep. This mutation is also associated with the fecundity of small-tail han (STH) sheep, an important maternal breed used to produce hybrid offspring for mutton production in China. Previous research showed that the FecB gene affects reproduction in STH sheep, based on litter size records. However, the effects of this gene on estrus, ovulation, and endocrine characteristics in these sheep remain unclear. Here, we analyzed the traits mentioned earlier and compared them among the three FecB genotypes of STH ewes using estrus synchronization. Overall, 53 pluriparous ewes were selected from among 890 STH ewes and subjected to FecB genotyping for experiments to characterize estrous and ovulation rates. FecB heterozygous (+B) ewes presented an earlier onset of estrus (42.9 ± 2.2 h) and a shorter estrous cycle (17.2 ± 0.2 days) (P ≤ 0.05). The ovulation rates increased with the increasing copy number of the B allele (P ≤ 0.01). Ovulation time showed no significant differences among the three FecB genotypes. The serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone, estrogen (E2), and progesterone (P4) were measured in 19 of the ewes. Serum concentrations of E2 and FSH dramatically varied around the time of behavioral estrus. In FecB mutant homozygous (BB) ewes, E2 concentration had two peaks, which were higher (P ≤ 0.05) than those of ++ genotypes. FSH concentration of BB ewes was higher (P ≤ 0.05) than that of the ++ ewes just after estrus. The expression of the estrogen receptor 1 (ESR1) gene in the +B genotype was higher than in the other genotypes. Based on the data for the reproductive performance of STH ewes with the three FecB genotypes, our study suggests that the development of follicles in ewes with the B allele is dependent on the response to FSH regulated by E2 in the early stage. +B ewes, exhibiting moderate ovulation and litter size and a shorter estrous cycle, can be highly recommended in sheep crossbreeding systems for commercial mutton production. Moreover, this study provides useful information to conserve better and use the genetic resources of STH sheep in China.

The change pattern in serum G protein-coupled estrogen receptor-1 (GPER1) levels during pregnancy with and without gestational diabetes mellitus.

The purpose of this study was to evaluate serum G protein-coupled estrogen receptor-1 (GPER1) levels in non-pregnant and pregnant with and without gestational diabetes mellitus (GDM). The study comprised 40 pregnant women with (n=20) and without GDM (n=20) and 20 healthy non-pregnant women. Data as maternal age, gestational age, and body mass index (BMI) of participants were recorded and serum samples were collected. Serum GPER1 levels were measured by enzyme-linked immunosorbent assays. Serum GPER1 level was significantly higher in GDM (p=0.03) and non-pregnant women (p=0.005) than those of normal pregnancy. There was no significant correlation between the serum GPER1 levels age (r=0.18, p=0.34), gestational age (r=-0.22, p=0.47), and BMI (r=0.004, p=0.975). Our results suggest that changes in serum GPER1 levels in pregnancy and GDM may be associated with estrogen. More detailed studies should be conducted to monitor the changes and their interactions in serum sex hormones and serum GPER1 levels during GDM.

Regulation of AKT Signaling in Mouse Uterus.

17β-estradiol (E2) treatment of ovariectomized adult mice stimulates the uterine PI3K-AKT signaling pathway and epithelial proliferation through estrogen receptor 1 (ESR1). However, epithelial proliferation occurs independently of E2/ESR1 signaling in neonatal uteri. Similarly, estrogen-independent uterine epithelial proliferation is seen in adulthood in mice lacking Ezh2, critical for histone methylation, and in wild-type (WT) mice treated neonatally with estrogen. The role of AKT in estrogen-independent uterine epithelial proliferation was the focus of this study. Expression of the catalytically active phosphorylated form of AKT (p-AKT) and epithelial proliferation were high in estrogen receptor 1 knockout and WT mice at postnatal day 6, when E2 concentrations were low, indicating that neither ESR1 nor E2 are essential for p-AKT expression and epithelial proliferation in these mice. However, p-AKT levels and proliferation remained estrogen responsive in preweaning WT mice. Expression of p-AKT and proliferation were both high in uterine luminal epithelium of mice estrogenized neonatally and ovariectomized during adulthood. Increased expression of phosphorylated (inactive) EZH2 was also observed. Consistent with this, Ezh2 conditional knockout mice show ovary-independent uterine epithelial proliferation and high epithelial p-AKT. Thus, adult p-AKT expression is constitutive and E2/ESR1 independent in both model systems. Finally, E2-induced p-AKT expression and normal uterine proliferation did not occur in mice lacking membrane (m)ESR1, indicating a key role for membrane ESR1 in AKT activation. These findings emphasize the importance of AKT activation in promoting uterine epithelial proliferation even when that proliferation is not E2/ESR1 dependent and further indicate that p-AKT can be uncoupled from E2/ESR1 signaling in several experimental scenarios.

