Intricate roles of estrogen and estrogen receptors in digestive system cancers:a systematic review

Gender disparities are evident across different types of digestive system cancers,which are typically characterized by a lower incidence and mortality rate in females compared to males.This finding suggests a potential protective role of female steroid hormones,particularly estrogen,in the development of these cancers.Estrogen is a well-known sex hormone that not only regulates the reproductive system but also exerts diverse effects on non-reproductive organs mediated through interactions with estrogen receptors(ERs),including the classic(ERαand ERβ)and non-traditional ERs[G protein-coupled estrogen receptor(GPER)].Recent advances have contributed to our comprehension of the mechanisms underlying ERs in digestive system cancers.In this comprehensive review we summarize the current understanding of the intricate roles played by estrogen and ERs in the major types of digestive system cancers,including hepatocellular,pancreatic,esophageal,gastric,and colorectal carcinoma.Furthermore,we discuss the potential molecular mechanisms underlying ERα,ERβ,and GPER effects,and propose perspectives on innovative therapies and preventive measures targeting the pathways regulated by estrogen and ERs.The roles of estrogen and ERs in digestive system cancers are complicated and depend on the cell type and tissue involved.Additionally,deciphering the intricate roles of estrogen,ERs,and the associated signaling pathways may guide the discovery of novel and tailored therapeutic and preventive strategies for digestive system cancers,eventually improving the care and clinical outcomes for the substantial number of individuals worldwide affected by these malignancies.

The sexually dimorphic expression of glutamate transporters and their implication in pain after spinal cord injury

In addition to the loss of motor function,~60% of patients develop pain after spinal cord injury.The cellular-molecular mechanisms are not well understood,but the data suggests that plasticity within the rostral,epicenter,and caudal penumbra of the injury site initiates a cellularmolecular interplay that acts as a rewiring mechanism leading to central neuropathic pain.Sprouting can lead to the formation of new connections triggering abnormal sensory transmission.The excitatory glutamate transporters are responsible for the reuptake of extracellular glutamate which makes them a critical target to prevent neuronal hyperexcitability and excitotoxicity.Our previous studies showed a sexually dimorphic therapeutic window for spinal cord injury after treatment with the selective estrogen receptor modulator tamoxifen.In this study,we investigated the anti-allodynic effects of tamoxifen in male and female rats with spinal cord injury.We hypothesized that tamoxifen exerts anti-allodynic effects by increasing the expression of glutamate transporters,leading to reduced hyperexcitability of the secondary neuron or by decreasing aberrant sprouting.Male and female rats received a moderate contusion to the thoracic spinal cord followed by subcutaneous slow-release treatment of tamoxifen or matrix pellets as a control(placebo).We used von Frey monofilaments and the“up-down method”to evaluate mechanical allodynia.Tamoxifen treatment decreased allodynia only in female rats with spinal cord injury revealing a sexdependent effect.The expression profile of glutamatergic transporters(excitatory amino acid transporter 1/glutamate aspartate transporter and excitatory amino acid transporter 2/glutamate transporter-1)revealed a sexual dimorphism in the rostral,epicenter,and caudal areas of the spinal cord with a pattern of expression primarily on astrocytes.Female rodents showed a significantly higher level of excitatory amino acid transporter-1 expression while male rodents showed increased excitatory amino acid transporter-2 expression compared with female rodents.Analyses of peptidergic(calcitonin gene-related peptide-α)and non-peptidergic(isolectin B4)fibers outgrowth in the dorsal horn after spinal cord injury showed an increased calcitonin gene-related peptide-α/isolectin B4 ratio in comparison with sham,suggesting increased receptive fields in the dorsal horn.Although the behavioral assay shows decreased allodynia in tamoxifen-treated female rats,this was not associated with overexpression of glutamate transporters or alterations in the dorsal horn laminae fibers at 28 days post-injury.Our findings provide new evidence of the sexually dimorphic expression of glutamate transporters in the spinal cord.The dimorphic expression revealed in this study provides a therapeutic opportunity for treating chronic pain,an area with a critical need for treatment.

