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.

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.

Estrogen, estrogen receptors, and hepatocellular carcinoma: Are we there yet?

A protective role of the sex steroid hormone estrogenin hepatocellular carcinoma(HCC) was suggested a few decades ago according to clinical data showing higher HCC morbidity and mortality among males. Several recent studies further confirmed the anti-cancer effects of estrogen in the liver. However, it remains to be identified how to exploit estrogen signalling within clinical settings for HCC treatment. There are several unresolved issues related to the estrogen pathway in liver cells. The main problems include the absence of a clear understanding of which estrogen receptor(ER) isoform is predominantly expressed in normal and malignant liver cells, the ER isoform expression difference between males and females, and which ER isoform should be targeted when designing HCC therapy. Some of those questions were recently addressed by Iyer and coauthors. The current editorial review critically analyses the study by Iyer et al(WJG, 2017) that investigated the expression of ER subtypes in liver samples collected from patients with a healthy liver, hepatitis C virus cirrhosis, and HCC. ER presence was evaluated in association with gender, intracellular localization, inflammation marker NF-kB, and proliferation-related effector cyclin D1. The study limitations and advantages are discussed in light of recent advances in the HCC and estrogen signalling areas.

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.

Lack of estrogen receptors expression in malignant and pre-malignant colorectal lesions in Egyptian patients

Background: incidence of Colorectal cancer (CRC) is increasing globally. In Egypt, CRC ranks the sixth most common cancer in males and the fifth in females. Aim: To assess the expression of estrogen receptors (alpha and beta) in pre-malignant (adenomatous polyps and IBD), malignant colorectal lesions and normal colonic mucosa in group of Egyptian patients. Methods: This prospective study was done on 45 patients presenting with colonic symptoms, patients were divided into four groups;15 CRC patients, 10 patients with adenomatous polyps, 10 IBD patients and 10 patients in the control group. Patients subjected to: Stool analysis, FOBT, CBC, CEA, Abdominal ultrasound & colonoscopy and biopsy (number = 80), Pathological, immunohistochemistry and RT- PCR quantification of ERα and ERβ were done. Results: Mean age: 39.2 (12 - 73), gender: M/F: 28/17. Bleeding per rectum was the commonest presentation;29/45 (64.4%). CEA was significantly elevated in the CRC group compared with other studied groups (1692 mg/L vs. 4.0, 4.0 and 4.4 mg/L). Ultrasonography of the studied patients showed that metastatic CRC: 3/15 (20%);Colonic wall thickening: 5/15 (33.3%), 1/10 showed colonic polypoidal lesions in adenomatous polyps groups, in IBD group: 4/10 (40%) showed colonic and ileocecal thicknening. All the studied patients showed negative results for estrogen receptors (alpha and beta) by the use of immunohistochemistry staining and RT-PCR technique. Conclusion: Role of estrogen receptors in the colonic mucosa, precancerous and colorectal cancer is doubtful, contradictory results with some literature data could be due to racial and genetic difference in the studied population.

The Effect of Administration of Rutin on Plasma Levels of Estrogen, Prolactin, Growth Hormone and Gene Expression of Their Receptors in Mammary Glands in Ovariectomized Rats

The development of mammary glands, endocrine hormone concentrations and the gene expression of related receptors were measured in ovariectomized virgin rats after adminstration of an estrogen-like plant extract, rutin. Thirty-two ovariectomized virgin Wistar rats were randomly assigned to 4 treatments with 8 animals each： gastric infusion of 2 mL normal saline per unovariectomized rat per day （Sham）, gastric infusion of 2 mL normal saline per ovariectomized rat per day （Ova）, gastric infusion of 60 mg rutin kg-1 body weight （BW） per ovariectomized rat per day （Ova＋Rut）, or intramuscular injection of 60 ug estradiol kg-1 BW per ovariectomized rat weekly （Ova＋Est）. Samples of blood and mammary glands were harvested to determine the levels of estrogen （E2）, prolactin （PRL） and growth hormone （GH）, and the gene expression of estrogen receptors （ER）, prolactin receptors （PRLR） and growth hormone receptors （GHR） with radioimmunoassy （RIA） and RT-PCR technology, respectively. The E2 concentration in plasma and gland tissues from the rats of Ovx＋Rut or Ovx＋Est was higher than that of Ovx （P〈0.05）, but the plasma E2 concentration from the rats of Ovx＋Rut was lower than that of Sham （P〈0.05）. The order of the PRL concentration in plasma and gland tissues was Ovx〈Ovx＋Rut〈Ovx＋Est 〈Sham, and the difference in each treatment （P〈0.05）. The plasma GH concentration was lower in Ovx than in Ovx＋Rut or Ovx＋Est, and lower in Ovx＋Rut than in Sham （P〈0.05）. The GH concentration in gland tissues was lower in Ovx than in Ovx＋Rut or Ovx＋Est （P〈0.05）, and lower in Ovx＋Rut than in Sham （P〈0.05）. The gene expression of ER in gland tissues was increased in an order as Ovx〈Ovx＋Rut〈Ovx＋Est〈Sham （P〈0.05）, and PRLR, GHR showed the same trend. In conclusion, adminstration of rutin increased the E2 concentration in plasma and mammary glands, promoted pituitary PRL and GH release, up-regulated the gene expression of ER, PRLR and GHR, and stimulated mammary development in ovariectomized virgin rats.

