Objective: To study the effect of Chineseherbal medicine for replenishing Kidney combined with acupuncture in treating anovulationand infertility, and the relationship betweenits ovulation inducing effect and endometr...Objective: To study the effect of Chineseherbal medicine for replenishing Kidney combined with acupuncture in treating anovulationand infertility, and the relationship betweenits ovulation inducing effect and endometrialcontents of estradiol receptor (ER) and progesterone receptor (PR). Methods: Twentynine cases were treated with replenishing Kidney drugs combined with acupuncture for 1～3months. Patients' ER and PR were measuredby immunohistochemical method. And pa- tients were classified according to PR contentinto PR positive group and mild PR positivegroup. Results: Fifteen cases of PR positivegroup, completed treatment for 45 cycles, among them, 40 cycles showed ovulation, theovulation rate being 88. 89 %. Ten in 14 cases, who complicated with infertility, becamepregnant, the pregnant rate being 71. 43%.While in 11 cases of Ph mild positive group, 9complicated with in fertility, completed treatment for 33 cycle, 10 cycles showed ovulation(30. 30 % ), and pregnant rate 22. 22 % (2/9). The difference between the two groupswas significant (P < 0. 01 ). Conclusion: Thereplenishing Kidney drugs combined withacupuncture treatment could result a good effect in treating infertility due to anovulation,especially on those with high endometrial PRcontent.展开更多
The aim of this study was to determine the influence of collagen I and III on the expression of estrogen and progesterone receptors in equine endometrial fibrosis. A total of 25 crossbred mares were studies. Two endom...The aim of this study was to determine the influence of collagen I and III on the expression of estrogen and progesterone receptors in equine endometrial fibrosis. A total of 25 crossbred mares were studies. Two endometrial samples were collected from each mare,1 inthe estrus and1 inthe diestrus phase. The samples were classified according to histological changes. Collagen was typed and quantified using the picrosirius red histochemical technique, and steroid receptors were identified by immunohistochemistry. The results showed a predominance of collagen type III in all the endometrial samples. The expression of estrogen (RE2) and progesterone (RP4) receptors varied according to the estrous cycle. RE2 and RP4 expression varied in the estrus and diestrus phases;there was no influence of collagen I or II on receptor expression.展开更多
Estrogen plays an important role in regulating Sertoli cell number in the testis. The objective of the study was to identify whether 17β-estradiol affected the proliferation of cultured, immature boar Sertoli cells v...Estrogen plays an important role in regulating Sertoli cell number in the testis. The objective of the study was to identify whether 17β-estradiol affected the proliferation of cultured, immature boar Sertoli cells via the estrogen receptor β （ERβ） and the cAMP-extracellular signal-regulated kinase （ERK1/2） pathway. Low levels （10-10-10-8 mol L-1） of 17β-estradiol increased cell number, but high levels （10-7-10-6 mol L-1） decreased it （P〈0.05）. Sertoli cell number began to recover for an additional 24 h in the medium without 17β-estradiol （10-6 mol L-l） （P〉0.05）. The effects of 17β-estradiol （10-9 mol L-1） peaked at the first 24 h （P〈0.05）. 17β-estradiol activated ERK1/2 from 5 min to 24 h, but the activiy of ERK1/2 began to decrease after 4 h. Both PD98059 and U0126, two ERK inhibitors, blocked cell division （P〈0.05）. 17β-estradiol （10-10-10-6 mol L-1） dose-dependently increased cAMP production （P 〈 0.05）, and both 17β-estradiol （10-9 mol L-1） and forskolin, which increases cAMP levels, induced cell proliferation and activated ERK1/2 （P〈 0.05）. Rp-cAMP, an antagonist of cAMP, blocked this 17β-estradiol activity （P〈 0.05）. Two estrogen receptor antagonists, ICI 182780 and ERβ antagonist （ERβAnt）, reduced Sertoli cell number, cAMP production and ERK1/2 activation （P〈 0.05）, but ERaAnt did not （P〉 0.05）. Therefore, 17β- estradiol mainly promotes pig Sertoli cell proliferation via ERβ to induce cAMP production and ERK activation to promote cell proliferation.展开更多
Background: Mechanisms underlying overeating-induced obesity in post-menopausal woman include functional lack of 17β-estradiol dysregulating dopamine D2 receptors, thereby inducing food addiction, glucose craving or ...Background: Mechanisms underlying overeating-induced obesity in post-menopausal woman include functional lack of 17β-estradiol dysregulating dopamine D2 receptors, thereby inducing food addiction, glucose craving or alcohol dependence through reward circuitry. This study aimed at further understanding 17β-estradiol and dopamine D2 receptors interferences in the etiology of woman obesity. Method: Seventy-two Wistar female rats weighing 200 - 205 g, individually-housed, were divided into non-ovariectomized control (C = 6 groups) and ovariectomized rats (OVX = 6 groups) which were concurrently subjected to the following treatments: Non-drug-treated (DMSO vehicle), 17β-estradiol (E2, 5 μg/kg, s.c.), sulpiride (SUL, 20 mg/kg, i.p.), bromocriptine (BR, 0.1 mg/kg, i.p.), E2 + SUL or E2 + BR, designating the 6 constitutive groups of either control or ovariectomy. Within each experimental group, consumption