Effects Of 17beta-estradiol Research Articles

Estradiol regulates the expression of CD45 splicing isoforms in lymphocytes.

CD45, a common leukocyte antigen expressed on the surface of all nucleated hematopoietic cells, indicates the developmental stage and functional status of lymphocytes by its alternative splicing isoforms. Estrogen is correlated with the immune activity of lymphocytes and is involved in the sex bias of several human autoimmune diseases, but the effect of estrogen on the expression of the CD45 splicing isoforms remains unknown. In the present study, a potential estrogen response element was identified on the opposite strand of the CD45 gene by bioinformatics software prediction. The results from RT-qPCR results showed that the expression levels of CD45RO isoform and CD45 antisense RNA were increased after the lymphocytes were treated with 10nM 17beta-estradiol, and this effect of 17beta-estradiol was reversed when the lymphocytes were cotreated with an estrogen receptor antagonist. Moreover, bisulfite sequencing PCR showed that CD45 DNA methylation in lymphocytes was increased after the treatment with 10nM 17beta-estradiol. In conclusion, estradiol regulated the expression of CD45 in an estrogen receptor-dependent manner and was associated with CD45 antisense RNA and DNA methylation. The results helped elucidate the regulatory mechanism of the expression of CD45 isoforms and the correlation between estrogen levels and immune activity in females.

Effects of the loss of estrogen on the heart's hypertrophic response to chronic left ventricle volume overload in rats.

Aortic valve regurgitation (AR) can result in heart failure from chronic overloading of the left ventricle (LV). Little is known of the role of estrogens in the LV responses to this condition. The aim of the study was to compare LV remodeling in female rats with severe AR in absence of estrogens by ovariectomy (Ovx). In a first study, we investigated over 6 months the development of hypertrophy in four groups of female Wistar rats: AR or sham-operated (sham) and Ovx or not. Ovx reduced normal heart growth. As expected, volume overload (VO) from AR resulted in significant LV dilation (42% and 32% increase LV end-diastolic diameter in intact and Ovx groups vs. their respective sham group; p < 0.0001). LV weight was also significantly and similarly increased in both AR groups (non-Ovx and Ovx). Increase in stroke volume or cardiac output and loss of systolic function were similar between AR intact and AR Ovx groups compared to sham. We then investigated what were the effects of 17beta-estradiol (E2; 0.03 mg/kg/day) treatment on the parameters studied in Ovx rats. Ovx reduced uterus weight by 85% and E2 treatment restored up to 65% of the normal weight. E2 also helped normalize heart size to normal values. On the other hand, it did not influence the extent of the hypertrophic response to AR. In fact, E2 treatment further reduced LV hypertrophy in AR Ovx rats (41% over Sham Ovx + E2). Systolic and diastolic functions parameters in AR Ovx + E2 were similar to intact AR animals. Ovx in sham rats had a significant effect on the LV gene expression of several hypertrophy markers. Atrial natriuretic peptide (Nppa) gene expression was reduced by Ovx in sham-operated females whereas brain natriuretic peptide (Nppb) expression was increased. Alpha (Myh6) and beta (Myh7) myosin heavy chain genes were also significantly modulated by Ovx in sham females. In AR rats, LV expression of both Nppa and Nppb genes were increased as expected. Ovx further increased it of AR rats for Nppa and did the opposite for Nppb. Interestingly, AR in Ovx rats had only minimal effects on Myh6 and Myh7 genes whereas they were modulated as expected for intact AR animals. In summary, loss of estrogens by Ovx in AR rats was not accompanied by a worsening of hypertrophy or cardiac function. Normal cardiac growth was reduced by Ovx in sham females but not the hypertrophic response to AR. On the other hand, Ovx had important effects on LV gene expression both in sham and AR female rats.

