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High-grade urothelial carcinoma either non- Schistosoma (NS-UBC) or Schistosoma (S-UBC)-associated is the tenth cause of death worldwide and represents a serious therapeutic problem. Evaluation of the immmunohistochemical expression of tumor necrosis factor-alpha (TNFα), epidermal growth factor receptor (EGFR), programmed cell death protein-1 (PDL1), estrogen receptor-alpha (ERα) and UroplakinIII, in the high-grade in NS-UBC and S-UBC as potential prognostic and therapeutic targets analyzed through estimation of area percentage, optical density and international pathological scoring system for each marker. Sixty high grade urothelial carcinoma cases were enrolled in the study (30 cases of NS-UBC and 30 cases of S-UBC). The cases were immunohistochemically-assessed for TNFα, EGFR, PDL1, ERα and Uroplakin III expression. In S-UBC, parasite load was also evaluated for correlation with the immunohistochemical markers' expression in S-UBC. The area percentage of immune-expression of TNFα and EGFR was higher in S-UBC compared to NS-UBC. On the other hand, the NS-UBC displayed statistically-higher expression of PDL1 and uroplakinIII (p-value <0.001). ERα revealed higher, yet, non-significant expressions in S-UBC compared to NS-UBC (p-value =0.459). PDL1 expression showed the most superior record regarding area percentage (64.6± 34.5). Regarding optical density, TNF-α showed the highest transmittance expression (2.4 ± 0.9). EGFR positively correlated with PDL1 in S-UBC (r= 0.578, p-value =0.001) whereas in NS-UBC, TNFα and PDL1 (r=0.382, p-value=0.037) had positive correlation. Schistosoma eggs in tissues oppose uroplakin III expression and trigger immunomodulation via PDL1. Due to lower UroplakinIII expression, S-UBC is supposed to have a poorer prognosis. Hormonal therapy is not hypothesized due to a very minimal ERα expression in both NS-UBC and S-UBC. Regarding immunotherapy, anti-TNF-α is suggested for S-UBC whilst in NS-UBC, blockading PDL1 might be useful. Targeted EGFR therapy seems to carry emphasized outcomes in S-UBC. Correlations encourage combined immune therapy in NS-UBC; nevertheless, in S-UBC, combined anti-EGFR and PDL1 seem to be of benefit. • Uroplakin III showed minimal expression in S-UBC indicating poor prognosis. • The weak expression of ER does not support hormonal therapy in both S-UBC and NS-UBC. • Anti-TNF is recommended in S-UBC. • Blockage of the PD-1/PDL1 pathway is suggested be efficient in NS-UBC. [ABSTRACT FROM AUTHOR]

Although different types of drugs are available for postmenopausal osteoporosis, the limitations of the current therapies including drug resistances and adverse effects require identification of novel anti-osteoporosis agents. Here, we defined that norlichexanthone (NOR), a natural product, is a ligand of estrogen receptor-alpha (ER α) and revealed its therapeutic potential for postmenopausal osteoporosis. We used mammalian-one hybrid assay to screen for ER α modulators from crude extracts of several plant endophytes. As a result, NOR purified from the extract of endophyte ARL-13 was identified as a selective ER α modulator. NOR directly bound to ER α with an affinity in nanomolar range, revealing that it is a natural ligand of ER α. NOR induced osteoblast formation in MC3T3-E1 precursor cells. Conversely, NOR inhibited receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast formation in both RAW264.7 macrophages and mouse primary monocytes. Mechanistically, NOR inhibited RANKL-induced association of ER α and TRAF6 to prevent ER α -mediated TRAF6 activation via Lys63-linked ubiquitination. Importantly, NOR exhibited potent anti-osteoporosis efficacy in an ovariectomized mouse model. Comparing to estrogen, NOR was of much less capability in stimulating endometrial hyperplasia and promoting mammalian cancer cell proliferation. Taken together, our study identified NOR as a natural and high affinity ligand of ER α with substantial anti-osteoporosis but less estrogenic activity. Image 1 [ABSTRACT FROM AUTHOR]