of different solutions (10% alcohol, 10% sucrose and water) as well as food intake and body weight were daily measured, for 10 consecutive days. Results: This study indicated that D2S was a specific inducer of alcohol and food intakes, but reduced sugar consumption. In addition, 17β- estradiol regulated the body weight set point, modulating D2S functions towards increased food intake at lower weights and decreased food intake at higher weights. D2S met the slow genomic actions induced by 17β-estradiol. Conversely, D2L inhibited alcohol and food intakes, but induced specifically sugar consumption, thereby regulating blood glucose levels and promoting energy expenditure in reducing body weight. Indeed, 17β-estradiol exerted a tonic inhibition on D2L which was released by OVX, exacerbating sugar intake and increasing body weight. D2L mediated the rapid metabolic effects of 17β-estradiol. Conclusion: Our results supported physiological data reporting that activation of the mostly expressed presynaptically D2S-class autoreceptors decreased dopamine release stimulating food intake, whereas activation of the predominantly postsynaptic isoform D2L receptors increased dopamine activity inhibiting food intake. Our studies indicated that 17β-estradiol acted on the two types of D2 receptors showing opposite functions to equilibrate energy intake vs. expenditure for weight set point regulation. Our data also supported biochemical findings reporting that 17β-estradiol induced D2 genes transcriptional regulation, thereby involving both types of D2 receptors in the etiology of obesity. The combined dysregulated effects of D2L and D2S receptors, as 17β-estradiol was lacking, would be causal factors underlying the etiology of obesity.展开更多
17-β-estradiol (estrogen) is a steroid hormone important to human development;however, high levels of this molecule are associated with increased risk of breast cancer primarily due to estrogen’s ability to bind and...17-β-estradiol (estrogen) is a steroid hormone important to human development;however, high levels of this molecule are associated with increased risk of breast cancer primarily due to estrogen’s ability to bind and activate the estrogen receptor (ER) and initiate gene transcription. Currently, estrogen mechanisms of action are classified as genomic and non-genomic and occur in an ER-dependent and ER-independent manner. In this study, we examine estrogen signaling pathways, by measuring changes in protein expression as a function of time of exposure to estrogen in both ER-positive (MCF-7) and ER-negative (MDA-MB-231) cell lines. Using a robust experimental design utilizing isotopic labeling, two-dimensional LC-MS, and bioinformatics analysis, we report genomic and non-genomic ER regulated estrogen responsive proteins. We find a little over 200 proteins differentially expressed after estrogen treatment. Cell proliferation, transcription, actin filament capping and cell to cell signaling are significantly enriched in the MCF-7 cell line alone. Translational elongation and proteolysis are enriched in both cell lines. Subsets of the proteins presented in this study are for the first time directly associated with estrogen signaling in mammary carcinoma cells. We find that estrogen affected the expression of proteins involved in numerous processes that are related to tumorigenesis such as increased cellular division and invasion in an ER-dependent manner. Moreover, we identified negative regulation of apoptosis as a non-genomic process of estrogen. This study complements gene expression studies and highlights the need for both genomic and proteomic analyses in unraveling the complex mechanisms by which estrogen affects progression of breast cancer.展开更多
Our previous studies showed that 17β-estradiol (E2) modulated dopamine D2 receptor in regulating body weight set-point. The aim of this study was to understand whether thiamine deficiency influenced the E2 modulation...Our previous studies showed that 17β-estradiol (E2) modulated dopamine D2 receptor in regulating body weight set-point. The aim of this study was to understand whether thiamine deficiency influenced the E2 modulation on dopamine D2 receptors, using bromocriptine mesylate (BR) and sulpiride (SUL) as selective central dopamine-D2 receptors agonist and antagonist respectively. We studied the E2-dopamine D2 receptors interferences in a 10-day thiamine-deficient female rats for which consumptions of water, sugar, alcohol and food were daily-recorded and their consequences on body weights assessed. Our results showed that the volume of water daily ingested doubled in thiamine-deficient female rats (OXT), while sugar and alcohol consumptions collapsed with decreased weight and food consumption. On the one hand, thiamine potentiated D2/BR activity (bromocriptine-activated D2 receptors) to induce sugar intake and inhibited the same D2/BR receptors to induce water intake. On the other hand, thiamine promoted D2/SUL receptors (sulpiride-inhibited D2 receptors) for enhanced alcohol intake, increased food consumption and weight gain. Taking together, thiamine modulated the actions of 17β-estradiol on both D2/BR and D2/SUL receptors activities.展开更多