Estradiol Protects against Noise-Induced Hearing Loss and Modulates Auditory Physiology in Female Mice.

Recent studies have identified sex-differences in auditory physiology and in the susceptibility to noise-induced hearing loss (NIHL). We hypothesize that 17β-estradiol (E2), a known modulator of auditory physiology, may underpin sex-differences in the response to noise trauma. Here, we gonadectomized B6CBAF1/J mice and used a combination of electrophysiological and histological techniques to study the effects of estrogen replacement on peripheral auditory physiology in the absence of noise exposure and on protection from NIHL. Functional analysis of auditory physiology in gonadectomized female mice revealed that E2-treatment modulated the peripheral response to sound in the absence of changes to the endocochlear potential compared to vehicle-treatment. E2-replacement in gonadectomized female mice protected against hearing loss following permanent threshold shift (PTS)- and temporary threshold shift (TTS)-inducing noise exposures. Histological analysis of the cochlear tissue revealed that E2-replacement mitigated outer hair cell loss and cochlear synaptopathy following noise exposure compared to vehicle-treatment. Lastly, using fluorescent in situ hybridization, we demonstrate co-localization of estrogen receptor-2 with type-1C, high threshold spiral ganglion neurons, suggesting that the observed protection from cochlear synaptopathy may occur through E2-mediated preservation of these neurons. Taken together, these data indicate the estrogen signaling pathways may be harnessed for the prevention and treatment of NIHL.

Polimorphic Explore of Esr1, Esr2 and Foxl2 Genes and Interaction Effect of Esri and Foxl2 with Productive Traits of Brown Local Iraqi Chickens

The estrogen receptor 1(ESR1) and estrogen receptor 2 (ESR2) plays a crucial role in the growth and development of follicles and ovulation in chickens. Fork-head box L2 (FOX L2) gene and its protein is active in several tissues, such as the ovaries, it has a pivotal role in ovarian development and function, like regulation of egg formation in poultry. This study aimed to detect the polymorphism of ESR1, ESR2 and, FOXL2 genes and investigate interaction between ESR1 and FOXL2 in the productive performance of brown local Iraqi chickens (BLIC). A total of 104 BLIC, at 17 weeks of age. Four novel single nucleotide polymorphism (SNPs). Every polymorphism a number had been given according to its location within gene, one of them in ESR1 (T57198C) intron 3 with three genotypes: Wild(TT), Heterozygous(TC),and Homozygous(CC), and two SNPs within ESR2 were assessed, one of the identified SNPsT39565C transition located within intron 7 with two alleles(T and C)and three genotypes were found: Wild(TT), Heterozygous(TC),and Homozygous(CC), another SNPG40100A transition within (3 prime UTR), with two alleles (G and A)and three genotypes were found: Wild(GG), Heterozygous(GA)and Homozygous(AA) and the SNP in FOXL2 (C919T) gene with two genotypes: Wild(CC) and Heterozygous(CT) within encoding region were identified through PCR-DNA sequencing. An interaction between the ESR1 and FOXL2 genes has been proposed, and six haplotypes (H1=TTCC, H2=TTCT, H3=TCCC, H4=TCCT, H5=CCCC, H6=CCCT) were obtained due to interaction between these two SNPs. Chi-square analysis showed no significant in genotypic and allelic frequencies for each SNP which revealed those genes were agreement with Hardy-Weinberg equilibrium. Association analysis of haplotypes with production traits revealed that individuals have H4 genotype achieved higher body weight at sexual maturity, at 60 weeks of age and egg weight at 45 and 60 weeks of age, whereas, the higher number of eggs were exhibited to individual with H6 from onset egg till 60 weeks of age. The two genotypes; TCCT and CCCT showed better combination than others with respect to production performance. In conclusion, our findings provided new evidence that the two SNPs (ESR1 and FOXLl2) with special interaction may have potential effects on productive traits of chickens and beneficial effects in laying breeding programs.

Disrupted PGR-B and ESR1 signaling underlies defective decidualization linked to severe preeclampsia.