Role of sex steroid receptors in pathobiology of hepatocellular carcinoma

The striking gender disparity observed in the incidence of hepatocellutar carcinoma （HCC） suggests an important role of sex hormones in HCC pathogenesis. Though the studies began as early as in 1980s, the precise role of sex hormones and the significance of their receptors in HCC still remain poorly understood and perhaps contribute to current controversies about the potential use of hormonal therapy in HCC. A comprehensive review of the existing literature revealed several shortcomings associated with the studies on estrogen receptor （ER） and androgen receptor （AR） in normal liver and HCC. These shortcomings include the use of less sensitive receptor ligand binding assays and immunohistochemistry studies for ERα alone until 1996 when ERβ isoform was identified. The animal models of HCC utilized for studies were primarily based on chemical-induced hepatocarcinogenesis with less similarity to virus-induced HCC pathogenesis. However, recent in vitro studies in hepatoma cells provide newer insights for hormonal regulation of key cellular processes including interaction of ER and AR with viral proteins. In light of the above facts, there is an urgent need for a detailed investigation of sex hormones and their receptors in normal liver and HCC. In this review, we systematically present the information currently available on androgens, estrogens and their receptors in normal liver and HCC obtained from in vitro, in vivo experimental models and clinical studies. This information will direct future basic and clinical research to bridge the gap in knowledge to explore the therapeutic potential of hormonal therapy in HCC.

Androgens and estrogens in skeletal sexual dimorphism

Bone is an endocrine tissue expressing androgen and estrogen receptors as well as steroid metabolizing enzymes. The bioactivity of circulating sex steroids is modulated by sex hormone-binding globulin and local conversion in bone tissue, for example, from testosterone （T） to estradiol （E2） by aromatase, or to dihydrotestosterone by 5（x-reductase enzymes. Our understanding of the structural basis for gender differences in bone strength has advanced considerably over recent years due to increasing use of （high resolution） peripheral computed tomography. These microarchitectural insights form the basis to understand sex steroid influences on male peak bone mass and turnover in cortical vs trabecular bone. Recent studies using Cre/LoxP technology have further refined our mechanistic insights from global knockout mice into the direct contributions of sex steroids and their respective nuclear receptors in osteoblasts, osteoclasts, osteocytes, and other cells to male osteoporosis. At the same time, these studies have reinforced the notion that androgen and estrogen deficiency have both direct and pleiotropic effects via interaction with, for example, insulin-like growth factor 1, inflammation, oxidative stress, central nervous system control of bone metabolism, adaptation to mechanical loading, etc., This review will summarize recent advances on these issues in the field of sex steroid actions in male bone homeostasis.

Ulcerative colitis: From inflammation to cancer. Do estrogen receptors have a role?

Ulcerative colitis(UC) is a condition at increased risk for colorectal carcinoma(CRC) development. Nowadays, screening and follow-up programs are routinely performed worldwide to promote the early detection of CRCs in subjects with well known risk factors(extent, duration and severity of the disorder). The diffusion of these procedures is presumably the main reason for the marked reduction of cancer incidence and mortality in the course of UC. In addition, chemoprevention has been widely investigated and developed in many medical fields, and aspirin has shown a preventive effect against CRC, while mesalazine has been strongly invoked as a potential chemopreventive agent in UC. However, available studies show some limitations due to the obvious ethical implications of drug withdrawal in UC in order to design a control group. The estrogenreceptors(ER) alpha/beta balance seems to have a relevant influence on colorectal carcinogenesis and ER beta appears to parallel apoptosis, and hence an anticarcinogenic effect. Phytoestrogens are compounds acting as ER beta agonists and have shown a promising chemopreventive effect on sporadic as well as genetically inherited CRC. There is evidence suggesting a role for ERs in UC-related carcinogenesis. In this perspective, since these substances can be considered as dietary supplements and are completely free from side effects, phytoestrogens could be an interesting option for CRC prevention, even when the disease is a consequence of long-term chronic inflammation, as in the course of UC. Further studies of their effects are warranted in both the basic research and clinical fields.