P720Atheroprotective effects of 17beta-estradiol are mediated by PPARgamma in human coronary artery smooth muscle cells

Abstract Background 17β-estradiol (E2) mediates vasculoprotection in various preclinical and clinical models of atherosclerosis and neointimal hyperplasia. However, the molecular mechanisms underlying these effects are still not fully elucidated. Previous studies have demonstrated the essential role of the peroxisome-proliferator-activated-receptor-γ (PPARγ) in mediating vasculoprotective effects of E2 in vivo. The aim of the current study was to investigate whether PPARγ is implicated in mediating vasculoprotective mechanisms of E2 in human coronary artery smooth muscle cells (HCASMC). Methods Primary HCASMC were purchased and stimulated with E2 [10 nM], the selective estrogen receptor α (ERα) agonist propylpyrazole triol (PPT) [50 nM] and the selective ERα antagonist methyl-piperidino-pyrazole (MPP) [1 μM], respectively. Changes in PPARγ mRNA and protein expression upon stimulation of ERα were assessed by qPCR and Western blot analyses. Nuclear PPARγ protein expression and DNA binding affinity was assessed after the isolation of the nuclear protein fraction. Hereafter, HCASMC were incubated with E2, PPARγ-antagonist GW9662 [1 μM – 30 μM], or both. HCASMC proliferation was assessed by nuclear BrdU staining and reactive oxygen species (ROS) formation was assessed by L-012- and DCF-DA assays. Results E2 significantly increased PPARγ expression in HCASMC (1.95±0.41 –fold; n=5; p=0.0335). This effect was mimicked by ERα agonist PPT (1.63±0.27 –fold; n=7; p=0.0489) and was abrogated by co-incubation with ERα antagonist MPP (1.17±0.18 –fold; n=3; pvs. control &gt;0.05). Nuclear PPARγ expression was enhanced by E2 (1.53±0.16 –fold; n=4; pvs. control = 0.0074; Fig. 2A) whereas PPARγ's DNA binding activity to PPRE remained unchanged upon stimulation with E2 (0.94±0.11 –fold; n=4; pvs. control &gt;0.05). Pharmacological inhibition of PI3K/Akt by LY294002 abrogated E2-induced expression of PPARγ (0.24±0.09 –fold; n=3; pvs. E2 = 0.0017), arguing for a PI3K/Akt-dependent activation by E2. The role of PPARγ in mediating vasculoprotective effects of E2 was assessed in functional assays using PPARγ-antagonist GW9662. E2 diminished HCASMC proliferation which was restored by GW9662. While E2 only slightly decreased ROS production by HCASMC, GW9662 significantly increased ROS levels (1,036±169 RLU x s–1 x cell–1 versus 561±99 RLU x s–1 x cell–1; n=5–6; p=0.0287). Conclusion In summary, the present study identifies PPARγ as a downstream mediator of E2-related atheroprotective effects in HCASMC. 17β-estradiol regulates vascular PPARγ-expression in HCASMC via the ERα receptor and the PI3K/Akt pathway. PPARγ agonism might be a promising therapeutic strategy to prevent cardiovascular events in postmenopausal women with depleted E2 plasma levels. Acknowledgement/Funding This work was supported by the Bonfor program of the University of Bonn [grant number O-109.0057 to JJ].

Impact of steroid hormones E2 and P on the NLRP3/ASC/Casp1 axis in primary mouse astroglia and BV-2 cells after in vitro hypoxia

Clinical and animal model studies have demonstrated the neuroprotective and anti-inflammatory effects of 17beta-estradiol (E2) and progesterone (P) in different disease models of the central nervous system (CNS) including ischemic stroke. Inflammasomes are involved in the interleukin-1 beta (IL1beta) maturation, in particular, NLRP3, the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) and the active caspase-1 (Casp1) form. Recently, we showed that administration of E2 or P selectively regulated these components after experimental ischemic stroke in rats. Therefore, we investigated the impact of E2 and P on the NLRP3/ASC/Casp1 axis in the murine microglia-like cell line BV-2 cells and primary astrocytes after short-term in vitro hypoxia.The inflammatory cytokine IL1beta but not IL18 was increased after short-term hypoxia in astroglia and BV-2 cells. The same applied to NLPR3 and ASC. Casp1 activity was also elevated in astroglia and BV-2 cells after hypoxia. The administration of E2 or P selectively dampened IL1beta, ASC and NLRP3 expression mainly in BV-2 cells. Both steroid hormones failed to reduce Casp1 activity after hypoxia.We conclude that E2- and P-mediated anti-inflammatory mechanisms occur upstream of Casp1 through the regulation of NLRP3 and its adaptor ASC.