17β-estradiol modulates the activity of D2 receptors in the regulation of food intake and body weight. The functional lack of 17β-estradiol in postmenopausal women could create a dietary imbalance and cause body wei...17β-estradiol modulates the activity of D2 receptors in the regulation of food intake and body weight. The functional lack of 17β-estradiol in postmenopausal women could create a dietary imbalance and cause body weight gain. This study aimed to better understand the interferences that could exist between 17β-estradiol, D2 receptors and the selection of carbohydrate, fat and protein consumption, as well as their consequences on body weight gain by using an animal model of the menopause. Ovariectomy exacerbates the consumption of foods rich in lipids. Thus confirming an inhibitory action of 17β-estradiol (E2) on the consumption of these types of foods. This consumption stimulates body weight gain, which is promoted by the high caloric content of these foods and not by the amount consumed. Our results showed a direct involvement of D2 receptors in food choice. This choice would be made according to the two (2) isoforms of the D2 receptors. The D2/BR isoform directs towards a high carbohydrate consumption, without causing a gain in body weight. While D2/SUL, promotes high fat food consumption, causing an increase in body weight. In women, 17β-estradiol modulates the activity ratio between these two D2 receptor isoforms to ensure energy and homeostatic balance, stabilizing food intake and body weight.展开更多
Estrogen plays an important role in regulating testicular Sertoli cell number. Furthermore, S-phase kinase-associated protein 2 （SKP2） plays a central role in mammalian cell cycle progression. The objective of this ...Estrogen plays an important role in regulating testicular Sertoli cell number. Furthermore, S-phase kinase-associated protein 2 （SKP2） plays a central role in mammalian cell cycle progression. The objective of this study was to determine whether 17β-estradiol can regulate the expression of SKP2, and the Sertoli cell cycle, via estrogen receptor β （ERβ）, the cyclic adenosine monophosphate （cAMP）-protein kinase A （PKA） and extracellular signal-regulated kinase （ERK1/2） pathway. When cultured immature boar Sertoli cells were treated with 17β-estradiol, a time-dependent increase in SKP2 mRNA and protein level was observed by real-time PCR and Western blot, and 17β-estradiol activity peaked at 30 min. Treatment with ICI182780 and ERβ antagonist reduced 17β-estradiol-induced expression of SKP2 and proliferating cell nuclear antigen （PCNA）, while increasing the protein concentration of p27kip1. However, the effect of ERa antagonist on these parameters was lower than that of ICI 182780 and ERβ. Forskolin had a similar effect as 17β-estradiol on the expression of SKP2, PCNA and p27kip1, Rp-cAMP, H-89 and U0126 treatment reduced 17β-estradiol-induced changes, while H-89 also inhibited ERK1/2 activation. Therefore, 17β-estradiol mainly regulates SKP2 mRNA and protein expression via ERβ-cAMP-PKA and ERK1/2 activation. SKP2 and PCNA expression were positively correlated, while increased SKP2 expression likely resulted in p27kip1 degradation.展开更多
Objective： Retinopathy of prematurity is becoming obvious with the improvement of neonatal ambulance. However there is still not a good treatment. The present study is to observe the effect of 17 beta-estradiol （E2...Objective： Retinopathy of prematurity is becoming obvious with the improvement of neonatal ambulance. However there is still not a good treatment. The present study is to observe the effect of 17 beta-estradiol （E2） on oxygen-induced retinopathy （OIR）, and explore the relationship between the changes of avascular area and malondialdehyde （MDA） in retina. Methods： Newborn oxygen-exposed mice underwent subcutaneous injections of different dose of E2 （0.1 μg, 1.0 μg, 10.0 μg ）, tamoxifen or phosphate buffered saline （PBS; controls）everyday from post-natal day （p）7 to p17. At p17, retinal flat mounts were scored for the percentage of avascular/total retinal area, and pathological changes during revascularization. The MDA concentration in the retina was determined also. In the most efficacious E2 group （10.0 μg）, 100.0 μg tamoxifen was also administered, and the percentage of capillary-free/total retinal area determined, and the retinal malondialdehyde concentration assayed. Results： The mean percentage of capillary-free area over total retinal area was 0（PBS, in room air）, 34.197±1.301（PBS, in hyperoxia）, 23.685±0.407 （0.1 μg E2）, 14.648±0.355 （1.0 μg E2）, 4.693±0.450 （10.0 μg E2） and 32.240±0.654 （10.0 μg E2 ＋100.0 μg tamoxifen）. The difference was significant （F = 2778.759, P 〈 0.01）, and the difference between any two groups were also significant （all P value were less than 0.01）. The predilection of tufts and clusters during revascularization was mainly aggregated in zones 2 and 3, but the difference of retinal neovascular clusters and tufts in fourth zone among different groups were significant [clusters （F = 44.719, P 〈 0.01） vs tufts （F = 39.997,P 〈 0.01）]. The mean MDA concentration were 0.711 ±0.037（PBS, in room air）, 2.084±0.066 （PBS, in hyperoxia）, 1.829±0.091（0.1 μg E2）, 1.152± 0.067（1.0 μg E2）, 0.796 ±0.027（10.0 μg E2）, 1.988 ± 0.049（10.0μg E2 ＋100.0 μg tamoxifen） （F = 628.103, P 〈 0.01）. The difference between any two groups were also significant （all P value were less than 0.05）. The close relation between the percentage of avascular/total retinal area and MDA concentration was also verified （r = 0.981, P 〈 0.01）. Conclusion： Oxidative stress responses play a pivotal role in OIR, by means of receptor pathway. E2 can alleviate oxidative stress reaction, and thus ameliorate the severity of oxygen induced retinopathy.展开更多