Estrogens and the regulation of glucose metabolism

The main estrogens:estradiol,estrone,and their acyl-esters have been studied essentially related to their classical estrogenic and pharmacologic functions.However,their main effect in the body is probably the sustained control of core energy metabolism.Estrogen nuclear and membrane receptors show an extraordinary flexibility in the modulation of metabolic responses,and largely explain gender and age differences in energy metabolism:part of these mechanisms is already sufficiently known to justify both.With regard to energy,the estrogen molecular species act essentially through four key functions:(1)Facilitation of insulin secretion and control of glucose availability;(2)Modulation of energy partition,favoring the use of lipid as the main energy substrate when more available than carbohydrates;(3)Functional protection through antioxidant mechanisms;and(4)Central effects(largely through neural modulation)on whole body energy management.Analyzing the different actions of estrone,estradiol and their acyl esters,a tentative classification based on structure/effects has been postulated.Either separately or as a group,estrogens provide a comprehensive explanation that not all their quite diverse actions are related solely to specific molecules.As a group,they constitute a powerful synergic action complex.In consequence,estrogens may be considered wardens of energy homeostasis.

Correlations between Expression of Estrogen and Androgen Receptors and the Clinical Characteristics of Prolactinoma~*

Objective： To study the correlations between estrogen receptor （ER） and androgen receptor （AR） and the clinical presentations of prolactinoma and investigate the effect of ER and AR expression on the pathogenesis of prolactinoma in sexual difference. Methods： The clinical data of 30 patients who had undergone transsphenoidal operations in Tongji Hospital from December 2000 to December 2001 were reviewed retrospectively. The clinical information included sex, age, serum-prolactin, size, tumor invasiveness, history of use of bromocriptine and frequency of recurrence. In 20 out of the 30 patients, the ER and AR expression was detected by using immunohistochemistry method. With help of Chi-square test, the relationship between ER, AR and the clinical presentations was analyzed. Results： The statistical values revealed that there was no significant correlation between the ER and AR expression levels with the clinical presentations such as sex, age, tumor size or tumor invasiveness among the 20 patients studied （P〉0.05）. Conclusion： The expression of ER or AR is not influenced by the clinical data of prolactinoma such as sex, age, tumor diameter or extent of tumor invasiveness. The tumor is more aggressive in males than in females. In maroadenoma or tumor with hyperprolactineamia （〉200 ng/mL） simple surgical treatment can＇t successfully cure the prolactinoma. Post-operative bromocriptine therapy can＇t be determined by the sex of the patients, but is greatly related to the tumor size and serum-prolactin level before operation.

The Prognostic Significance of a Combined Determination of Cathepsin D and Estrogen Receptors in Breast Carcinomas with Positive Axillary Lymph Nodes

OBJECTIVE The aim of this study was to investigate the correlation between cathepsin D （Cath-D） and estrogen receptor （ER）expression in breast cancer tissue and to explore the prognostic significance of their combined determination in breast carcinoma patients with positive axillary lymph nodes. METHODS One hundred and thirty-eight cases of breast carcinoma were examined by immunohistochemistry （IHC） and the results relating to patient follow-up analyzed. RESULTS The overall 5-year disease-free survival rate （DFS） was 60.9% （84/138） in the series. The positive rate of Cath-D expression in the tumor cells was 55.07% and the positive ER staining was 51.4%. A definite significant negative correlation was found between the positive rates for Cath-D and ER （r=-0.294, P=0.001） The Cath-D expression for the cases in clinical Stage Ⅱ, ≥10 positive-node and recurrence or distant metastasis, was higher than that those cases in clinical Stage II with fewer node-metastasis and with 5 year DFS （X^2=13.926, P=0.000; X^2=13.070, P=0.001; X^2=10.545, P=0.001）. However, there was no significant difference of Cath-D expression between 2 groups of patients with different ages or among the different histopathologic types of the nonspecific invasive carcinoma. In the combined examination of Cath-D and ER, the cases that were ER （＋） and Cath-D （-） had the highest 5-year DFS compared to other situations. In contrast, the cases that were reversed in expression, ie, ER（-） and Cath-D（＋）, had a lower 5-year DFS. There was a significant difference between the 2 conditions （X2=18.675, P=0.000）. CONCLUSION A combined determination and analysis of Cath-D and ER expression may be more useful to establish a prognosis than the biological characteristics of carcinomas with positive lymph nodes.

