• Applied Microscopy
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• v.41 no.1
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• pp.37-45
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• 2011

Known as a female hormone, estrogen, has an effect on the male reproductive organs. The estrogen has to combine with the estrogen receptor to communicate a signal. Propyl pyrazole triol (PPT) is an estrogen receptor alpha selective agonist with a 410-, or 1,000-fold relative binding affinity for estrogen receptor alpha versus estrogen receptor beta. In this study, adult male mice were treated weekly with subcutaneously injections of PPT (0.01 mg, 0.1 mg, 1mg and 4 mg) suspended in castor oil (as control) for 8 weeks and observed histologically changes in testis, efferent ductule and epididymis. In the high concentrations of PPT 4 mg treatment group, a remarkable reduction was observed in the weight of the body, testis and epididymis. Microscopic examination revealed a reduction in seminiferous tubular diameter of the testis, and epithelial cell height of the epididymis in treated group during the experiment. In addition, as the diameter of the efferent ductule increased gradually, the height of epithelial cells was decreased. PPT 4 mg treatment group caused inhibition of spermatogenesis due to atrophied germinal epithelium in the testis, and decrease of adipocyte size attached to the epididymis. Sperm was not observed in the caudal epididymis of PPT 4 mg treated group. In conclusion, the injection of high concentrations of PPT into adult male mice induced physiological changes, such as an inhibition of spermatogenesis, and also histological changes within the reproductive organs.

• The Korean Journal of Pharmacology
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• v.26 no.2
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• pp.167-176
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• 1990

In the present study, we examined the effects of tamoxifen and LY117018 on various parameters for the estrogenic actions in order to understand the mechanism by which tamoxifen and LY117018 act on the uterine cells in 21-23 day old immature rats. Tamoxifen and LY117018 stimulated uterine weight and uterine contents of DNA, protein, and peroxidase activity in the absence of estradiol while inhibited above parameters in the presence of estradiol. Both cytosolic and nuclear progesterone receptors were increased by the treatment of tamoxifen and LY117018 as well as estradiol, but estradiol-induced increase in the progesterone receptors were reduced by the treatment of antiestrogens. These effects were enhanced by the multiple injections of antiestrogens. It seemed that tamoxifen was more agonistic than LY117018 but less antagonistic than LY117018, judged by their effects on various parameters for the estrogenic action. The affinities of estradiol, tamoxifen, and LY117018 for the estrogen receptor were $0.17{\pm}0.01nM(100%)$, $1.10{\pm}0.01nM(6.3%)$, and $0.23{\pm}0.01nM(77%)$, respectively. Furthermore, LY117018 was the competitive ligand for the estrogen receptor in dose-related manner but tamoxifen was not. Following estradiol treatment, nuclear estrogen receptor was sharply increased by 1 h, reaching the maximum by 16 h, while tamoxifen and LY117018 slightly increased nuclear estrogen receptor by 1 h and then decreased thereafter. It is therefore concluded that LY117018 is a competitive antagonist for the estrogen receptor with less estrogenic activity, compared to tamoxifen with low affinity to the estrogen receptor, and tamoxifen may act through other binding site than the estrogen receptor.

• BMB Reports
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• v.44 no.7
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• pp.423-434
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• 2011

A female hormone, estrogen, is linked to breast cancer incidence. Estrogens undergo phase I and II metabolism by which they are biotransformed into genotoxic catechol estrogen metabolites and conjugate metabolites are produced for excretion or accumulation. The molecular mechanisms underlying estrogen-mediated mammary carcinogenesis remain unclear. Cell proliferation through activation of estrogen receptor (ER) by its agonist ligands and is clearly considered as one of carcinogenic mechanisms. Recent studies have proposed that reactive oxygen species generated from estrogen or estrogen metabolites are attributed to genotoxic effects and signal transduction through influencing redox sensitive transcription factors resulting in cell transformation, cell cycle, migration, and invasion of the breast cancer. Conjuguation metabolic pathway is thought to protect cells from genotoxic and cytotoxic effects by catechol estrogen metabolites. However, methoxylated catechol estrogens have been shown to induce ER-mediated signaling pathways, implying that conjugation is not a simply detoxification pathway. Dual action of catechol estrogen metabolites in mammary carcinogenesis as the ER-signaling molecules and chemical carcinogen will be discussed in this review.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.6
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• pp.2161-2166
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• 2015