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.

Determination of the concentration of estrogen,progestin and androgen cytosol receptors in human uterine tissues

The specific bindings of estrogen,progestin and androgen were determined inthe cytosol fraction of myomatous,adenomyotic and postmenopausal uterine tissues andof the normal endometrium and myometrium as well.It was found that theconcentrations of estrogen,progestin and androgen cytosol receptors were significantlyhigher in myomatous tissue than in normal myometrium;there was also an obvious differ-ence of the concentration of the sex steroid receptors between normal endometrium andadenomyotic tissue;and the uterine tissues of postmenopausal women still retained highlevels of these sex steroid receptors.In addition,the regulation of sex steroids in thepathogenesis of myoma and adenomyosis is discussed.

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.

Olfactory receptors in neural regeneration in the central nervous system

Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring.The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous system.Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent deficits.Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's disease.Olfa ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian body.This ectopic expression provides insights into the chemical structures that can activate olfactory receptors.In addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota.The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation mechanisms.This review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative processes.Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries.

Correlation of estrogen and progesterone receptors ER and PR expression with the growth of endometrial cancer

Objective:To study the correlation of estrogen and progesterone receptors ER and PR expression with the growth of endometrial cancer.Methods: A total of 80 patients with endometrial cancer who were treated collected in the Fourth People's Hospital of Shaanxi and the First Affiliated Hospital of Xi'an Jiaotong University between January 2013 and January 2017 were collected, endometrial cancer tissue and para-carcinoma normal tissue were collected, immunohistochemical method was used to detect positive expression of ER and PR, and fluorescence quantitative PCR was used to detect the mRNA expression of proliferation and apoptosis genes.Results: The positive expression of ER and PR in tumor tissue were significantly lower than those in para-carcinoma tissue;proliferation genes KCC1, RRM2, SRPX2 and Snail mRNA expression in tumor tissue of ER-positive group and PR-positive group were lower than those of ER-negative group and PR-negative group;anti-apoptosis genes Wip-1 and Bcl-2 mRNA expression were lower than those of ER-negative group and PR-negative group respectively while pro-apoptosis genes Bid, Bax and Fas mRNA expression were higher than those of ER-negative group and PR-negative group respectively.Conclusion:Patients with positive expression of endometrial estrogen and progesterone receptors ER and PR are with lower tumor proliferation activity, higher apoptosis activity and lower malignant degree than patients with negative ER and PR expression.

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 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.

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.

Correlation of Hormonal Receptors Estrogen Receptor, Progesterone Receptor and Her-2/Neu with Tumor Characteristics in Breast Carcinoma: Study of 100 Consecutive Cases

Introduction-Breast cancer is the most common cancer and leading cause of death in women. In India, its incidence is rapidly rising over last few decades. Present study is aimed to study the pattern of expression of hormonal receptors and Her-2/neu in invasive breast carcinoma and to correlate estrogen receptor (ER), progesterone receptor (PR) and Her-2/neu expressions with various clinicopathological parameters. Material and methods: The present study was carried out in Department of Pathology, S.C.B. Medical College, Cuttack in the year 2013 taking consecutive 100 cases. Routine H&E staining for histological diagnosis and IHC analysis for ER, PR and Her 2/neu was carried out in all 100 cases of breast malignancies. Results: 99% of cases are invasive breast carcinoma, not otherwise specify (IDC-NOS). The age ranges from 23 years to 72 years. Majority of tumors are of grade 2 (70%) followed by grade 3 (30%). ER PR and Her-2/neu expression are seen in 45%, 35% and 30% respectively. Triple negative cases comprise 35%. Higher number of grade 2 tumor shows ER, PR positivity as compared to grade 3 tumors. Her-2/neu expression does not show any significant correlation with age or lymph node status of the patient. Conclusion: ER and PR expression in breast cancers in the current study are found to be comparable to the findings of other authors, but the frequency of HER-2/neu expression is slightly higher. Significant correlation is observed between hormonal receptor status and the grade of the tumor. Inverse relationship is found between Her-2/neu expression and ER, PR receptor status. Her-2/neu expression is increased with size and high grade of tumor.