Cancer therapy is a strategic measure in inhibiting breast cancer stem cell (BCSC) pathways. Naringenin, a citrus flavonoid, was found to increase breast cancer cells' sensitivity to chemotherapeutic agents. Bioinformatics study and 3D tumorsphere in vitro modeling in breast cancer (mammosphere) were used in this study, which aims to explore the potential therapeutic targets of naringenin (PTTNs) in inhibiting BCSCs. Bioinformatic analyses identified direct target proteins (DTPs), indirect target proteins (ITPs), naringenin-mediated proteins (NMPs), BCSC regulatory genes, and PTTNs. The PTTNs were further analyzed for gene ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, protein–protein interaction (PPI) networks, and hub protein selection. Mammospheres were cultured in serum-free media. The effects of naringenin were measured by MTT-based cytotoxicity, mammosphere forming potential (MFP), colony formation, scratch wound-healing assay, and flow cytometry-based cell cycle analyses and apoptosis assays. Gene expression analysis was performed using real-time quantitative polymerase chain reaction (q-RT PCR). Bioinformatics analysis revealed p53 and estrogen receptor alpha (ERα) as PTTNs, and KEGG pathway enrichment analysis revealed that TGF-ß and Wnt/ß-catenin pathways are regulated by PTTNs. Naringenin demonstrated cytotoxicity and inhibited mammosphere and colony formation, migration, and epithelial to mesenchymal transition in the mammosphere. The mRNA of tumor suppressors P53 and ERα were downregulated in the mammosphere, but were significantly upregulated upon naringenin treatment. By modulating the P53 and ERα mRNA, naringenin has the potential of inhibiting BCSCs. Further studies on the molecular mechanism and formulation of naringenin in BCSCs would be beneficial for its development as a BCSC-targeting drug. [ABSTRACT FROM AUTHOR]

Among obesity-associated metabolic diseases, non-alcoholic fatty liver disease (NAFLD) represents an increasing public health issue due to its emerging association with atherogenic dyslipidemia and cardiovascular diseases (CVDs). The lower prevalence of NAFLD in pre-menopausal women compared with men or post-menopausal women led us to hypothesize that the female-inherent ability to counteract this pathology might strongly rely on estrogen signaling. In female mammals, estrogen receptor alpha (ERα) is highly expressed in the liver, where it acts as a sensor of the nutritional status and adapts the metabolism to the reproductive needs. As in the male liver this receptor is little expressed, we here hypothesize that hepatic ERα might account for sex differences in the ability of males and females to cope with an excess of dietary lipids and counteract the accumulation of lipids in the liver. Through liver metabolomics and transcriptomics we analyzed the relevance of hepatic ERα in the metabolic response of males and females to a diet highly enriched in fats (HFD) as a model of diet-induced obesity. The study shows that the hepatic ERα strongly contributes to the sex-specific response to an HFD and its action accounts for opposite consequences for hepatic health in males and females. This study identified hepatic ERα as a novel target for the design of sex-specific therapies against fatty liver and its cardio-metabolic consequences. • Hepatic ERα contributes to sex-specific response to a fat-enriched diet. • Hepatic ERα action accounts for contrasting consequences in males and females. • In males, hepatic ERα action does not prevent liver lipid accumulation. • The lack of ERα is responsible for an altered plasma lipid profile in males. • In females, liver ERα controls lipid catabolism and counteracts NAFLD development. [ABSTRACT FROM AUTHOR]

Abstract Objective The endogenous estrogen 17β-estradiol (E2) promotes metabolic homeostasis in premenopausal women. In a mouse model of post-menopausal metabolic syndrome, we reported that estrogens increased energy expenditure, thus preventing estrogen deficiency-induced adiposity. Estrogens' prevention of fat accumulation was associated with increased serum concentrations of fibroblast growth factor 21 (FGF21), suggesting that FGF21 participates in estrogens' promotion of energy expenditure. Methods We studied the effect of E2 on FGF21 production and the role of FGF21 in E2 stimulation of energy expenditure and prevention of adiposity, using female estrogen receptor (ER)- and FGF21-deficient mice fed a normal chow and a cohort of ovariectomized women from the French E3N prospective cohort study. Results E2 acting on the hepatocyte ERα increases hepatic expression and production of FGF21 in female mice. In vivo activation of ERα increases the transcription of Fgf21 via an estrogen response element outside the promoter of Fgf21. Treatment with E2 increases oxygen consumption and energy expenditure and prevents whole body fat accumulation in ovariectomized female WT mice. The effect of E2 on energy expenditure is not observed in FGF21-deficient mice. While E2 treatment still prevents fat accumulation in FGF21-deficient mice, this effect is decreased compared to WT mice. In an observational cohort of ovariectomized women, E2 treatment was associated with lower serum FGF21 concentrations, which may reflect a healthier metabolic profile. Conclusions In female mice, E2 action on the hepatocyte ERα increases Fgf21 transcription and FGF21 production, thus promoting energy expenditure and partially decreasing fat accumulation. Highlights • Activation of the hepatocyte ERα increases FGF21 production in female mice. • ERα increases Fgf21 transcription in vivo via an estrogen response element. • Estrogen stimulation of energy expenditure is lost in female FGF21-deficient mice. • In women, estrogen treatment is associated with lower serum FGF21 concentrations. [ABSTRACT FROM AUTHOR]