Effects of Fuke Qianjin Formula on hormones and their receptors and metabonomics study in uterine fibroids model rats

Objective To investigate the effects of different fractions from Fuke Qianjin Formula(妇科千金方,FKQJF)on uterine leiomyoma(UL)to determine the best fraction.Methods FKQJF was extracted and isolated to obtain polysaccharides(FKP),flavonoids(FKF),and grease(FKG).140 female SPF SD rats were divided into 14 groups[model(MOD),normal control(NC),Gouliuqing(GLQ),Mifepristone(MFST),FKQJF,low,medium,and high dose of polysaccharides(l-FKP,m-FKP,and h-FKP),low,medium,and high dose of flavonoids(l-FKF,m-FKF,and h-FKF),low,medium,and high dose of grease(l-FKG,m-FKG,and h-FKG)],and uterine fibroids model rats were treated with drugs for four weeks.Serum levels of estrogen and progesterone were measured using enzyme-linked immunoassay assay(ELISA)kits.The expression of estrogen receptor(ER-α,ER-β)and progesterone receptor(PR)in the uterus was observed using immunohistochemistry(IHC).Serum metabolite profiles and FKG were analyzed using gas chromatography-mass spectrometry(GC-MS).Results FKQJF,h-FKF,m-FKG,and h-FKG significantly downregulated the estrogen level in the uterine fibroid model rats(P<0.01).FKQJF,h-FKF,and h-FKG significantly reduced the level of progesterone in the uterine fibroid model rats(P<0.01).The levels of ER-α,ER-β,and PR in uterine fibroid model rats were significantly decreased by FKQJF and h-FKG(P<0.01).The levels of ER-α,ER-β,and PR in the fibroid model rats were decreased by m-FKG(P<0.05).Additionally,serum metabolism results revealed that h-FKG and FKQJF could regulate related endogenous metabolites and make the pathological indices of uterine fibroids in rats close to the normal group.Forty-six components were identified in the oil,accounting for 91.97%of the total oil components.Conclusion FKQJF and h-FKG showed a significant anti-myoma activity and significantly improved the pathological state of the uterus in rats with hysteromyoma.The mechanism of action may be related to the regulation of estrogen progesterone and its receptor in uterine fibroid model animals.These findings proved the effect of FKQJF on uterine leiomyoma and provided an experimental basis for its clinical research and application.

The expression of estrogen receptors in thyroid cancer and its significance

Objective The study aimed to detect the expression of estrogen receptors(ERs) in thyroid cancer and investigate the correlation between their expression and clinical features and different pathological types.Methods The expression of ERs in 56 samples of thyroid cancer tissues was detected by an immunochemical approach. The expression of ERs in thyroid cancer tissues and different pathological types were analyzed using the χ~2 test. Results The number of cases with positive expression of ER in thyroid cancer tissues was 36. The number of papillary thyroid cancers(PTCs) was 48, with positive expression of ERs in 32 cases. The number of follicular thyroid cancers was 4, with positive expression of ERs in 2 cases. The number of medullary thyroid cancers was 4, with negative expression of ERs in all cases. The difference between the expression and different pathological types showed statistical significance. The expression of ERs showed no correlation with sex, age, or TNM stage, with no statistical significance. However, the expression of ERs was correlated with metastasis of lymph nodes, which had statistical significance. The expression of ERs was negatively correlated with pathological types and metastasis of lymph nodes. The correlated coefficient index was –0.313 and –0.334, respectively. Conclusion The expression of ERs showed no correlation with sex, age, or TNM stage, but was negatively correlated with pathological types and metastasis of lymph nodes.