Effects of Topical 17beta Estradiol on Wound Healing and Hemato-Biochemical Changes In West African Dwarf Goats

Animal studies have shown that steroid sex hormones such as estrogen may be helpful in the regulation of several pathophysiologic stages that are involved in wound healing. This study therefore investigated the effects of topical estradiol on wound healing and haemato-biochemical changes in West African dwarf (WAD) goats. Ten WAD goats were used for the study and randomly divided into two equal groups of five animals each; the first group served as the control while the second group was treated topically with estrogen. Healing process was compared between the two groups, haematology and serum biochemistry werecarried out at each phases of the healing process. The result showed significant improved wound contractions in the estrogen treated by day 12, 15 and 17. Haematology and serum analyses revealed significantly (P

Estrogen administration modulates hippocampal GABAergic subpopulations in the hippocampus of trimethyltin-treated rats.

Given the well-documented involvement of estrogens in the modulation of hippocampal functions in both physiological and pathological conditions, the present study investigates the effects of 17-beta estradiol (E2) administration in the rat model of hippocampal neurodegeneration induced by trimethyltin (TMT) administration (8 mg/kg), characterized by loss of pyramidal neurons in CA1, CA3/hilus hippocampal subfields, associated with astroglial and microglial activation, seizures and cognitive impairment. After TMT/saline treatment, ovariectomized animals received two doses of E2 (0.2 mg/kg intra-peritoneal) or vehicle, and were sacrificed 48 h or 7 days after TMT-treatment. Our results indicate that in TMT-treated animals E2 administration induces the early (48 h) upregulation of genes involved in neuroprotection and synaptogenesis, namely Bcl2, trkB, cadherin 2 and cyclin-dependent-kinase-5. Increased expression levels of glutamic acid decarboxylase (gad) 67, neuropeptide Y (Npy), parvalbumin, Pgc-1α and Sirtuin 1 genes, the latter involved in parvalbumin (PV) synthesis, were also evident. Unbiased stereology performed on rats sacrificed 7 days after TMT treatment showed that although E2 does not significantly influence the extent of TMT-induced neuronal death, significantly enhances the TMT-induced modulation of GABAergic interneuron population size in selected hippocampal subfields. In particular, E2 administration causes, in TMT-treated rats, a significant increase in the number of GAD67-expressing interneurons in CA1 stratum oriens, CA3 pyramidal layer, hilus and dentate gyrus, accompanied by a parallel increase in NPY-expressing cells, essentially in the same regions, and of PV-positive cells in CA1 pyramidal layer. The present results add information concerning the role of in vivo E2 administration on mechanisms involved in cellular plasticity in the adult brain.

Effects of 17-beta estradiol in a novel co-culture system of human Wharton’s jelly-derived mesenchymal stem cells with adult-heart murine ventricular slices on cardiac regeneration

Effects of 17-beta estradiol in a novel co-culture system of human Wharton’s jelly-derived mesenchymal stem cells with adult-heart murine ventricular slices on cardiac regeneration

Modulation of hippocampal gabaergic subpopulations induced by estrogen administration in the Trimethyltin model of hippocampal neurodegeneration