Altered Expression of Aromatase, Estrogen Receptors and Progesterone Receptors in Human Leydig Cell Hyperplasia

Testicular function is regulated by pituitary hormones and also by paracrine and autocrine factors. A number of reports have pointed out the importance of estrogens and progesterone in male reproductive tract. Recently, we have reported in testicular biopsies from men with Sertoli Cell Only Syndrome (SCO) or Hypospermatogenesis (H) with Leydig cell hyperplasia (LCH) an increase in the expression of the TGFB1 and its receptors ALK1 and endoglin, which are involved in the proliferation of Leydig cells. The aim of the present work was to analyze the expression of aromatase, estrogen and progesterone receptors (ERs, PR) in pathological testicular biopsies with SCO or H with and without LCH. The ERs and CYP19 proteins were detected in the Leydig cells from all pathological biopsies analyzed. Biopsies with SCO or H with LCH showed an increment in the immunostaining of CYP19 and ERs in the Leydig cells respect to biopsies without LCH. The gene expression of CYP19 was increased in SCO or H biopsies with LCH respect to SCO and H biopsies without LCH. PR was localized in Leydig cells and showed a significant increment in biopsies with LCH respect from biopsies without LCH. The gene expression of both PRA and PRB was increased in biopsies with LCH respect to biopsies without LCH. In concussion, alterations in the gene expression of aromatase, ERs, and PR and the likely interactions of these systems with locally produced factors such as growth factors and cytokines, might lead to Leydig cell proliferation in testicular pathology.

Involvement of Estrogen Receptors in the Anxiolytic-Like Effect of Phytoestrogen Genistein in Rats with 12-Weeks Postovariectomy

Phytoestrogens are natural compounds found in some vegetables, and they replicate many of the physiochemical and physiological properties of estrogens, including the regulation of mood. The phytoestrogen genistein exerts anxiolytic-like effects in rats with a chronic absence of ovarian hormones, but the mechanism involved in this effect remains to be explored. The present study explored the participation of estrogen receptor-β in the anxiolytic-like effect of genistein (1.0 mg/kg, i.p., for 4 days) in Wistar rats with 12-weeks postovariectomy, considered as experimental model of post-surgical menopause. In the light/dark test, a useful tool for anxiety study and for the screening of anxiolytic drugs, genistein reduced the latency to enter and increased the time spent in the light compartment and significantly increased the frequency and time spent exploring the light compartment compared with the control group, which is considered as an anxiolytic-like effect at experimental level. All behavioral effects produced by genistein in the light/dark test were blocked by previous tamoxifen administration (5.0 mg/kg, s.c., for 6 days), a non selective antagonist for estrogen receptor-β. The effects produced by genistein or tamoxifen in this test were not related to significant changes in general motor activity evaluated in the open field test. In conclusion, the specific contribution of present investigation was identify that estrogen receptor-β is involved in the anxiolytic-like effect produced by phytoestrogen genistein in rats with a long-term absence of ovarian hormones;supporting the hypothesis that estrogen receptor-β participates in the regulation of anxiety associated with low concentration of ovarian hormones and in the anxiolytic-like effects produced by natural estrogenic compounds such as phytoestrogens.

Low-molecular-weight estrogenic phytoprotein suppresses osteoporosis development through positive modulation of skeletal estrogen receptors

Age-related osteoporosis is a metabolic skeletal disorder caused by estrogen deficiency in postmenopausal women.Prolonged use of anti-osteoporotic drugs such as bisphosphonates and FDA-approved anti-resorptive selective estrogen receptor modulators(SERMs)has been associated with various clinical drawbacks.We recently discovered a low-molecular-weight biocompatible and osteoanabolic phytoprotein,called HKUOT-S2 protein(32 kDa),from Dioscorea opposita Thunb that can accelerate bone defect healing.Here,we demonstrated that the HKUOT-S2 protein treatment can enhance osteoblasts-induced ossification and suppress osteoporosis development by upregulating skeletal estrogen receptors(ERs)ERα,ERβ,and GPR30 expressions in vivo.Also,HKUOT-S2 protein estrogenic activities promoted hMSCs-osteoblasts differentiation and functions by increasing osteogenic markers,ALP,and RUNX2 expressions,ALP activity,and osteoblast biomineralization in vitro.Fulvestrant treatment impaired the HKUOT-S2 protein-induced ERs expressions,osteoblasts differentiation,and functions.Finally,we demonstrated that the HKUOT-S2 protein could bind to ERs to exert osteogenic and osteoanabolic properties.Our results showed that the biocompatible HKUOT-S2 protein can exert estrogenic and osteoanabolic properties by positively modulating skeletal estrogen receptor signaling to promote ossification and suppress osteoporosis.Currently,there is no or limited data if any,on osteoanabolic SERMs.The HKUOT-S2 protein can be applied as a new osteoanabolic SERM for osteoporosis treatment.

Immunomodulation of Proton-activated G Protein-coupled Receptors in Inflammation

Proton-activated G protein-coupled receptors(GPCRs),initially discovered by Ludwig in 2003,are widely distributed in various tissues.These receptors have been found to modulate the immune system in several inflammatory diseases,including inflammatory bowel disease,atopic dermatitis,and asthma.Proton-activated GPCRs belong to the G protein-coupled receptor family and can detect alternations in extracellular pH.This detection triggers downstream signaling pathways within the cells,ultimately influencing the function of immune cells.In this review,we specifically focused on investigating the immune response of proton-activated GPCRs under inflammatory conditions.