Epithelial turnover in duodenal familial adenomatous polyposis: A possible role for estrogen receptors?

AIM: To investigate estrogen receptors expression in duodenal familial adenomatous polyposis (FAP) and any relationship with epithelial proliferation/apoptosis markers.METHODS: Twenty-two patients affected by FAP undergoing duodenal resection for malignancies were recruited. Controls were 15 healthy subjects undergoing endoscopy for dyspeptic symptoms. ER-&#x003b1;, ER-&#x003b1;, Ki-67, TUNEL and caspase 3 expression (labeling index: percentage of positive cells) were evaluated by immunohistochemistry or immunofluorescence and examined by light or confocal microscopy. Samples were assigned to four groups: normal tissue, low (LGD) and high-grade dysplasia (HGD), adenocarcinoma (AC). One-way analysis of variance, corrected by Bonferroni&#x02019;s test, and Pearson&#x02019;s correlation test were applied for statistical analysis.RESULTS: ER-beta showed a progressive decline: normal tissue (23.5 &#x000b1; 4.9), LGD (21.1 &#x000b1; 4.8), HGD (9.3 &#x000b1; 3.5), AC (7.1 &#x000b1; 3.1). The normal tissue of FAP subjects expressed ER-beta like the controls (23.9 &#x000b1; 6.2). Conversely, ER-&#x003b1; showed a progressive increase from normal tissue (24.8 &#x000b1; 5.6) to AC (52.0 &#x000b1; 8.2); the expression in normal tissue was similar to controls (22.5 &#x000b1; 5.3). Ki67 demonstrated a statistically significant progressive increase at each disease stage up to AC. TUNEL did not reveal differences between controls and normal tissue of FAP subjects, but progressive decreases were observed in LGD, through HGD to AC. Pearson&#x02019;s correlation test showed a direct relationship between ER-&#x003b2; and TUNEL LI (r = 0.8088, P &#x0003c; 0.0001). Conversely, ER-&#x003b1; was inversely correlated with TUNEL LI (r = - 0.7257, P &#x0003c; 0.0001). The co-expression of ER-&#x003b2; and caspase 3 declined progressively from normal to neoplastic tissue.CONCLUSION: This study confirmed that ER-&#x003b2; is strongly decreased in duodenal FAP carcinomas, declining in a multiple step fashion, thereby suggesting a putative anti-carcinogenic effect. ER-&#x003b1; showed the opposite trend. ER-&#x003b2;/caspase 3 co-expression suggests this hormone&#x02019;s possible involvement in apoptosis. Hormonal influences in FAP duodenal tumorigenesis, and modulation of these as a possible chemoprevention strategy, may be a promising approach.

Effects of Mifepristone Compound on the Receptors of Estrogen and Progesterone in Early Pregnancy Deciduas

To examine the effect of mifepristone compound (mifepristone + anor- drin) on estrogen receptor (ER) and progesterone receptor (PR) in early pregnancy decidua. Materials & Methods A Controlled study was carried out among 60 normal early pregnant volunteers (≤49d) in the department of obstetric and gynecology of Peking Union Medical Hospital. The concentrations of ER and PR were measured by radio- ligand and were compared with the control subjects after oral administration of mifepristone or mifepristone compound in different doses. Results The concentration of PR decreased while that of ER increased significantly in the decidua from all subjects administrated with mifepristone compound. We also found the concentration of EcR in Group 5 (mifepristone 30 mg + AF-53 5 mg) was the highest among 6 groups. The compound may be in favor of estrogen's action on endometrium. Conclusion The results indicate that mifepristone compound with AF- 53 has a coordi- nated function and can change the proportion of PR and ER. Hence, it can facilitate abortion. The compound dose of mifepristone 30 mg + AF-53 5mg is in favor of the endometrium recovering.