Several epidemiological,cellular,and molecular studies demonstrate the role of environmental chemicals with endocrine disrupting activities,typical of Westernized societies,in the pathogenesis of numerous diseases inc...Several epidemiological,cellular,and molecular studies demonstrate the role of environmental chemicals with endocrine disrupting activities,typical of Westernized societies,in the pathogenesis of numerous diseases including cancer.Nonetheless this information,the design and execution of studies on endocrine disruptors are not yet cognizant that the specific actions of individual hormones often change with development and ageing,they may be different in males and females and may be mediated by different receptors isoforms expressed in different tissues or at different life stages.These statements are particularly true when assessing the hazard of endocrine disruptors against 17β-estradiol(E2)actions in that this hormone is crucial determinant of sexrelated differences in anatomical,physiological,and behavioral traits which characterize male and female physiology.Moreover,E2 is also involved in carcinogenesis.The oncogenic effects of E2 have been investigated extensively in breast and ovarian cancers where hormone-receptor modulators are now an integral part of targeted treatment.Little is known about the E2preventive signalling in colorectal cancer,although this disease is more common in men than women,the difference being more striking amongst pre-menopausal women and age-matched men.This review aims to dissect the role and action mechanisms of E2 in colorectal cancer evaluating the ability of estrogen disruptors(i.e.,xenoestrogens)in impair these E2 actions.Data discussed here lead to define the possible role of xenoestrogens in the impairment and/or activation of E2signals important for colorectal cancer prevention.展开更多
We have previously found that several families of nonpolar short chain 11β-ethers and esters ofestradiol are selective estrogen receptor modulators （SERMs）. Surprisingly, the transformation from potent estrogen to ...We have previously found that several families of nonpolar short chain 11β-ethers and esters ofestradiol are selective estrogen receptor modulators （SERMs）. Surprisingly, the transformation from potent estrogen to anti-estrogen occurs when the 11β-side chain is increased slightly in length from four to five non-hydrogen atoms. To generate strong antagonists for preclinical development, we have synthesized other similar ER ligands with 11β-ethers and with an additional ethinyl group at the 17β-position in order to slow metabolism of the steroidal moiety. Here we report the synthesis and biological activity of two such compounds （11β-i-PrO-propyl and 11β-t-BuO-propyl ethers） with extremely strong antagonist activities.展开更多
In order to study the mechanism of estrogen and other events involved in the development of breast cancer,we observed the cell growth as well as the expression of p185 and epidermal growth factor(EGF) receptor in huma...In order to study the mechanism of estrogen and other events involved in the development of breast cancer,we observed the cell growth as well as the expression of p185 and epidermal growth factor(EGF) receptor in human breast cancer cell line SK-BR-3 in the presence of estradiol(E2) using flow cytometry. The results showed that E2 could act to expedite the proliferation of breast cancer cells and promote DNA synthesis , and that the percentage in S phase rose significantly (E2 group 26. 7?2. 5,control group 21. 2?2.1, P<0. 05). Under E2 action,p185 presented a reduced expression (E2 35?5. 6, control 61?13.1, P<0. 05) while the EGF receptor expression was greatly enhanced (E, 39?6. 9, control 21?5. 4,P<0. 05),suggesting that EGF may play a more important role in early development of breast cancer.展开更多
The correlation or serum estradiol concentrstion and uterine estrogen receptor (ER) gene expression (ERn and ERc quantitated by Dextrsn Coat Charcoal assay and ER mRNA by Northern blotting) was studied during the rat ...The correlation or serum estradiol concentrstion and uterine estrogen receptor (ER) gene expression (ERn and ERc quantitated by Dextrsn Coat Charcoal assay and ER mRNA by Northern blotting) was studied during the rat estrous cycle and early Pregnant stage (dl-d10). The ER gone expression was up - regulated by estrogen and the levels of ER mRNA synchronized with the changes of ER protein, suggesting that estrogen influenced the trsnscriPtional step of the ER gene. Post-coitum ER expression increased with the serum estrsdiol progressively, reached a peak on d4-ds (Just before implantation), but drastically dropped to the nadir on d6-d7 (during implantation) and then recovered. It was of interest to discover that ER mRNA level in the nonimplantstion sites (NIS) of uterus was much higher than that in the implantstion sites (IS).展开更多