Estrogens exert neuroprotection through multiple mechanisms, including increased neuronal plasticity [1]. Due to their involvement in the modulation of hippocampal functions, the present study investigates the effects of exogenous 17-beta estradiol (E2) in the rat model of Trimethyltin (TMT)-induced hippocampal neurodegeneration (8mg/kg), characterized by pyramidal cell death selectively localized in CA1,CA3/hilus hippocampal subfields accompanied by glial activation, seizures and cognitive impairment [2,3,4]. After TMT or saline treatment, ovariectomized animals received two E2 (0.2 mg/kg i.p.) or vehicle (oil) doses and were sacrificed 48h or 7 days after TMT- treatment. Our data indicate that E2, although not influencing the extent of neuronal loss in TMT-treated animals, induces the early upregulation of the antiapoptotic gene Bcl2l and of BDNF and TrkB, , essentially involved in neuroprotection and cell survival. In addition, in the TMT+E2-treated group a significant upregulation of glutamic acid decarboxylase (Gad) 67, neuropeptide Y (npy)- and parvalbumin (pva) genes, as well as the peroxisome proliferator-activated receptor coactivator-1α pathway, involved in both parvalbumin (PV) synthesis and neuroprotection, was detected. Unbiased stereology performed on rats sacrificed 7 days after TMT-treatment pointed out that E2 significantly affects the size of specific hippocampal GABAergic subpopulations in selected hippocampal subfields of TMT-treated animals. In particular, a significant increase of GAD67-expressing interneurons in CA1 stratum oriens, CA3 pyramidal layer, hilus and dentate gyrus, accompanied by a parallel increase of NPYexpressing cells and of PV-positive basket cells in CA1pyramidal layer was detectable. Due the relevance of interneuron role in restoring the inhibitory drive in circuit reorganization, our results add Information on the role of in vivo E2 administration on mechanisms involved in cellular plasticity in the adult brain.

Retarding the senescence of human vascular endothelial cells induced by hydrogen peroxide: effects of 17beta-estradiol (E2) mediated mitochondria protection.

This study investigates the influence of 17beta-estradiol (E2) on hydrogen peroxide (H2O2)-induced human vascular endothelial cell (HUVEC) senescence. HUVECs were divided into four groups, namely control group, H2O2 stimulation group, E2 intervention group and ICI182780 (ICI) intervention group. The aging-related β-galactosidase activities, cytochrome C oxidase activities, intracellular ATP levels, intracellular reactive oxygen species (ROS) levels and phosphorylated Rb protein expressions were mainly observed. Of which, senescence-associated β-galactosidase activities were detected using immunohistochemical staining, cytochrome C oxidase activities and intracellular ATP levels were detected using commercial kits, ROS levels were detected by fluorescence microscopy and fluorescence microplate reader, immunoblotting was used to quantitatively detect the expressions of phosphorylated Rb proteins. After continuous treatment of H2O2, the senescent phenotypes appeared in the HUVECs. The percentage of positive SA-βgal staining cells and the phosphorylated Rb expressions were significantly increased; intracellular ROS levels, cytochrome C oxidase activities and intracellular ATP levels were elevated. Compared with the H2O2 stimulation group, E2 intervention significantly decreased the positive rate of SA-β-gal staining, the phosphorylated Rb protein levels, the intracellular ROS levels, cytochrome C oxidase activities and intracellular ATP levels. Pretreatment of estrogen receptor blocker ICI182780 weakened the role of E2. These results indicated that H2O2 could induce HUVEC senescence; 17beta-E2 might relieve H2O2-induced mitochondrial damage through estrogen receptor and delay the vascular endothelial cell senescence.

The protective effects of 17beta-estradiol against ischemia–reperfusion injury and its effect on pacing postconditioning protection to the heart

The role of pacing postconditioning (PPC) in the heart protection against ischemia-reperfusion injury is not completely understood. The aim of this study was to investigated if 17-β-estradiol (estrogen, E2), endogenous atrial natriuretic peptide (ANP), endogenous brain natriuretic peptide (BNP), and tumor necrosis factor-alpha (TNF-α) are involved in PPC-mediated protection. Langendorff perfused female Wistar rat hearts were used for this study. Hearts challenged with regional ischemia for 30 min subjected to no further treatment served as a control. The PPC protocol was 3 cycles of 30 s pacing alternated between the right atrium and left ventricle (LV). Protection was assessed by recovery of LV contractility and coronary vascular-hemodynamics. Ischemia induced a significant (P < 0.05) deterioration in the heart function compared with baseline data. PPC alone or in combination with short-term E2 treatment (E2 infusion at the beginning of reperfusion) significantly (P < 0.05) improved the heart functions. Short-term E2 treatment post-ischemically afforded protection similar to that of PPC. However, long-term E2 substitution for 6 weeks completely attenuated the protective effects of PPC. Although no changes were noted in endogenous ANP levels, PPC significantly increased BNP expression level and decreased TNF-α in the cardiomyocyte lysate and coronary effluent compared to ischemia and controls. Our data suggested a protective role for short-term E2 treatment similar to that of PPC mediated by a pathway recruiting BNP and downregulating TNF-α. Our study further suggested a bad influence for long-term E2 substitution on the heart as it completely abrogated the protective effects of PPC.