Clinical Significance of Estrogen and Progesterone Receptors Assays in Pancreatic Carcinoma

Cyochemical methods for demonstrating estrogen receptor (ER) and progesterone receptor (PgR)within pancreas-cancer cells showed positive reation of ER or/and PgR in 4 out of 8 pancreatic carcinomas.This result suggested that sex hormone might be closely linked to pancreatic cancer.Pancreatic carcinoma could be considered a hormoneresponsive-neoplasm. The hormone migh be a cause influencing the growth of pancreatic carcinoma in association with receptors described. Endocrine therapy would be a treatment of choice for pancreatic carcinoma.

Expression of Progesterone and Estrogen Receptors in Human Renal Cell Carcinoma

Progesterone receptor(PR) and estrogen receptor(ER) were investigated in 29 specimens of renal cell carcinoma (RCC) and its autologous kidneys, 12 samples of control kidnerys with high sensitive and specific enzymelabelled histochemical techniques. The positive expression rates of PR in RCC, its autologous kidneys and control kidneys were 31.0%, 82.8% and 83.3% respectively, while the positive expression rates of ER of those tissues were 58.6%, 79.3% and 83.3%, respectively. It showed that the positive rate and the value of PR and ER in RCC were significantly less than those determined in the autologous kidneys and normal tissues(P<0.05) and no significant differences of PR and ER were found between autologous and normal kidneys(P>0.05). The level and positive rate of PR in stage Ⅰ were higher than those in stage Ⅱ to Ⅳ of RCC tissues (P<0.05). There was no relationship between the status of PR, ER and patient sex(P>0.05). Expression of PR in RCC had correlation to Robson stage closely. The positive rate of PR may be treated as a prognostic factor because it decreased as the stage rose. Our result provided an experimental basis for the application of hormonal therapy in RCC and emphasized that patients who may be benefited from hormonal therapy must have sufficient hormone receptors.

PRODUCTION AND APPLICATION OF MOUSE ANTISERUM TO HUMAN ESTROGEN RECEPTORS

A polyclonal antibody to peptide containign 15 amino acids and corresponding to reion-D of human estrogen receptors(hERD)was obtained in mice by immunization with the coupler of peptide and KLH. Usuig this antiserum,the ER stathe of paraffin-embeded sections of 95 human breast carcinomas were studied. The corresponding rate for determination of ER status between immunohistochemical staining(IHC)and dextran coated charcoal(DCC)assay was 89. 5%. The concordance for semiquantitative grades was 69.3%. In addition, in situ hybridization(ISH)of 15 frozen sections of same sample using digoxigenin labeled dUTP to identify the expreesion of ER mRNA for confirming the 1HC also be used. This technique revealed more specific,sensitive and convenient than DCC.The results of ISH were fully consistent with IHC(100%). Above results show that the mouse antsierum hERD obtained in this study is specific and sensitive for IHC assay of ER and IHC is a valuable adjunct and/or alternative to the biochemical method for determination of the ER status of breast cancer.