TFIIB-related factor 1 (Brf1) modulates the transcription of RNA Pol III genes (polymerase-dependent genes). Upregulation of Pol III genes enhances tRNA and 5S RNA production and increases the translational capacity of cells to promote cell transformation and tumor development. However, the significance of Brf1 overexpression in human breast cancer ( HBC) remains to be investigated. Here, we investigate whether Brf1 expression is increased in the samples of HBC, and we explore its molecular mechanism and the significance of Brf1 expression in HBC. Two hundred and eighteen samples of HBC were collected to determine Brf1 expression by cytological and molecular biological approaches. We utilized colocalization, coimmunoprecipitation, and chromatin immunoprecipitation methods to explore the interaction of Brf1 with estrogen receptor alpha ( ERα). We determined how Brf1 and ERα modulate Pol III genes. The results indicated that Brf1 is overexpressed in most cases of HBC, which is associated with an ER-positive status. The survival period of the cases with high Brf1 expression is significantly longer than those with low levels of Brf1 after hormone treatment. ERα mediates Brf1 expression. Brf1 and ERα are colocalized in the nucleus. These results indicate an interaction between Brf1 and ERα, which synergistically regulates the transcription of Pol III genes. Inhibition of ERα by its si RNA or tamoxifen reduces cellular levels of Brf1 and Pol III gene expression and decreases the rate of colony formation of breast cancer cells. Together, these studies demonstrate that Brf1 is a good biomarker for the diagnosis and prognosis of HBC. This interaction of Brf1 with ERα and Brf1 itself are potential therapeutic targets for this disease. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA) has a number of adverse effects on the reproductive development of females. In particular, the mechanism of disruption of ovarian development in adolescent mice is still unclear. Based on transcriptome sequencing results, a differentially expressed lncRNA, Fhad1os2 , was detected in the ovaries of BPA-exposed pubertal mice. In our study, the lncRNA Fhad1os2 , localized in the ovarian granulosa cell cytoplasm, could regulate the proliferation of mouse ovarian granulosa cells. Mechanistically, the results of RNA pull-down experiments as well as mass spectrometry analysis showed that ERα, an interfering signaling molecule of BPA, could directly bind lncRNA Fhad1os2 and decrease the transcription of lncRNA Fhad1os2 in response to the estrogen-like effect of BPA. BPA exposure also caused abnormal lncRNA Fhad1os2 pulldown protein-related signaling pathways in the ovaries of adolescent mice. Furthermore, lncRNA Fhad1os2 interacted with RUNX3, a transcription factor related to follicle development and hormone synthesis. As a negative regulator, lncRNA Fhad1os2 transactivated the expression of Runx3 , which in turn induced RUNX3 to positively regulate aromatase (Cyp19a1) expression in mouse ovarian granulosa cells and promote estrogen synthesis. In conclusion, our study indicates that BPA exposure interferes with ERα-regulated lncRNA Fhad1os2 interactions with RUNX3 in pubertal mice, affecting estrogen synthesis in mouse granulosa cells and contributing to premature ovarian maturation in pubertal mice. [Display omitted] • LncRNA Fhad1os2 regulates the proliferation of mouse ovarian granulosa cells. • ERα directly binds lncRNA Fhad1os2 and decreases the transcription of lncRNA Fhad1os2 in response to the estrogen-like effect of BPA. • BPA exposure interferes with ERα-regulated lncRNA Fhad1os2 interactions with RUNX3 in adolescent mouse. [ABSTRACT FROM AUTHOR]