Decidualization of the uterine mucosa drives the maternal adaptation to invasion by the placenta. Appropriate depth of placental invasion is needed to support a healthy pregnancy; shallow invasion is associated with the development of severe preeclampsia (sPE). Maternal contribution to sPE through failed decidualization is an important determinant of placental phenotype. However, the molecular mechanism underlying the in vivo defect linking decidualization to sPE is unknown. Global RNA sequencing was applied to obtain the transcriptomic profile of endometrial biopsies collected from nonpregnant women who suffer sPE in a previous pregnancy and women who did not develop this condition. Samples were randomized in two cohorts, the training and the test set, to identify the fingerprinting encoding defective decidualization in sPE and its subsequent validation. Gene Ontology enrichment and an interaction network were performed to deepen in pathways impaired by genetic dysregulation in sPE. Finally, the main modulators of decidualization, estrogen receptor 1 (ESR1) and progesterone receptor B (PGR-B), were assessed at the level of gene expression and protein abundance. Here, we discover the footprint encoding this decidualization defect comprising 120 genes-using global gene expression profiling in decidua from women who developed sPE in a previous pregnancy. This signature allowed us to effectively segregate samples into sPE and control groups. ESR1 and PGR were highly interconnected with the dynamic network of the defective decidualization fingerprint. ESR1 and PGR-B gene expression and protein abundance were remarkably disrupted in sPE. Thus, the transcriptomic signature of impaired decidualization implicates dysregulated hormonal signaling in the decidual endometria in women who developed sPE. These findings reveal a potential footprint that could be leveraged for a preconception or early prenatal screening of sPE risk, thus improving prevention and early treatments. This work has been supported by the grant PI19/01659 (MCIU/AEI/FEDER, UE) from the Spanish Carlos III Institute awarded to TGG. NCM was supported by the PhD program FDGENT/2019/008 from the Spanish Generalitat Valenciana. IMB was supported by the PhD program PRE2019-090770 and funding was provided by the grant RTI2018-094946-B-100 (MCIU/AEI/FEDER, UE) from the Spanish Ministry of Science and Innovation with CS as principal investigator. This research was funded partially by Igenomix S.L.

Weighted gene coexpression network analysis reveals ESR1, FLNA and Furin as hub genes for DEHP-induced prepubertal testicular injury

Di-(2-ethylhexyl) phthalate (DEHP) is an environmental endocrine disruptor that accumulates in organisms in various ways and induces male reproductive system disorders. In this study, we established a testicular injury model by gavage with different concentrations of DEHP. The testes were then collected for RNA sequencing (RNA-seq), and the results were analyzed by bioinformatics and verified by experiments. Our research results show that different concentrations of DEHP interfere with testicular development differently. Weighted gene coexpression network analysis (WGCNA) generated sixteen modules and identified the turquoise module as key. Then, estrogen receptor 1 (ESR1), filamin A (Flna) and Furin were identified as hub genes. qPCR and immunohistochemistry results revealed that all three hub genes were upregulated. We detected the locations of these genes by immunohistochemistry. ESR1 was mainly located in Leydig cells; Flna immunostaining is observed in the Leydig and some germ cells and Furin staining was seen in almost all types of testicular cells. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed enrichment mainly in MAPK signaling pathways, p53 signaling pathways, HIF-1 signaling pathways, protein processing in the endoplasmic reticulum, apoptosis, the cell cycle, RNA degradation, etc. This is the first study using WGCNA to investigate the mechanism of DEHP-induced injury in the prepubertal testis, providing new research angles to further understand the mechanism of DEHP-induced injury in the prepubertal testis.

ESR2 regulates PINK1-mediated mitophagy via transcriptional repression of microRNA-423 expression to promote asthma development

Asthma represents an inflammatory airway disease related to the induction of airway eosinophilia, mucus overproduction, and bronchial hyperresponsiveness. This study explored the effects of microRNA-423 (miR-423) on mitophagy and inflammation in asthmatic mice challenged with house dust mites (HDMs) and rhinovirus (RV). By searching for differentially expressed miRNAs in the GSE25230 microarray, miR-423 was identified as our target. Moreover, miR-423 was expressed at low levels in the lung tissues from patients with asthma, and agomiR-423 significantly inhibited RV-induced inflammatory injury and activation of inflammasome signaling in mouse lung tissues. Additionally, miR-423 downregulated the expression of IL-1β/NLRP3/Caspase-1 inflammasome signaling by targeting phosphatase and tensin homolog-induced putative kinase 1 (PINK1). Furthermore, luciferase reporter experiments and ChIP-qPCR assays revealed that estrogen receptor 2 (ESR2) transcriptionally repressed miR-423 expression by coordinating with H3K9me2 modification of the miR-423 promoter histone. Overall, ESR2 synergized with the H3K9me2 modification of the miR-423 promoter histone to transcriptionally repress miR-423 expression and increase PINK1 expression in lung tissues, resulting in asthma exacerbation.