Clinicopathological Features and Long-Term Prognostic Role of Human Epidermal Growth Factor Receptor-2 Low Expression in Chinese Patients with Early Breast Cancer:A Single-Institution Study

Objective This study aimed to comprehensively analyze and compare the clinicopathological features and prognosis of Chinese patients with human epidermal growth factor receptor 2(HER2)-low early breast cancer(BC)and HER2-IHC0 BC.Methods Patients diagnosed with HER2-negative BC(N=999)at our institution between January2011 and December 2015 formed our study population.Clinicopathological characteristics,association between estrogen receptor(ER)expression and HER2-low,and evolution of HER2 immunohistochemical(IHC)score were assessed.Kaplan-Meier method and log-rank test were used to compare the long-term survival outcomes(5-year follow-up)between the HER2-IHC0 and HER2-low groups.Results HER2-low BC group tended to demonstrate high expression of ER and more progesterone receptor(PgR)positivity than HER2-IHC0 BC group(P<0.001).The rate of HER2-low status increased with increasing ER expression levels(Mantel-Haenszelχ^(2)test,P<0.001,Pearson’s R=0.159,P<0.001).Survival analysis revealed a significantly longer overall survival(OS)in HER2-low BC group than in HER2-IHC0 group(P=0.007)in the whole cohort and the hormone receptor(HR)-negative group.There were no significant differences between the two groups in terms of disease-free survival(DFS).The discordance rate of HER2 IHC scores between primary and metastatic sites was 36.84%.Conclusion HER2-low BC may not be regarded as a unique BC group in this population-based study due to similar clinicopathological features and prognostic roles.

17β-Estradiol,through activating the G protein-coupled estrogen receptor,exacerbates the complication of benign prostatic hyperplasia in type 2 diabetes mellitus patients by inducing prostate proliferation

Benign prostatic hyperplasia(BPH)is one of the major chronic complications of type 2 diabetes mellitus(T2DM),and sex steroid hormones are common risk factors for the occurrence of T2DM and BPH.The profiles of sex steroid hormones are simultaneously quantified by LC-MS/MS in the clinical serum of patients,including simple BPH patients,newly diagnosed T2DM patients,T2DM complicated with BPH patients and matched healthy individuals.The G protein-coupled estrogen receptor(GPER)inhibitor G15,GPER knockdown lentivirus,the YAP1 inhibitor verteporfin,YAP1 knockdown/overexpression lentivirus,targeted metabolomics analysis,and Co-IP assays are used to investigate the molecular mechanisms of the disrupted sex steroid hormones homeostasis in the pathological process of T2DM complicated with BPH.The homeostasis of sex steroid hormone is disrupted in the serum of patients,accompanying with the proliferated prostatic epithelial cells(PECs).The sex steroid hormone metabolic profiles of T2DM patients complicated with BPH have the greatest degrees of separation from those of healthy individuals.Elevated 17β-estradiol(E2)is the key contributor to the disrupted sex steroid hormone homeostasis,and is significantly positively related to the clinical characteristics of T2DM patients complicated with BPH.Activating GPER by E2 via Hippo-YAP1 signaling exacerbates high glucose(HG)-induced PECs proliferation through the formation of the YAP1-TEAD4 heterodimer.Knockdown or inhibition of GPER-mediated Hippo-YAP1 signaling suppresses PECs proliferation in HG and E2 co-treated BPH-1 cells.The anti-proliferative effects of verteporfin,an inhibitor of YAP1,are blocked by YAP1 overexpression in HG and E2 co-treated BPH-1 cells.Inactivating E2/GPER/Hippo/YAP1 signaling may be effective at delaying the progression of T2DM complicated with BPH by inhibiting PECs proliferation.

The Role of GPER in Sepsis-Induced Myocardial Cell Damage and 28-Day Mortality Risk

Purpose: The role of GPER in sepsis-induced myocardial cell injury and its potential impact on the risk of death within 28 days in sepsis. Methods: An in vitro experiment was conducted to establish a sepsis-induced myocardial cell model. H9C2 myocardial cells were treated with 10 μg/ml lipopolysaccharide (LPS) for 24 hours. The effects of different concentrations of the GPER agonist G1 (1, 3, and 10 μmol/L) on cell viability, expression of inflammatory markers, cell apoptosis, and the NF-κB pathway were evaluated. A Mendelian randomization analysis was conducted using Single Nucleotide Polymorphism (SNPs) related to the GPER gene as instrumental variables to investigate the causal relationship between the GPER gene variations and sepsis (28-day death). Results: The results indicate that the group treated with LPS showed a significant decrease in myocardial cell viability, an increase in concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), higher apoptosis rates, and increased phosphorylation levels of NF-κB p65 (p-P65/P65) and IκB-α (p-IκB-α/IκB-α) compared to the control group (P κB pathway. However, genetic evidence did not show a causal relationship between GPER gene variations and sepsis (28-day death) (P κB pathway. However, genetic evidence did not show a causal relationship between GPER gene variations and sepsis (28-day death).