Perfluoroalkyl substances (PFASs) are a classic environmental endocrine disruptor with carcinogenic risk. Epidemiological studies have shown that PFASs contamination is associated with breast cancer development, but the mechanism remains largely unknown. This study first obtained complex biological information about PFASs-induced breast cancer through the comparative toxicogenomics database (CTD). The Protein-Protein Interaction (PPI) network, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis were utilized to investigate molecular pathways. The ESR1 and GPER expression levels at different pathological stages and the prognosis of Breast Cancer patients were confirmed using the Cancer Genome Atlas (TCGA) database. Furthermore, we verified this by cellular experiments and the results showed breast cancer cell migration and invasion were promoted by PFOA. Two estrogen receptors (ER), ERα and G protein-coupled estrogen receptor (GPER), mediated the promoting effects of PFOA by activating MAPK/Erk and PI3K/Akt signaling pathways. These pathways were regulated by ERα and GPER in MCF-7 cells or independently by GPER in MDA-MB-231 cells. Overall, our study provides a better overview of the mechanisms associated with PFASs-induced breast cancer development and progression. [Display omitted] • We used public database to provide a new perspective on PFASs-induced breast cancer. • PFOA can promote breast cancer cell migration and invasion via ERα and GPER. • PFOA activate PI3K/Akt and MAPK/Erk pathways which were regulated by ERα and GPER. [ABSTRACT FROM AUTHOR]

It has been suggested that metastasis-associated proteins 1 and 2 (MTA1 and MTA2) are capable of suppressing estrogen receptor alpha (ERα) transactivation activity in breast cancer cells. ERα, which is present in the epididymis, is a crucial mediator of maintaining the luminal environment necessary for proper sperm maturation and function. The present study was undertaken to analyze the expression profile of both MTA1 and MTA2 in the epididymis of rats and to ascertain whether MTA1/2 colocalizes with ERα in the epididymis and primary cultured epididymal epithelial cells. Reverse transcription polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry analyses were utilized to demonstrate that MTA1 and MTA2 are expressed in the epididymis. Furthermore, these analyses revealed that MTA1 and MTA2 are predominantly localized in the nuclei of almost all epididymal epithelial cells. Immunofluorescence staining revealed that MTA1/2 colocalizes with ERα in epididymal epithelial cells. In conclusion, MTA1 and MTA2 are expressed in the epididymis of rats; these proteins colocalize with ERα in epididymal epithelial cells, suggesting that MTA1 and MTA2 may be involved in the regulation of ERα transactivation activity in the epididymis of rats to facilitate a stable environment in the lumen. [ABSTRACT FROM AUTHOR]

Objective/Background Chronic venous disease (CVD) is a common and relevant problem affecting Western people. The role of estrogens and their receptors in the venous wall seems to support the major prevalence of CVD in women. The effects of the estrogens are mediated by three estrogen receptors (ERs): ERα, ERβ, and G protein-coupled ER (GPER). The expression of ERs in the vessel walls of varicose veins is evaluated. Methods In this prospective study, patients of both sexes, with CVD and varicose veins undergoing open venous surgery procedures, were enrolled in order to obtain vein samples. To obtain control samples of healthy veins, patients of both sexes without CVD undergoing coronary artery bypass grafting with autologous saphenous vein were recruited (control group). Samples were processed in order to evaluate gene expression. Results Forty patients with CVD (10 men [25%], 30 women [75%], mean age 54.3 years [median 52 years, range 33–74 years]) were enrolled. Five patients without CVD (three men, two women [aged 61–73 years]) were enrolled as the control group. A significant increase of tissue expression of ERα, ERβ and GPER in patients with CVD was recorded ( p < .01), which was also related to the severity of venous disease. Conclusion ERs seem to play a role in CVD; in this study, the expression of ERs correlated with the severity of the disease, and their expression was correlated with the clinical stage. [ABSTRACT FROM AUTHOR]