Estrogen affects the generation and transmission of neuropathic pain,but the specific regulatory mechanism is still unclear.Activation of the N-methyl-D-aspartate acid receptor 1（NMDAR1） plays an important role in t...Estrogen affects the generation and transmission of neuropathic pain,but the specific regulatory mechanism is still unclear.Activation of the N-methyl-D-aspartate acid receptor 1（NMDAR1） plays an important role in the production and maintenance of hyperalgesia and allodynia.The present study was conducted to determine whether a relationship exists between estrogen and NMDAR1 in peripheral nerve pain.A chronic sciatic nerve constriction injury model of chronic neuropathic pain was established in rats.These rats were then subcutaneously injected with 17β-estradiol,the NMDAR1 antagonist D（-）-2-amino-5-phosphonopentanoic acid（AP-5）,or both once daily for 15 days.Compared with injured drug na？ve rats,rats with chronic sciatic nerve injury that were administered estradiol showed a lower paw withdrawal mechanical threshold and a shorter paw withdrawal thermal latency,indicating increased sensitivity to mechanical and thermal pain.Estrogen administration was also associated with increased expression of NMDAR1 immunoreactivity（as assessed by immunohistochemistry） and protein（as determined by western blot assay） in spinal dorsal root ganglia.This 17β-estradiol-induced increase in NMDAR1 expression was blocked by co-administration with AP-5,whereas AP-5 alone did not affect NMDAR1 expression.These results suggest that 17β-estradiol administration significantly reduced mechanical and thermal pain thresholds in rats with chronic constriction of the sciatic nerve,and that the mechanism for this increased sensitivity may be related to the upregulation of NMDAR1 expression in dorsal root ganglia.展开更多
文摘Objective: To study the effect of Chineseherbal medicine for replenishing Kidney combined with acupuncture in treating anovulationand infertility, and the relationship betweenits ovulation inducing effect and endometrialcontents of estradiol receptor (ER) and progesterone receptor (PR). Methods: Twentynine cases were treated with replenishing Kidney drugs combined with acupuncture for 1～3months. Patients' ER and PR were measuredby immunohistochemical method. And pa- tients were classified according to PR contentinto PR positive group and mild PR positivegroup. Results: Fifteen cases of PR positivegroup, completed treatment for 45 cycles, among them, 40 cycles showed ovulation, theovulation rate being 88. 89 %. Ten in 14 cases, who complicated with infertility, becamepregnant, the pregnant rate being 71. 43%.While in 11 cases of Ph mild positive group, 9complicated with in fertility, completed treatment for 33 cycle, 10 cycles showed ovulation(30. 30 % ), and pregnant rate 22. 22 % (2/9). The difference between the two groupswas significant (P < 0. 01 ). Conclusion: Thereplenishing Kidney drugs combined withacupuncture treatment could result a good effect in treating infertility due to anovulation,especially on those with high endometrial PRcontent.
文摘The aim of this study was to determine the influence of collagen I and III on the expression of estrogen and progesterone receptors in equine endometrial fibrosis. A total of 25 crossbred mares were studies. Two endometrial samples were collected from each mare,1 inthe estrus and1 inthe diestrus phase. The samples were classified according to histological changes. Collagen was typed and quantified using the picrosirius red histochemical technique, and steroid receptors were identified by immunohistochemistry. The results showed a predominance of collagen type III in all the endometrial samples. The expression of estrogen (RE2) and progesterone (RP4) receptors varied according to the estrous cycle. RE2 and RP4 expression varied in the estrus and diestrus phases;there was no influence of collagen I or II on receptor expression.
基金supported by the National Natural Science Foundation of China(30270955)the Foundamental Research Funds for the Central Universities,China(XDJK2009B035)
文摘Estrogen plays an important role in regulating Sertoli cell number in the testis. The objective of the study was to identify whether 17β-estradiol affected the proliferation of cultured, immature boar Sertoli cells via the estrogen receptor β （ERβ） and the cAMP-extracellular signal-regulated kinase （ERK1/2） pathway. Low levels （10-10-10-8 mol L-1） of 17β-estradiol increased cell number, but high levels （10-7-10-6 mol L-1） decreased it （P〈0.05）. Sertoli cell number began to recover for an additional 24 h in the medium without 17β-estradiol （10-6 mol L-l） （P〉0.05）. The effects of 17β-estradiol （10-9 mol L-1） peaked at the first 24 h （P〈0.05）. 17β-estradiol activated ERK1/2 from 5 min to 24 h, but the activiy of ERK1/2 began to decrease after 4 h. Both PD98059 and U0126, two ERK inhibitors, blocked cell division （P〈0.05）. 17β-estradiol （10-10-10-6 mol L-1） dose-dependently increased cAMP production （P 〈 0.05）, and both 17β-estradiol （10-9 mol L-1） and forskolin, which increases cAMP levels, induced cell proliferation and activated ERK1/2 （P〈 0.05）. Rp-cAMP, an antagonist of cAMP, blocked this 17β-estradiol activity （P〈 0.05）. Two estrogen receptor antagonists, ICI 182780 and ERβ antagonist （ERβAnt）, reduced Sertoli cell number, cAMP production and ERK1/2 activation （P〈 0.05）, but ERaAnt did not （P〉 0.05）. Therefore, 17β- estradiol mainly promotes pig Sertoli cell proliferation via ERβ to induce cAMP production and ERK activation to promote cell proliferation.