PSV-6 Single nucleotide polymorphisms associated with advanced skeletal maturity in finished beef heifers

Abstract Accelerated skeletal maturity is prevalent in modern commercial heifers harvested under 30 months of age. It is hypothesized that selection for increased growth and earlier reproductive maturity over several decades, unintentionally co-selected for precocious skeletal ossification in heifers. This study examines the relationship of single nucleotide polymorphisms (SNPs) in beef heifers with developmental maturity (A-, B-, C- Maturity) assessed at harvest, and evaluates specific genotype and production implant potency interactions. Two SNPs within Estrogen Receptor 1 (ESR1) and one SNP within Alkaline Phosphatase (ALPL) genes that have been previously associated with carcass skeletal maturity were examined. USDA inspected beef heifer carcasses (< 30 months) that were A- (n = 318), B- (n = 296), or C- (n = 251) skeletal maturity were sampled. DNA was extracted and SNP genotypes were ascertained using custom designed allelic discrimination assays (Taqman® Custom SNP Assays). Dominant and basic association tests were performed, and the impact of implants were evaluated as co-variates against genotypes using a linear regression model in the SNP and Variation Suite (SVS) software (Golden Helix, Inc.). A significant association with skeletal maturity was detected with ESR1 SNP 1 (P < 0.05) and a trend observed with ALPL (P < 0.1), but there was no significance identified in ESR1 SNP 2. A highly significant interaction with genotype and incidence of skeletal maturity was identified for ESR1 SNP 1 (P < 0.01) and ALPL (P < 0.01) when estrogenic implant concentration was included. There exists a strong relationship for these genotypes and advanced skeletal maturity in commercial heifers which is influenced by estrogenic potency of the commercial implant used. This study confirms the association of previously identified genotypes with advanced skeletal maturity and provides evidence that genetic variations in ESR1 play an important role in the regulation of bone mineralization in heifers.

Type 2 Diabetes Mellitus Mediation by the Disruptive Activity of Environmental Toxicants on Sex Hormone Receptors: In Silico Evaluation.

This study investigates the disruptive activity of environmental toxicants on sex hormone receptors mediating type 2 diabetes mellitus (T2DM). Toxicokinetics, gene target prediction, molecular docking, molecular dynamics, and gene network analysis were applied in silico techniques. From the results, permethrin, perfluorooctanoic acid, dichlorodiphenyltrichloroethane, O-phenylphenol, bisphenol A, and diethylstilbestrol were the active toxic compounds that could modulate androgen (AR) and estrogen-α and –β receptors (ER) to induce T2DM. Early growth response 1 (EGR1), estrogen receptor 1 (ESR1), and tumour protein 63 (TP63) were the major transcription factors, while mitogen-activated protein kinases (MAPK) and cyclin-dependent kinases (CDK) were the major kinases upregulated by these toxicants via interactions with intermediary proteins such as PTEN, AKT1, NfKβ1, SMAD3 and others in the gene network analysis to mediate T2DM. These toxicants pose a major challenge to public health; hence, monitoring their manufacture, use, and disposal should be enforced. This would ensure reduced interaction between people and these toxic chemicals, thereby reducing the incidence and prevalence of T2DM.

ESR1 mediated circ_0004018 suppresses angiogenesis in hepatocellular carcinoma via recruiting FUS and stabilizing TIMP2 expression