Effect of ovariectomy, 17-beta estradiol, and progesterone on histology and estrogen receptors of bladder in female partial bladder outlet obstruction rat model

The aim of this study was to investigate the effect of bilateral ovariectomy (OVX), 17-beta estradiol (E2), and progesterone (P4) on the histology and estrogen receptor (ER) expression of the bladder using a female partial bladder outlet obstruction (pBOO) rat model. A total of 60 female Sprague-Dawley rats were evenly assigned into six groups of 10 each. Group A served as the control. Groups B-F underwent induced pBOO. Groups C-F underwent OVX. Groups D-F were given E2 (0.1 mg/kg/day), Group E was given P4 (1 mg/kg/day), and Group F was given P4 and dehydroepiandrosterone (DHEA) (300 μg/kg/day) by an Alzet pump. Four weeks later, serum E2 and P4 levels were evaluated. Each rat was anesthetized and the urinary bladder was removed for weighing and histological study. Expression of ER-β was not significantly different between the control group and the other study groups. pBOO was shown to increase both bladder weight and detrusor muscle thickness. OVX had an additive effect to BOO on increased blood vessel density in the bladder. E2 was shown to increase blood vessel density, while P4 supplementation decreased blood vessel density. DHEA did not cause any significant effects on blood vessel density. Hormone therapy did not change the expression of ER in bladder outlet obstruction. Estradiol stimulated the increased angiogenesis of the bladder detrusor but P4 decreased the angiogenesis of the bladder detrusor. DHEA had no effect on the bladder detrusor.

Protective effects of 17beta-estradiol on post-ischemic cardiac dysfunction and norepinephrine overflow through the non-genomic estrogen receptor/nitric oxide-mediated pathway in the rat heart

The present study was undertaken to examine the effect of acute treatment with 17β-estradiol on post-ischemic cardiac dysfunction and norepinephrine overflow and its possible mechanisms. Male rat hearts were perfused with the Langendorff method and subjected to 40min of global ischemia followed by 30min of reperfusion. Each drug was perfused from 15min before ischemia to 5min after reperfusion. During reperfusion, 17β-estradiol treatment showed significantly greater functional recovery of left ventricular developed pressure (LVDP), left ventricular end diastolic pressure (LVEDP), and dP/dtmax. Excessive norepinephrine release in coronary effluent from the post-ischemic heart was notably suppressed by treatment with 17β-estradiol. These beneficial effects of 17β-estradiol were not observed in the presence of the nitric oxide synthase inhibitor NG-nitro-l-arginine and estrogen receptor antagonist ICI 182,780 ((7α, 17β)-7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol), respectively. When NO2/NO3 levels in coronary effluents after the onset of reperfusion were measured, reverse-correlation relationships between NO2/NO3 production and ischemia/reperfusion-induced cardiac dysfunction, as well as norepinephrine overflow were observed. These findings suggest that 17β-estradiol exerts cardioprotective effects against ischemia/reperfusion-induced cardiac dysfunction, at least in part, by suppressing norepinephrine overflow, and that nitric oxide production via estrogen receptor activation plays a key role in this process.