文摘Background: Mechanisms underlying overeating-induced obesity in post-menopausal woman include functional lack of 17β-estradiol dysregulating dopamine D2 receptors, thereby inducing food addiction, glucose craving or alcohol dependence through reward circuitry. This study aimed at further understanding 17β-estradiol and dopamine D2 receptors interferences in the etiology of woman obesity. Method: Seventy-two Wistar female rats weighing 200 - 205 g, individually-housed, were divided into non-ovariectomized control (C = 6 groups) and ovariectomized rats (OVX = 6 groups) which were concurrently subjected to the following treatments: Non-drug-treated (DMSO vehicle), 17β-estradiol (E2, 5 μg/kg, s.c.), sulpiride (SUL, 20 mg/kg, i.p.), bromocriptine (BR, 0.1 mg/kg, i.p.), E2 + SUL or E2 + BR, designating the 6 constitutive groups of either control or ovariectomy. Within each experimental group, consumption of different solutions (10% alcohol, 10% sucrose and water) as well as food intake and body weight were daily measured, for 10 consecutive days. Results: This study indicated that D2S was a specific inducer of alcohol and food intakes, but reduced sugar consumption. In addition, 17β- estradiol regulated the body weight set point, modulating D2S functions towards increased food intake at lower weights and decreased food intake at higher weights. D2S met the slow genomic actions induced by 17β-estradiol. Conversely, D2L inhibited alcohol and food intakes, but induced specifically sugar consumption, thereby regulating blood glucose levels and promoting energy expenditure in reducing body weight. Indeed, 17β-estradiol exerted a tonic inhibition on D2L which was released by OVX, exacerbating sugar intake and increasing body weight. D2L mediated the rapid metabolic effects of 17β-estradiol. Conclusion: Our results supported physiological data reporting that activation of the mostly expressed presynaptically D2S-class autoreceptors decreased dopamine release stimulating food intake, whereas activation of the predominantly postsynaptic isoform D2L receptors increased dopamine activity inhibiting food intake. Our studies indicated that 17β-estradiol acted on the two types of D2 receptors showing opposite functions to equilibrate energy intake vs. expenditure for weight set point regulation. Our data also supported biochemical findings reporting that 17β-estradiol induced D2 genes transcriptional regulation, thereby involving both types of D2 receptors in the etiology of obesity. The combined dysregulated effects of D2L and D2S receptors, as 17β-estradiol was lacking, would be causal factors underlying the etiology of obesity.
文摘17-β-estradiol (estrogen) is a steroid hormone important to human development;however, high levels of this molecule are associated with increased risk of breast cancer primarily due to estrogen’s ability to bind and activate the estrogen receptor (ER) and initiate gene transcription. Currently, estrogen mechanisms of action are classified as genomic and non-genomic and occur in an ER-dependent and ER-independent manner. In this study, we examine estrogen signaling pathways, by measuring changes in protein expression as a function of time of exposure to estrogen in both ER-positive (MCF-7) and ER-negative (MDA-MB-231) cell lines. Using a robust experimental design utilizing isotopic labeling, two-dimensional LC-MS, and bioinformatics analysis, we report genomic and non-genomic ER regulated estrogen responsive proteins. We find a little over 200 proteins differentially expressed after estrogen treatment. Cell proliferation, transcription, actin filament capping and cell to cell signaling are significantly enriched in the MCF-7 cell line alone. Translational elongation and proteolysis are enriched in both cell lines. Subsets of the proteins presented in this study are for the first time directly associated with estrogen signaling in mammary carcinoma cells. We find that estrogen affected the expression of proteins involved in numerous processes that are related to tumorigenesis such as increased cellular division and invasion in an ER-dependent manner. Moreover, we identified negative regulation of apoptosis as a non-genomic process of estrogen. This study complements gene expression studies and highlights the need for both genomic and proteomic analyses in unraveling the complex mechanisms by which estrogen affects progression of breast cancer.
文摘Our previous studies showed that 17β-estradiol (E2) modulated dopamine D2 receptor in regulating body weight set-point. The aim of this study was to understand whether thiamine deficiency influenced the E2 modulation on dopamine D2 receptors, using bromocriptine mesylate (BR) and sulpiride (SUL) as selective central dopamine-D2 receptors agonist and antagonist respectively. We studied the E2-dopamine D2 receptors interferences in a 10-day thiamine-deficient female rats for which consumptions of water, sugar, alcohol and food were daily-recorded and their consequences on body weights assessed. Our results showed that the volume of water daily ingested doubled in thiamine-deficient female rats (OXT), while sugar and alcohol consumptions collapsed with decreased weight and food consumption. On the one hand, thiamine potentiated D2/BR activity (bromocriptine-activated D2 receptors) to induce sugar intake and inhibited the same D2/BR receptors to induce water intake. On the other hand, thiamine promoted D2/SUL receptors (sulpiride-inhibited D2 receptors) for enhanced alcohol intake, increased food consumption and weight gain. Taking together, thiamine modulated the actions of 17β-estradiol on both D2/BR and D2/SUL receptors activities.