Estrogen receptors (ERs) are steroid receptors located in the cytoplasm and on the nuclear membrane. The sequence similarities of human $ER{\alpha}$, mouse $ER{\alpha}$, rat $ER{\alpha}$, dog $ER{\alpha}$, and cat $ER{\alpha}$ are above 90%, but structures of $ER{\alpha}$ may different among species. Estrogen can be agonist and antagonist depending on its target organs. This hormone play roles in several diseases including breast cancer. There are variety of the relative binding affinity (RBA) of ER and estrogen species in comparison to $17{\beta}-estradiol$ (E2), which is a natural ligand of both $ER{\alpha}$ and $ER{\beta}$. The RBA of the estrogen species are as following: diethyl stilbestrol (DES) > hexestrol > dienestrol > $17{\beta}-estradiol$ (E2) > 17- estradiol > moxestrol > estriol (E3) >4-OH estradiol > estrone-3-sulfate. Estrogen mimetic drugs, selective estrogen receptor modulators (SERMs), have been used as hormonal therapy for ER positive breast cancer and postmenopausal osteoporosis. In the postgenomic era, in silico models have become effective tools for modern drug discovery. These provide three dimensional structures of many transmembrane receptors and enzymes, which are important targets of de novo drug development. The estimated inhibition constants (Ki) from computational model have been used as a screening procedure before in vitro and in vivo studies.

• Applied Microscopy
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• v.39 no.4
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• pp.301-309
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• 2009

Estrogens induce pronounced structural and functional changes in male and female reproductive system, but the exact mechanisms of estrogen are not fully understood. In relation to estrogen's function, the present study was designed to identify effects of estrogen receptor agonist, 4,4',4"- (4-propyl-[1H]-pyrazole-1,3,5-triyl)tris phenol (PPT) in the reproductive organ of the female mouse. The PPT was subcutaneously given to adult female mice at a weekly dosage of 3 mg in a volume 0.06 mL of vehicle for 3, 5 or 8 weeks whereas controls received weekly injections of the castor oil vehicle. Effects of PPT on reproductive organs were analyzed using a light microscope. PPT induced decreases of body, ovary and adipose tissue weights with experimental time. Ovary diameter of PPT treatment group was reduced as compared with control group. The number of Graffian follicle and corpus luteum was reduced in PPT treatment group. The luminal diameter of uterus was increased in relation with decrease of myometrium and endometrium height by PPT administration. The number of uterine glands was decreased by PPT treatment. These data indicate that PPT treatment induced morphological change of female reproductive organs resulting in alteration of fertility.

• Toxicological Research
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• v.22 no.4
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• pp.365-373
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• 2006

The present study was designed to characterize the effects of estrogen receptor agonist (4,4',4'-(4-Propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol, PPT) on liver and kidney in male mouse using a light microscopic analysis. PPT was subcutaneously given to adult male mice at a weekly dosage of 178.6mg/kg in a volume 0.08 ml of vehicle for 3, 5 and 8 weeks. There were differences in body and organ weights between control and the treated groups. Body and kidney weights were decreased in treated group whereas, liver weight was increased. In microscopic observations, sinusoidal diameter in liver of treated group was increased 156%, 216% and 255% on week 3, 5 and 8 respectively. Compared to the control, diameter of proximal convoluted tubules in kidney was increased 37% and 43% or week 5 and 8 in treated group. Whereas, height of epithelial cells in the proximal tubules was reduced at all time points. These results suggest that microstructure of liver and kidney was changed by treatment of estrogen receptor agonist PPT in the male mice.