Sex hormone estrogen is one of the most active intrinsic angiogenesis regulators; its therapeutic use has been limited due to its carcinogenic potential. Plant-derived phytoestrogens are attractive alternatives, but reports on their angiogenic activities often lack in-depth analysis and sometimes are controversial. Herein, we report a data-mining study with the existing literature, using IPA system to classify and characterize phytoestrogens based on their angiogenic properties and pharmacological consequences. We found that pro-angiogenic phytoestrogens functioned predominantly as cardiovascular protectors whereas anti-angiogenic phytoestrogens played a role in cancer prevention and therapy. This bidirectional regulation were shown to be target-selective and, for the most part, estrogen-receptor-dependent. The transactivation properties of ERα and ERβ by phytoestrogens were examined in the context of angiogenesis-related gene transcription. ERα and ERβ were shown to signal in opposite ways when complexed with the phytoestrogen for bidirectional regulation of angiogenesis. With ERα, phytoestrogen activated or inhibited transcription of some angiogenesis-related genes, resulting in the promotion of angiogenesis, whereas, with ERβ, phytoestrogen regulated transcription of angiogenesis-related genes, resulting in inhibition of angiogenesis. Therefore, the selectivity of phytoestrogen to ERα and ERβ may be critical in the balance of pro- or anti-angiogenesis process. [ABSTRACT FROM AUTHOR]

Panax ginseng is widely used as a functional food in Asia because of its bioactivities. Here, we report that ginsenoside Rh2, an extract of red Panax ginseng, suppressed growth of uterine leiomyomas (ULs) in a rat model and decreased serum hormone levels in a dose-dependent manner. Rh2 also inhibited the growth of cultured human UL cells in vitro . After Rh2 treatment, cells showed morphological changes that were consistent with apoptosis. Using ELISA, real-time RT-PCR, and Western blot methods, we found that Rh2 significantly reduced the activity of oestrogen receptor alpha (ERα) and c-Src, increased p38 MAPK activity, and reversed ERα activity mediated by PP2 and SB203580, specific inhibitors of c-Src and p38 MAPK, respectively, in UL cells. These findings provide a novel mechanism for the anti-proliferative efficacy of Rh2 that likely involves regulating ERα/Src/p38 MAPK activity. [ABSTRACT FROM AUTHOR]

Abstract: Phytoestrogens are popular alternatives to estrogen therapy however their effects on hemostasis in post-menopausal women are unknown. The aim of this study was to determine the effect of the phytoestrogens, genistein, daidzein and equol on the expression of key genes from the hemostatic system in human hepatocyte cell models and to determine the role of estrogen receptors in mediating any response seen. HepG2 cells and Hep89 cells (expressing estrogen receptor alpha (ERα)) were incubated for 24h with 50nM 17β-estradiol, genistein, daidzein or equol. Tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), Factor VII, fibrinogen γ, protein C and protein S mRNA expression were determined using TaqMan PCR. Genistein and equol increased tPA and PAI-1 expression in Hep89 cells with fold changes greater than those observed for estradiol. In HepG2 cells (which do not express ERα), PAI-1 and tPA expression were unchanged. Increased expression of Factor VII was observed in phytoestrogen treated Hep89 cells but not in similarly treated HepG2s. Prothrombin gene expression was increased in equol and daidzein treated HepG2 cells in the absence of the classical estrogen receptors. These data suggest that phytoestrogens can regulate the expression of coagulation and fibrinolytic genes in a human hepatocyte cell line; an effect which is augmented by ERα. [Copyright &y& Elsevier]

The aim of this study was investigated if estrogen deficiency during puberty affects the expression of miRNA30a and miRNA503 in maxillary and mandibular growth centers, and also evaluated if ERα and ERβ are correlated with miRNA30a and miRNA503 expressions. Samples from 12 female Wistar rats randomized into experimental group (OVX) and control group (SHAM). At an age of 45 days animals were euthanized for miRNA expression analyses. RT-qPCR was performed to determine miRNA30a and miRNA503 expression in growth sites: midpalatal suture, condyle, mandibular angle, symphysis/parasymphysis and coronoid process. The data was carried out using the parametric tests at 5% of significance level. miRNA 30a and miRNA503 presented higher levels in the condylar site in SHAM group when compared with OVX (p = 0.002 and p = 0.020, respectively). In the growth centers, a statistical significant difference was observed only for miRNA30a (p = 0.004), when compared mandibular angle with condyle the in OVX group (p = 0.001). A strong positive correlation between miRNA503 and ERα in the condyle of OVX group was observed (r = 0.90; p = 0.039 and it also between miRNA503 and ERβ in the coronoid process of the OVX group (r = 0.88; p = 0.05). The results suggested that estrogen regulates specific miRNAs in maxillary and mandibular growth centers, which may participate in posttranscriptional regulation of estrogen-regulated genes. [ABSTRACT FROM AUTHOR]