文摘17β-estradiol modulates the activity of D2 receptors in the regulation of food intake and body weight. The functional lack of 17β-estradiol in postmenopausal women could create a dietary imbalance and cause body weight gain. This study aimed to better understand the interferences that could exist between 17β-estradiol, D2 receptors and the selection of carbohydrate, fat and protein consumption, as well as their consequences on body weight gain by using an animal model of the menopause. Ovariectomy exacerbates the consumption of foods rich in lipids. Thus confirming an inhibitory action of 17β-estradiol (E2) on the consumption of these types of foods. This consumption stimulates body weight gain, which is promoted by the high caloric content of these foods and not by the amount consumed. Our results showed a direct involvement of D2 receptors in food choice. This choice would be made according to the two (2) isoforms of the D2 receptors. The D2/BR isoform directs towards a high carbohydrate consumption, without causing a gain in body weight. While D2/SUL, promotes high fat food consumption, causing an increase in body weight. In women, 17β-estradiol modulates the activity ratio between these two D2 receptor isoforms to ensure energy and homeostatic balance, stabilizing food intake and body weight.
基金grants from the National Natural Science Foundation of China(31072183)the Fundamental Research Funds for the Central Universities,China(XDJK2009B035)
文摘Estrogen plays an important role in regulating testicular Sertoli cell number. Furthermore, S-phase kinase-associated protein 2 （SKP2） plays a central role in mammalian cell cycle progression. The objective of this study was to determine whether 17β-estradiol can regulate the expression of SKP2, and the Sertoli cell cycle, via estrogen receptor β （ERβ）, the cyclic adenosine monophosphate （cAMP）-protein kinase A （PKA） and extracellular signal-regulated kinase （ERK1/2） pathway. When cultured immature boar Sertoli cells were treated with 17β-estradiol, a time-dependent increase in SKP2 mRNA and protein level was observed by real-time PCR and Western blot, and 17β-estradiol activity peaked at 30 min. Treatment with ICI182780 and ERβ antagonist reduced 17β-estradiol-induced expression of SKP2 and proliferating cell nuclear antigen （PCNA）, while increasing the protein concentration of p27kip1. However, the effect of ERa antagonist on these parameters was lower than that of ICI 182780 and ERβ. Forskolin had a similar effect as 17β-estradiol on the expression of SKP2, PCNA and p27kip1, Rp-cAMP, H-89 and U0126 treatment reduced 17β-estradiol-induced changes, while H-89 also inhibited ERK1/2 activation. Therefore, 17β-estradiol mainly regulates SKP2 mRNA and protein expression via ERβ-cAMP-PKA and ERK1/2 activation. SKP2 and PCNA expression were positively correlated, while increased SKP2 expression likely resulted in p27kip1 degradation.
基金funded by Xi'an Science and Technology Agency (K2007-7)
文摘Objective： Retinopathy of prematurity is becoming obvious with the improvement of neonatal ambulance. However there is still not a good treatment. The present study is to observe the effect of 17 beta-estradiol （E2） on oxygen-induced retinopathy （OIR）, and explore the relationship between the changes of avascular area and malondialdehyde （MDA） in retina. Methods： Newborn oxygen-exposed mice underwent subcutaneous injections of different dose of E2 （0.1 μg, 1.0 μg, 10.0 μg ）, tamoxifen or phosphate buffered saline （PBS; controls）everyday from post-natal day （p）7 to p17. At p17, retinal flat mounts were scored for the percentage of avascular/total retinal area, and pathological changes during revascularization. The MDA concentration in the retina was determined also. In the most efficacious E2 group （10.0 μg）, 100.0 μg tamoxifen was also administered, and the percentage of capillary-free/total retinal area determined, and the retinal malondialdehyde concentration assayed. Results： The mean percentage of capillary-free area over total retinal area was 0（PBS, in room air）, 34.197±1.301（PBS, in hyperoxia）, 23.685±0.407 （0.1 μg E2）, 14.648±0.355 （1.0 μg E2）, 4.693±0.450 （10.0 μg E2） and 32.240±0.654 （10.0 μg E2 ＋100.0 μg tamoxifen）. The difference was significant （F = 2778.759, P 〈 0.01）, and the difference between any two groups were also significant （all P value were less than 0.01）. The predilection of tufts and clusters during revascularization was mainly aggregated in zones 2 and 3, but the difference of retinal neovascular clusters and tufts in fourth zone among different groups were significant [clusters （F = 44.719, P 〈 0.01） vs tufts （F = 39.997,P 〈 0.01）]. The mean MDA concentration were 0.711 ±0.037（PBS, in room air）, 2.084±0.066 （PBS, in hyperoxia）, 1.829±0.091（0.1 μg E2）, 1.152± 0.067（1.0 μg E2）, 0.796 ±0.027（10.0 μg E2）, 1.988 ± 0.049（10.0μg E2 ＋100.0 μg tamoxifen） （F = 628.103, P 〈 0.01）. The difference between any two groups were also significant （all P value were less than 0.05）. The close relation between the percentage of avascular/total retinal area and MDA concentration was also verified （r = 0.981, P 〈 0.01）. Conclusion： Oxidative stress responses play a pivotal role in OIR, by means of receptor pathway. E2 can alleviate oxidative stress reaction, and thus ameliorate the severity of oxygen induced retinopathy.