• Biomolecules & Therapeutics
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• v.20 no.3
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• pp.256-267
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• 2012

Tamoxifen is a central component of the treatment of estrogen receptor (ER)-positive breast cancer as a partial agonist of ER. It has been clinically used for the last 30 years and is currently available as a chemopreventive agent in women with high risk for breast cancer. The most challenging issue with tamoxifen use is the development of resistance in an initially responsive breast tumor. This review summarizes the roles of ER as the therapeutic target of tamoxifen in cancer treatment, clinical values and issues of tamoxifen use, and molecular mechanisms of tamoxifen resistance. Emerging knowledge on the molecular mechanisms of tamoxifen resistance will provide insight into the design of regimens to overcome tamoxifen resistance and discovery of novel therapeutic agents with a decreased chance of developing resistance as well as establishing more efficient treatment strategies.

• BMB Reports
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• v.55 no.11
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• pp.547-552
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• 2022

Sorafenib, originally identified as an inhibitor of multiple oncogenic kinases, induces ferroptosis in hepatocellular carcinoma (HCC) cells. Several pathways that mitigate sorafenib-induced ferroptosis confer drug resistance; thus strategies that enhance ferroptosis increase sorafenib efficacy. Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is upregulated in human HCC tissues and plays a role in cancer cell proliferation. The aim of this study was to determine whether inhibition of ERRγ with DN200434, an orally available inverse agonist, can overcome resistance to sorafenib through induction of ferroptosis. Sorafenib-resistant HCC cells were less sensitive to sorafenibinduced ferroptosis and showed significantly higher ERRγ levels than sorafenib-sensitive HCC cells. DN200434 induced lipid peroxidation and ferroptosis in sorafenib-resistant HCC cells. Mechanistically, DN200434 increased mitochondrial ROS generation by reducing glutathione/glutathione disulfide levels, which subsequently reduced mTOR activity and GPX4 levels. DN200434 induced amplification of the antitumor effects of sorafenib was confirmed in a tumor xenograft model. The present results indicate that DN200434 may be a novel therapeutic strategy to re-sensitize HCC cells to sorafenib.

• Journal of Veterinary Science
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• v.22 no.4
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• pp.53.1-53.13
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• 2021

Background: Canine adipose-derived stem cells (cADSCs) exhibit various differentiation properties and are isolated from the canine subcutaneous fat. Although cADSCs are valuable as tools for research on adipogenic differentiation, studies focusing on adipogenic differentiation methods and the underlying mechanisms are still lacking. Objectives: In this study, we aimed to establish an optimal method for adipogenic differentiation conditions of cADSCs and evaluate the role of peroxisome proliferator-activated receptor gamma (PPARγ) and estrogen receptor (ER) signaling in the adipogenic differentiation. Methods: To induce adipogenic differentiation of cADSCs, 3 different adipogenic medium conditions, MDI, DRI, and MDRI, using 3-isobutyl-1-methylxanthine (M), dexamethasone (D), insulin (I), and rosiglitazone (R) were tested. Results: MDRI, addition of PPARγ agonist rosiglitazone to MDI, was the most significantly facilitated cADSC into adipocyte. GW9662, an antagonist of PPARγ, significantly reduced adipogenic differentiation induced by rosiglitazone. Adipogenic differentiation was also stimulated when 17β-estradiol was added to MDI and DRI, and this stimulation was inhibited by the ER antagonist ICI182,780. Conclusions: Taken together, our results suggest that PPARγ and ER signaling are related to the adipogenic differentiation of cADSCs. This study could provide basic information for future research on obesity or anti-obesity mechanisms in dogs.

• Proceedings of the Korean Society of Life Science Conference
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• 2006.09a
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• pp.54.1-54.1
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• 2006