Stroke has been recognized as a sex dimorphic disease. But a gender-specific therapy has not been taken into consideration in current therapy management of stroke. For understanding of the sex dimorphism with respect to the pathophysiology of stroke and the endogenous protective mechanism, we reviewed the underlying mechanism in which 17β-estradiol (E2) is involved in the sex dimorphism of brain injury after stroke, especially hemorrhagic stroke. Because the elderly female population continues to increase, the severity of hemorrhagic stroke in postmenopausal women is expected to increase. The neuroprotective property of E2 has been reported to contribute to less injury severity after intracerebral hemorrhage in women. Multiple pathways including ERα and GPR30 may transmit the neuroprotection conferred by E2. Interestingly, ferrous iron accumulation after hemorrhagic stroke induces a high level of autophagic cell death in the caudate nucleus of male rats than that in females. Moreover, suppression of ferrous iron-induced autophagy through an ERα-dependent pathway might participate in the E2-mediated neuroprotection on the ferrous iron-induced brain injury in female rats. In summary, the development of gender-specific therapeutic strategies for counteracting brain functional deficit after hemorrhagic stroke should be investigated. Better understanding of the downstream molecular mechanism of E2, such as ERα, GPR30, and autophagy, may help develop better therapeutic strategies to improve stroke care in both genders. [ABSTRACT FROM AUTHOR]

Abstract: The present study focuses on the synthesis of stable selenium nanoparticles (SeNPs) and the elucidation of their mechanism of action in preventing the growth of mammary tumors. Selenious acid and reduced glutathione in the presence of sodium alginate were used as precursors for synthesis of SeNPs. Cell viability and expression of apoptotic markers (pp38, Bax, and cytochrome c) were assessed in MCF-7 and MDA-MB-231 breast cancer cells treated with SeNPs. Reduction in tumor volume was measured in rats with dimethylbenz[a]anthracene-induced mammary tumors. Synthesized SeNPs ranged in size from 40 to 90 nm and were stable up to 3 months of storage. We report that SeNP-induced cell death and expression of pp38, Bax, and cytochrome c were significantly higher in estrogen receptor-α (ERα)–positive cells (MCF-7) but not in ERα-negative cells (MDA-MB-231). Interestingly, animals showing significant decrease in tumor volume (small tumors) had lower levels of ERα as compared with animals showing a nonsignificant decrease in tumor volume (large tumor). This is the first report in our knowledge suggesting that the anticancer activity of SeNPs correlates with the level of ERα in breast cancer cells both in vivo and in vitro. From the Clinical Editor: This study focuses on the synthesis of selenium nanoparticles (SeNPs) with the goal of preventing the growth of breast cancer cells, suggesting that the anticancer activity of SeNPs correlates with the level of ERα in breast cancer cells both in vivo and in vitro. [Copyright &y& Elsevier]

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The article presents an immunohistochemical study and histopathological evaluation of estrogen receptor α, Ki-67, and HER-2 in canine neoplastic mammary lesions and their association with tumors. The study shows that common breeds affected include German shepherd dogs, cross breeds, and cocker spaniels. The results of the study revealed HER-2 protein and high Ki-67 in malignant tumors.