Comprehensive Analysis of Estrogen Receptor 1 Dysregulation in Liver Hepatocellular Carcinoma: Implications for Prognosis and Therapeutic Targeting - A Secondary Publication

The study investigates the expression pattern and regulatory mechanisms of estrogen receptor 1 (ESR1) in liver hepatocellular carcinoma (LIHC) through comprehensive bioinformatics analysis. Utilizing UALCAN and GEPIA2 databases, significant down-regulation of ESR1 expression is observed in LIHC samples compared to normal controls, indicating its potential role in tumor progression. Further analysis reveals consistent down-regulation across different clinical variables including patient age, gender, race, and various stages of LIHC, affirming the regulatory role of ESR1 in tumor development and progression. Additionally, promoter methylation analysis demonstrates hypermethylation of ESR1 in LIHC samples, negatively correlating with its expression. This association persists across different clinical parameters, emphasizing the inverse relationship between ESR1 methylation and expression levels. Survival analysis indicates that up- regulation of ESR1 is associated with better overall survival, suggesting its potential as a prognostic biomarker in LIHC. Furthermore, genetic mutation analysis using cBioPortal reveals a spectrum of alterations in ESR1, including amplification, missense mutation, deep deletion, splice mutation, and truncating mutation, highlighting the genetic complexity of ESR1 in LIHC. These findings collectively contribute to a deeper understanding of ESR1 dysregulation in LIHC and its clinical implications as a potential therapeutic target and prognostic marker.

Changes of Estrogen in Serum and Estrogen Receptor β in the Relevant Brain Regions Following Mating Behavior of the Male Mandarin Vole Microtus mandarinus

In order to investigate the estrogen and estrogen receptor β changes after mating behavior of male mandarin vole （Microtus mandarinus）, the radioimmunoassay （RIA） and immunohistochemistry methods were used to investigate changes of the serum estrogen （E） concentrations, estrogen immunoreactive neurons （E-IRs） and estrogen receptor β immunoreactive neurons （ERβ-IRs） in the relevant brain regions following mating behavior. Fifteen sexually matured male voles were randomly divided into three groups and treated differently： （1） control group： voles were exposed to clean hard-wood shavings （n=5）, （2） exposure group： voles were exposed to the soiled bedding for more than 24h on which estrous females had been placed （n=5）, and （3） mating group： voles were placed with an estrous female for more than 24h （n=5）. The results showed circulating serum E concentrations were significantly higher in the mating group than in the exposure group and the control group, and there were no significant difference between the exposure group and the control group. E-IRs and ERβ-IRs were detected in the following brain regions related to mating behavior： the arcuate nucleus （ARC）, bed nucleus of the stria terminalis （BST）, lateral septal nucleus （LS）, medial amygdaloid nucleus （ME）, medial preoptic area （MPO） and ventromedial hypothalamic nucleus （VMH）. The results showed that there were significantly more E-IRs in the six brain regions in the mating group than in the control group and the exposure group, and there were no significant difference between the exposure group and the control group except for LS. There was no significant difference in ERβ-IRs in the six brain regions among the three groups, and there were some lighter -stained ERβ-IRs in these brain regions. The results suggested that estrogen affect mating activity of male mandarin voles, but ERβ might not play an important role in mating behavior of male mandarin voles. Instead, it might be through other receptors.