The ERalpha/ERbeta ratio determines oxidative stress in breast cancer cell lines in response to 17Beta‐estradiol

The effects of 17beta-estradiol (E2) are mediated through activation of estrogen receptors (ER): ERalpha and ERbeta. It is known that ERalpha/ERbeta ratio is higher in breast tumors than in normal tissue. Since antioxidant enzymes and uncoupling proteins (UCPs) are reactive oxygen species (ROS) production and mitochondrial biogenesis regulators, our aim was to study the E2-effect on oxidative stress, antioxidant enzyme expression, and UCPs in breast cancer cell lines with different ERalpha/ERbeta ratios. The lower ERalpha/ERbeta ratio T47D cell line showed low ROS production and high UCP5 levels. However, the higher ERalpha/ERbeta ratio MCF-7 cell line showed an up-regulation of antioxidant enzymes and UCPs, yet exhibited high oxidative stress. As a result, a decrease in antioxidant enzyme activities and UCP2 protein levels, coupled with an increase in oxidative damage was found. On the whole, these results show different E2-effects on oxidative stress regulation, modulating UCPs, and antioxidant enzymes, which were ERalpha/ERbeta ratio dependent in breast cancer cell lines.

Non-Genomic Effects of 17beta-Estradiol on Cardiomyocytes

Pre-menopausal women have a reduced risk from ischemic heart disease compared to men; this protection is lost after ovariectomy or menopause. Estrogen has been found to confer protection in whole-heart studies in animal models. ATP-sensitive K+ (KATP) channels act as metabolic sensors, opening when cellular energy levels fall and are thought to play a role in cardioprotection. We investigated whether the cardiac KATP currents play a role in the cardioprotective effects of 17β-estradiol in isolated cardiomyocytes. Ventricular myocytes were isolated from adult male Wistar rats by enzymatic digestion. The ability of myocytes to recover contractile function after simulated ischaemia/reperfusion injury was calculated by video microscopy. Contracting myocytes (1Hz) were continuously superfused with Tyrode solution, then subjected to 7 minutes of similated ischaemia by perfusion with a metabolic inhibition solution, comprising substrate-free Tyrode with cyanide (2mM) and idoacetic acid (1mM), followed by 10 minute reperfusion with Tyrode to simulate reperfusion. A 5 minute pre-treatment of 17β-estradiol (500nM) significantly increased contractile recovery; control 30% n=100, 17β-estradiol 68% n=185, DPN (ERβ agonist) 53% n= 111. Using the whole-cell patch-clamp mode we investigated the effect of estrogen on KATP channel activity. P1075 (10μM) elicited a KATP current which was completely blocked by bath application of estradiol (500nM). Both the classical estrogen receptors; ERα and ERβ have been implicated in several rapid effects of 17β-estradiol. DPN is a specific agonist of ERβ and application of DPN (500nM) following opening of KATP by P1075 (10μM) also resulted in 100% decrease in KATP current. We show that rapid estrogen signalling has a cardioprotective effect in isolated ventricular myocytes. Application of estradiol resulted in complete loss of KATP current recorded in cardiomyocytes; therefore questioning the role of KATP in estrogen-dependent cardioprotection. This work was supported by funding by The British Heart Foundation.

17Beta-estradiol attenuates programmed cell death in cortical pericontusional zone following traumatic brain injury via upregulation of ERalpha and inhibition of caspase-3 activation

Pericontusional zone (PCZ) of traumatic cerebral contusion is a target of pharmacological intervention. It is well studied that 17beta-estradiol has a protective role in ischemic brain injury, but its role in brain protection of traumatic brain damage deserves further investigation, especially in pericontusional zone. Here we show that 17beta-estradiol enhances the protein expression and mRNA induction of estrogen alpha receptor (ERalpha) and prevents from programmed cell death in cortical pericontusional zone. ERalpha specific antagonist blocks this protective effect of 17beta-estradiol. Caspase-3 activation occurs in cortical pericontusional zone of the oil-treated injured rat brain and its activation is inhibited by 17beta-estradiol treatment. Additionally, ERalpha specific antagonist reverses this inhibition. Pan-caspase inhibitor also protect cortical pericontusional zone from programmed cell death. Our present study indicates 17beta-estradiol protects from programmed cell death in cortical pericontusional zone via enhancement of ERalpha and decrease of caspase-3 activation.