Bisphenol A (BPA) and genistein (GEN) are selective estrogen receptor modulators, which are involved in the occurrence and development of metabolic syndrome. However, their roles in non-alcoholic fatty liver disease (NAFLD) of laying hens have not been reported. Here, we investigated the effects of different concentrations of GEN and BPA on the NAFLD of laying hens. Results showed that GEN ameliorated the high-energy and low-protein diet (HELP)-induced NAFLD by improving pathological damage, hepatic steatosis, and insulin resistance and blocking the expression of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-related factors. By contrast, high dose of BPA could aggravate these changes with serious symptom of NAFLD and suppress the level of ERα in the liver considerably, while GEN could reverse this phenomenon in a dose-dependent manner. In general, our research shows that the protective effect of GEN on NAFLD aims to improve the metabolic disorders and inflammation closely connected to ERα, while BPA can inhibit the expression of ERα and exacerbate the symptom of NAFLD. In conclusion, we elucidate the opposing effects of GEN and BPA in NAFLD of laying hens, thus providing a potential mechanism related to ERα and inflammation. [Display omitted] • BPA exposure markedly increased lipid deposition and inflammation in the liver of laying hens. • BPA exposure decreased expression of ERα, aggrieved NAFLD in laying hens. • Genistein ameliorated the hepatic steatosis and inflammation in laying hens by activating ERα. • The NLRP3 inflammasome is associated with NAFLD of laying hens. [ABSTRACT FROM AUTHOR]

Both androgens and estrogens play a significant role in the prostate and are critical for normal prostate growth and development, as well as the maintenance of adult prostatic homeostasis throughout life. It is the balance of these two hormones, rather than each individually, that is important for prostatic development and differentiation. Estrogen action is mediated by the estrogen receptors, ERα and ERβ. ERα is expressed throughout the prostatic tissue during fetal and early neonatal life, and if activated inappropriately, produces late-life disease, including inflammation and emergence of pre-malignant pathologies. In contrast, ERβ expression is initiated after ERα, is localized primarily to the epithelium, and appears to be important during later periods of development such as puberty and adulthood, acting to regulate cellular proliferation and differentiation in the adult tissue. Therefore, there is also a spatial and temporal balance between ERα and ERβ that is critical for development. Together with the shifting balance between androgens and estrogens themselves, the subtle, yet critical, balance between the activity of ERα and ERβ is what ultimately determines the response of the prostate to estrogen, and is crucial for prostate health. [ABSTRACT FROM AUTHOR]

Objective To explore the mechanisms by which genistein and daidzein inhibit the growth of prostate cancer cells. Methods LNCaP and PC-3 cells were exposed to genistein and daidzein and cell viability was determined by MTF assay and cytotoxicity of the drugs by LDH test. Flow cytometry (FCM) was used to assess the cell cycle in LNCaP and PC-3 cells. Reverse transcription-polymerase chain reaction (RT-PCR) was applied to examine the expression of VFEN gene (a tumor suppressor gene), estrogen receptor alpha gene (ERα), estrogen receptor beta gene (ERβ), androgen receptor gene (AR) and vascular endothelial growth factor gene (VEGF). Results The viability of PC-3 and LNCaP cells decreased with increasing concentrations and exposure time of genistein and daidzein. Genistein increased G2/M phase cells in PC-3 cells while decreased S phase cells in LNCaP cells in a dose-dependent manner. Daidzein exerted no influence on the cell cycle of LNCaP and PC-3 cells, but the apoptosis percentage of LNCaP cells was elevated significantly by daidzein. Genistein induced the expression of PTEN gene in PC-3 and LNCaP cells. Daidzein induced the expression of PTEN gene in LNCaP but not in PC-3 cells. The expression of VEGF, ERα and ERβ genes decreased and AR gene was not expressed after incubation with genistein and daidzein in PC-3 cells. In LNCaP cells, the expression of VEGF and AR gene decreased but there was no change in the expression of ERα and ERβ gene after incubation with genistein and daidzein. Conclusion Genistein and daidzein exert a time- and dose-dependent inhibitory effect on PC-3 and LNCaP cells. The down-regulation of ER gene by daidzein influences the growth of PC-3 cells directly. The inhibition of PC-3 cells by genistein and that of LNCaP cells by genistein and daidzein may be via Akt pathway that is repressed by PTEN gene, which subsequently down-regulates the expression of AR and VEGF genes. Our results suggest that the expression of PTEN gene plays a key role and several pathways may be involved in the suppression of prostate cancer cells by genistein and daidzein. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma is the most common type of lung cancer in women. Our previous studies demonstrated that 17β-estradiol (E2) promoted lung adenocarcinoma cell proliferation and tumor growth through estrogen receptor ERα. Transcriptomic analysis suggested that E2 potentiated TNFα-NFκB signaling in ERα-expressing lung adenocarcinoma cells. This study further demonstrated that E2 increased TNFα receptor expression and TNFα-triggered NFκB activity in ERα-expressing cells. E2-activated ERα had no physical association with NFκB p65/p50 heterodimer but facilitated TNFα-initiated IκBα degradation, NFκB nuclear translocation, and S468/S536 phosphorylation of p65 essential for NFκB activity. While knockdown of ERα prevented E2 from boosting NFκB activity, antiestrogen ICI 182,780 stimulated NFκB activity like E2. Inhibition of GSK3β hampered E2:ERα-promoted NFκB activity and abolished S468 phosphorylation of p65, suggesting that GSK3β played a role in the E2-TNFα signaling crosstalk. In ERα-expressing cells, E2 and TNFα synergistically regulated many genes that were not typically responsive to either E2 or TNFα. Functional analysis of microarray data inferred that E2/TNFα-induced transcriptomic changes improved cell survival and movement. Viability and colony formation assays validated that E2 and TNFα together increased cisplatin tolerance of ERα-expressing cells. Wound healing assays also confirmed that E2/TNFα cotreatment increased cell migration in an ERα-dependent manner. E2/TNFα-induced dysregulation of genes such as cell survival and movement-associated genes, proto-oncogenes, metallothioneins and histone core genes was correlated with poor overall survival in patients. In summary, E2 and TNFα engaged in an ERα-dependent positive crosstalk in lung adenocarcinoma cells, consequently increasing NFκB activation, cisplatin tolerance and cell migration and worsening prognosis. • Estrogen boosts TNFα-NFκB signaling via ERα in lung adenocarcinoma cells. • The estrogen-TNFα crosstalk involves the genomic and nongenomic actions of ERα. • The estrogen-TNFα crosstalk increases cisplatin tolerance and cell migration. • Estrogen/TNFα-induced gene dysregulation shows a trend towards worse survival. [ABSTRACT FROM AUTHOR]