Angiogenesis has been certified to account for tumor pathobiology. Circular RNAs (circRNAs) have been demonstrated to be involved in angiogenesis-related diseases, including hepatocellular carcinoma (HCC). Nevertheless, the regulatory roles of most circRNAs remain obscure. This study aims to uncover the function of hsa_circ_0004018 on angiogenesis in HCC. Firstly, quantitative real-time RT-PCR (RT-qPCR) analyzed that circ_0004018 was definitely down-regulated in HCC. Western blot analysis was conducted to detect the protein level of fused protein in sarcoma (FUS) and TIMP metallopeptidase inhibitor 2 (TIMP2). Functional assays were carried out to assess the impacts of circ_0004018 on HCC. From the experimental results, we found that overexpression of circ_0004018 significantly inhibited angiogenesis in HCC. The regulatory mechanism of circ_0004018 in HCC was determined by chromatin immunoprecipitation (ChIP), luciferase reporter assays and RNA immunoprecipitation (RIP) assay. Therefore, we proved that estrogen receptor 1 (ESR1) mediated circ_0004018 regulated TIMP2 by recruiting FUS. A series of rescue assays verified that circ_0004018 participated in angiogenesis in HCC via modulating TIMP2. In summary, this paper disclosed that ESR1 activated circ_0004018 inhibited angiogenesis in HCC via binding to FUS and stabilizing TIMP2 expression.

Active components and action mechanism of Shenmai Injection in treatment of atrial fibrillation based on network pharmacology and molecular docking

This study aims to explore the active components and molecular mechanism of Shenmai Injection in the treatment of atrial fibrillation(AF) based on the application of network pharmacology and molecular docking technology. The chemical components of single herbs of Shenmai Injection were collected from TCMSP and TCMID, with the standard chemical name and PubChem CID(referred to as CID) obtained from PubChem database. The active components were screened using SwissADME, and their targets were predicted using SwissTargetPrediction. Targets related to AF treatment were identified using GeneCards, OMIM, and other databases. Venn diagram was constructed using Venny 2.1 to obtain the intersection targets. The single herb-active component-potential target network was constructed using Cytoscape, and the clusterProfiler R function package was used to perform the gene ontology(GO) and Kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment. The protein-protein interaction(PPI) network of intersection targets was generated based on the STRING database. The hub target protein was identified by visualization using Cytoscape, and then docked to its reverse-selected active components. The analysis showed that there were 65 active components with 681 corresponding targets in Shenmai Injection, 2 798 targets related to AF treatment, and 235 intersection targets involving 2 549 GO functions and 153 KEGG pathways. Finally, hub target proteins, including RAC-alpha serine/threonine-protein kinase(AKT1), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha(PIK3 CA), and estrogen receptor 1(ESR1), were screened out by PPI network visualization. The molecular docking was performed for 39 active components screened out in reverse, among which 30 active components de-monstrated high affinity. Among them, homoisoflavanoids CID 10871974, CID 5319742, and CID 10361149 had stronger affinity docking with AKT1. This study preliminarily indicates that Shenmai Injection treats AF through multiple components, multiple targets, and multiple pathways. Homoisoflavonoids of Ophiopogon japonicus are its important active components, which target AKT1 to regulate metabolism, inflammation, and apoptosis in AF treatment.

Tripartite motif-containing 3 (TRIM3) enhances ER signaling and confers tamoxifen resistance in breast cancer

Tamoxifen resistance remains a clinical problem in estrogen receptor (ER)-positive breast cancer. SUMOylation of ERα enhances ERα-induced transcription activity. Tripartite motif-containing (TRIM) proteins are a new class of SUMO E3 ligases, which regulate the SUMOylation of proteins. However, the precise molecular mechanism and function of TRIM3 in SUMOylation and the response to tamoxifen remain unclear. In the present study, we observed that TRIM3 was dramatically overexpressed in breast cancer, which correlated with tamoxifen resistance. Furthermore, TRIM3 overexpression significantly correlated with poor survival of patients with ER+ breast cancer treated with tamoxifen. TRIM3 overexpression conferred cell survival and tumorigenesis, whereas knocking down of TRIM3 reduced these capabilities. Moreover, TRIM3, as a ubiquitin carrier protein 9 (UBC9) binding protein, promoted SUMO modification of estrogen receptor 1 (ESR1) and activated the ER pathway. Silencing UBC9 abolished the function of TRIM3 in regulating tamoxifen resistance. These results suggest TRIM3 as a novel biomarker for breast cancer therapy, indicating that inhibiting TRIM3 combined with tamoxifen might provide a potential treatment for breast cancer.

Inokosterone Is A Potential Drug Target of Estrogen Receptor 1 in Rheumatoid Arthritis Patients: Analysis from Active Ingredient of Cyathula Officinalis

To elucidate the active compounds and the molecular mechanism of Cyathula Officinalis as a drug treatment for rheumatoid arthritis (RA). 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. 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. ESR1, the transcription factor that binds inokosterone in the molecular binding analysis, is the target protein of Cyathula Officinalis.