Altered Spatiotemporal Expression of Collagen Types I, III, IV, and VI in Lpar3-Deficient Peri-Implantation Mouse Uterus

Lpar3 is upregulated in the preimplantation uterus, and deletion of Lpar3 leads to delayed uterine receptivity in mice. Microarray analysis revealed that there was higher expression of Col3a1 and Col6a3 in the Preimplantation Day 3.5 Lpar3(-/-) uterus compared to Day 3.5 wild-type (WT) uterus. Since extracellular matrix (ECM) remodeling is indispensable during embryo implantation, and dynamic spatiotemporal alteration of specific collagen types is part of this process, this study aimed to characterize the expression of four main uterine collagen types: fibril-forming collagen (COL) I and COL III, basement membrane COL IV, and microfibrillar COL VI in the peri-implantation WT and Lpar3(-/-) uterus. An observed delay of COL III and COL VI clearance in the Lpar3(-/-) uterus may be associated with higher preimplantation expression of Col3a1 and Col6a3. There was also delayed clearance of COL I and delayed deposition of COL IV in the decidual zone in the Lpar3(-/-) uterus. These changes were different from the effects of 17beta-estradiol and progesterone on uterine collagen expression in ovariectomized WT uterus, indicating that the altered collagen expression in Lpar3(-/-) uterus is unlikely to be a result of alterations in ovarian hormones. Decreased expression of several genes encoding matrix-degrading metallo- and serine proteinases was observed in the Lpar3(-/-) uterus. These results demonstrate that pathways downstream of LPA3 are involved in the dynamic remodeling of ECM in the peri-implantation uterus.

Effects of 17beta‐estradiol on cardiac apoptosis in ovariectomized rats

Cardiac apoptosis was found in ovariectomized rats without ischemia. Limited information regarding the protective effects of 17beta-estradiol (E2) on cardiac Fas-dependent and mitochondria-dependent apoptotic pathways after post-menopause or bilateral oophorectomy in women was available. Forty-eight female Wistar rats at 6-7 months of age were divided into sham-operated group (Sham, n = 16) and bilateral ovariectomized group (n = 32). After 4 weeks of operation, rats in ovariectomized group were injected intraperitoneally with either saline (OVX, n = 16) or 10 microg/kg/day 17beta-estradiol (E2) for 10 weeks (OVX-E2, n = 16). The excised hearts were measured by Hematoxylin-eosin staining, DAPI staining, positive TUNEL assays, and Western Blotting. 17beta-estradiol (E2) decreased OVX-induced cardiac widely dispersed TUNEL-positive apoptotic cells. 17beta-estradiol (E2) decreased OVX-induced TNF-alpha, Fas ligand (Fas L), Fas death receptors (Fas), Fas-associated death domain (FADD), activated caspase 8, and activated caspase 3 (Fas pathways). 17beta-estradiol (E2) decreased OVX-induced proapoptotic t-Bid, Bax, Bax-to-Bcl2 ratio, Bax-to-BclXL ratio, activated caspase 9, and activated caspase 3 as well as increased anti-apoptotic Bcl2 and Bcl-XL relative to OVX (mitochondria pathway). Our findings suggest that chronic 17beta-estradiol (E2) treatment can prevent ovariectomy-induced cardiac Fas-dependent and mitochondria-dependent apoptotic pathways in rat models. The findings may provide one of possible mechenisms of 17beta-estradiol (E2) for potentially preventing cardiac apoptosis after bilateral ovariectomy or menopause.