Estrogen protects animals from obesity through estrogen receptor α (ERα), partially by inhibiting overeating in animals fed ad libitum. However, the effects of estrogen on feeding behavior in hungry animals remain unclear. In this study, we examined the roles of 17β-estradiol (E2) and ERα in the regulation of feeding in hungry female animals and explored the underlying mechanisms. Wild-type female mice with surgical depletion of endogenous estrogens were used to examine the effects of E2 supplementation on acute refeeding behavior after starvation. ERα-C451A mutant mice deficient in membrane-bound ERα activity and ERα-AF20 mutant mice lacking ERα transcriptional activity were used to further examine mechanisms underlying acute feeding triggered by either fasting or central glucopenia (induced by intracerebroventricular injections of 2-deoxy- D -glucose). We also used electrophysiology to explore the impact of these ERα mutations on the neural activities of ERα neurons in the hypothalamus. In the wild-type female mice, ovariectomy reduced fasting-induced refeeding, which was restored by E2 supplementation. The ERα-C451A mutation, but not the ERα-AF20 mutation, attenuated acute feeding induced by either fasting or central glucopenia. The ERα-C451A mutation consistently impaired the neural responses of hypothalamic ERα neurons to hypoglycemia. In addition to previous evidence that estrogen reduces deviations in energy balance by inhibiting eating at a satiated state, our findings demonstrate the unexpected role of E2 that promotes eating in hungry mice, also contributing to the stability of energy homeostasis. This latter effect specifically requires membrane-bound ERα activity. • Endogenous E2 is required to maintain acute refeeding in hungry female mice after starvation. • Membrane-bound ERα activity in female mice is required for efficient refeeding after starvation. • Membrane-bound ERα activity is required for hypothalamic ERα neurons to respond to hypoglycemia. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 72-year-old woman who complains for hypogastrium pain for two months. Through magnetic resonance imaging (MRI) with intravenous contrast medium, she was diagnosed with cancerous adnexal tumor at the ovary. She was subjected to laparotomy to remove the tumor that was seen at the right fallopian tube and she also underwent chemotherapy after the surgery. After 26 month of oncological therapy, it was reported that there was no neoplastic relapse.