文摘Several epidemiological,cellular,and molecular studies demonstrate the role of environmental chemicals with endocrine disrupting activities,typical of Westernized societies,in the pathogenesis of numerous diseases including cancer.Nonetheless this information,the design and execution of studies on endocrine disruptors are not yet cognizant that the specific actions of individual hormones often change with development and ageing,they may be different in males and females and may be mediated by different receptors isoforms expressed in different tissues or at different life stages.These statements are particularly true when assessing the hazard of endocrine disruptors against 17β-estradiol(E2)actions in that this hormone is crucial determinant of sexrelated differences in anatomical,physiological,and behavioral traits which characterize male and female physiology.Moreover,E2 is also involved in carcinogenesis.The oncogenic effects of E2 have been investigated extensively in breast and ovarian cancers where hormone-receptor modulators are now an integral part of targeted treatment.Little is known about the E2preventive signalling in colorectal cancer,although this disease is more common in men than women,the difference being more striking amongst pre-menopausal women and age-matched men.This review aims to dissect the role and action mechanisms of E2 in colorectal cancer evaluating the ability of estrogen disruptors(i.e.,xenoestrogens)in impair these E2 actions.Data discussed here lead to define the possible role of xenoestrogens in the impairment and/or activation of E2signals important for colorectal cancer prevention.
文摘We have previously found that several families of nonpolar short chain 11β-ethers and esters ofestradiol are selective estrogen receptor modulators （SERMs）. Surprisingly, the transformation from potent estrogen to anti-estrogen occurs when the 11β-side chain is increased slightly in length from four to five non-hydrogen atoms. To generate strong antagonists for preclinical development, we have synthesized other similar ER ligands with 11β-ethers and with an additional ethinyl group at the 17β-position in order to slow metabolism of the steroidal moiety. Here we report the synthesis and biological activity of two such compounds （11β-i-PrO-propyl and 11β-t-BuO-propyl ethers） with extremely strong antagonist activities.
文摘In order to study the mechanism of estrogen and other events involved in the development of breast cancer,we observed the cell growth as well as the expression of p185 and epidermal growth factor(EGF) receptor in human breast cancer cell line SK-BR-3 in the presence of estradiol(E2) using flow cytometry. The results showed that E2 could act to expedite the proliferation of breast cancer cells and promote DNA synthesis , and that the percentage in S phase rose significantly (E2 group 26. 7?2. 5,control group 21. 2?2.1, P<0. 05). Under E2 action,p185 presented a reduced expression (E2 35?5. 6, control 61?13.1, P<0. 05) while the EGF receptor expression was greatly enhanced (E, 39?6. 9, control 21?5. 4,P<0. 05),suggesting that EGF may play a more important role in early development of breast cancer.
文摘The correlation or serum estradiol concentrstion and uterine estrogen receptor (ER) gene expression (ERn and ERc quantitated by Dextrsn Coat Charcoal assay and ER mRNA by Northern blotting) was studied during the rat estrous cycle and early Pregnant stage (dl-d10). The ER gone expression was up - regulated by estrogen and the levels of ER mRNA synchronized with the changes of ER protein, suggesting that estrogen influenced the trsnscriPtional step of the ER gene. Post-coitum ER expression increased with the serum estrsdiol progressively, reached a peak on d4-ds (Just before implantation), but drastically dropped to the nadir on d6-d7 (during implantation) and then recovered. It was of interest to discover that ER mRNA level in the nonimplantstion sites (NIS) of uterus was much higher than that in the implantstion sites (IS).
基金supported by the Youth Shihezi University Applied Basic Research Project of China,No.2015ZRKYQ-LH19
文摘Estrogen affects the generation and transmission of neuropathic pain,but the specific regulatory mechanism is still unclear.Activation of the N-methyl-D-aspartate acid receptor 1（NMDAR1） plays an important role in the production and maintenance of hyperalgesia and allodynia.The present study was conducted to determine whether a relationship exists between estrogen and NMDAR1 in peripheral nerve pain.A chronic sciatic nerve constriction injury model of chronic neuropathic pain was established in rats.These rats were then subcutaneously injected with 17β-estradiol,the NMDAR1 antagonist D（-）-2-amino-5-phosphonopentanoic acid（AP-5）,or both once daily for 15 days.Compared with injured drug na？ve rats,rats with chronic sciatic nerve injury that were administered estradiol showed a lower paw withdrawal mechanical threshold and a shorter paw withdrawal thermal latency,indicating increased sensitivity to mechanical and thermal pain.Estrogen administration was also associated with increased expression of NMDAR1 immunoreactivity（as assessed by immunohistochemistry） and protein（as determined by western blot assay） in spinal dorsal root ganglia.This 17β-estradiol-induced increase in NMDAR1 expression was blocked by co-administration with AP-5,whereas AP-5 alone did not affect NMDAR1 expression.These results suggest that 17β-estradiol administration significantly reduced mechanical and thermal pain thresholds in rats with chronic constriction of the sciatic nerve,and that the mechanism for this increased sensitivity may be related to the upregulation of NMDAR1 expression in dorsal root ganglia.