Upregulation of estrogen receptor subtypes and vitellogenin mRNA in cinnamon clownfish Amphiprion melanopus during the sex change process: Profiles on effects of 17β-estradiol

In the present study, we investigated the expression pattern of estrogen receptors (esr) and vitellogenin (vtg) mRNA in the gonads and liver during sex change in cinnamon clownfish by using quantitative polymerase chain reaction. We divided gonadal development during the sex change from male to female into 3 stages (mature male, male at 90days after removing female, and mature female) and investigated esr and vtg mRNA expressions during the sex change. With female, the esr and vtg mRNA expressions increased. In western blot analysis, Esr1 protein was detected only in the ovaries of female cinnamon clownfish. Also, to understand the effect of 17beta-estradiol (E(2)), we investigated the esr and vtg mRNA expression patterns in the gonads and liver, and the changes in plasma E(2) level after E(2) injection. E(2) treatment increased both mRNA expression levels of esr and vtg and plasma E(2) levels. The present study describes the molecular characterization of esr subtypes and the interactions between esr and vtg after E(2) treatment in cinnamon clownfish.

Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer

BackgroundEstrogens suppress tumor growth in prostate cancer which progresses despite anorchid serum androgen levels, termed castration resistant prostate cancers (CRPC), although the mechanisms are unclear. We hypothesize that estrogen inhibits CRPC in anorchid animals by suppressing tumoral androgens, an effect independent of the estrogen receptor.MethodsThe human CRPC xenograft LuCaP 35V was implanted into orchiectomized male SCID mice and established tumors were treated with placebo, 17β-estradiol or 17β-estradiol and estrogen receptor antagonist ICI 182,780. Effects of 17β-estradiol on tumor growth were evaluated and tissue testosterone (T) and dihydrotestosterone (DHT) evaluated by mass spectrometry.ResultsTreatment of LuCaP 35V with 17β-estradiol slowed tumor growth compared to controls (tumor volume at day 21: 785 ± 81 mm3 vs. 1195 ± 84 mm3, p = 0.002). Survival was also significantly improved in animals treated with 17β-estradiol (p = 0.03). The addition of the estrogen receptor antagonist ICI 182,780 did not significantly change survival or growth. 17β-estradiol in the presence and absence of ICI 182,780 suppressed tumor testosterone (T) and dihydrotestosterone (DHT) as assayed by mass spectrometry. Tissue androgens in placebo treated LuCaP 35V xenografts were; T = 0.71 ± 0.28 pg/mg and DHT = 1.73 ± 0.36 pg/mg. In 17β-estradiol treated LuCaP35V xenografts the tissue androgens were, T = 0.20 ± 0.10 pg/mg and DHT = 0.15 ± 0.15 pg/mg, (p < 0.001 vs. controls). Levels of T and DHT in control liver tissue were < 0.2 pg/mg.ConclusionsCRPC in anorchid animals maintains tumoral androgen levels despite castration. 17β-estradiol significantly suppressed tumor T and DHT and inhibits growth of CRPC in an estrogen receptor independent manner. The ability to manipulate tumoral androgens will be critical in the development and testing of agents targeting CRPC through tissue steroidogenesis.

Comparable Attenuation of Aβ25–35-Induced Neurotoxicity by Quercitrin and 17β-Estradiol in Cultured Rat Hippocampal Neurons

In the present work, potential protective effects of quercitrin (a phytoestrogen) on Abeta-induced neurotoxicity in cultured rat hippocampal neurons were investigated in comparison with 17beta-estradiol. Cell viability, oxidative status, and antioxidative potentials were used as comparative parameters. Co-exposure of cultured neurons to Abeta(25-35) with either quercitrin or 17beta-estradiol (50-100 microM) for 72 h attenuated Abeta(25-35)-induced neurotoxicity and lipid peroxidation, but not Abeta(25-35)-induced ROS accumulation. However, only 17beta-estradiol counteracted a reduction in glutathione content and only quercitrin counteracted a reduction in glutathione peroxidase activity. Both compounds displayed no effects on superoxide dismutase activity. A specific estrogen receptor antagonist, ICI 182780, did not abolish neuroprotective effects of quercitrin and 17beta-estradiol. These findings suggested that quercitrin and 17beta-estradiol attenuated Abeta(25-35)-induced neurotoxicity in a comparable manner. Underlying neuroprotective mechanisms of both compounds were probably not related to estrogen receptor-mediated genomic mechanisms but might involve with their antioxidant and free radical scavenging properties.