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Search results for: Recombinant Human Androgen receptor Proteins

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#34533124   // To Up

[RS102895 inhibits the proliferation, invasion, and migration of PC-3 prostate cancer cells by blocking CCL2/CCR2 pathway].

Objective To investigate the effect of RS102895, a specific C-C motif chemokine receptor 2 (CCR2) antagonist, on the biological behavior of prostate cancer (PCa) cells with different degrees of malignancy. Methods Non-androgen-dependent prostate cancer cells PC-3 and androgen-dependent prostate cancer cells 22RV1 were cultured in vitro. A control group, a recombinant C-C motif chemokine ligand 2 (rCCL2) treatment group, and a rCCL2 combined with RS102895 treatment group were established. Cell proliferation ability was detected by CCK-8 assay, cell invasion and migration abilities were detected by Transwell assay, mRNA expressions of cell antigen KI-67 (ki67) and matrix metalloproteinase 2 (MMP2) were detected by real-time quantitative PCR, and protein expression levels of ki67 and MMP2 were detected by Western blotting. Results The proliferation, invasion, and migration abilities of PC-3 cells were significantly enhanced by rCCL2, and the proliferation ability of 22RV1 cells was significantly increased as well. Meanwhile, the mRNA and protein expression levels of ki67 and MMP2 in PC-3 cells were significantly up-regulated by rCCL2. After RS102895 treatment, the above effects of rCCL2 were reversed. Conclusion RS102895 can inhibit the proliferation, invasion, and migration of PC-3 prostate cancer cells by specifically blocking the CCL2/CCR2 pathway and down-regulating the expressions of ki67 and MMP2.
Jingzhou Wang, Keru Chen, Xue Li, Bingqi Yang, Huai Pang, Cuizhe Wang, Jun Zhang

1539 related Products with: [RS102895 inhibits the proliferation, invasion, and migration of PC-3 prostate cancer cells by blocking CCL2/CCR2 pathway].

50 ug2 Pieces/Box50 ugEach50 ug

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#32991989   2020/09/28 To Up

Is the unique benzodiazepine structure interacting with CYP enzymes to affect steroid synthesis in vitro?

The aim of this project was to investigate the endocrine disrupting effects of three γ-aminobutyric acid type A receptor (GABAR) agonists, diazepam (DZ), oxazepam (OX) and alprazolam (AL) using the steroidogenic in vitro H295R cell line assay, a recombinant CYP17A1 assay, qPCR analysis and computational modelling. Similar effects for DZ and OX on the steroidogenesis were observed in the H295R experiment at therapeutically relevant concentrations. Progestagens and corticosteroids were increased up to 10 fold and androgens were decreased indicating CYP17A1 lyase inhibition. For DZ the inhibition on both the hydroxylase and lyase was confirmed by the recombinant CYP17A1 assay, whereas OX did not appear to directly affect the recombinant CYP17A1 enzyme. Androgens were decreased when exposing the H295R cells to AL, indicating a CYP17A1 lyase inhibition. However, this was not confirmed by the recombinant CYP17A1 assay but a down-regulation in gene expression was observed for StAR and CYP17A1. The present study showed that the three investigated benzodiazepines (BZDs) are rather potent endocrine disruptors in vitro, exerting endocrine effects close the therapeutic C. Both direct and indirect effects on steroidogenesis were observed, but molecular modelling indicated no direct interactions between the heme group in the steroidogenic CYP enzymes and the unique diazepin structure. In contrast, physicochemical properties such as high log P, structure and molecular weight similar to that of steroids appeared to influence the endocrine disrupting abilities of the investigated pharmaceuticals in vitro. Docking of the three BZDs in CYP17A1 and CYP21A2 confirmed that shape complementarity and hydrophobic effects seem to determine the binding modes.
Malene Louise Johannsen, Cecilie Hurup Munkboel, Flemming Steen Jørgensen, Bjarne Styrishave

1681 related Products with: Is the unique benzodiazepine structure interacting with CYP enzymes to affect steroid synthesis in vitro?

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#32668201   2020/07/14 To Up

Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes.

Steroid receptors activate gene transcription by recruiting coactivators to initiate transcription of their target genes. For most nuclear receptors, the ligand-dependent activation function domain-2 (AF-2) is a primary contributor to the nuclear receptor (NR) transcriptional activity. In contrast to other steroid receptors, such as ERα, the activation function of androgen receptor (AR) is largely dependent on its ligand-independent AF-1 located in its N-terminal domain (NTD). It remains unclear why AR utilizes a different AF domain from other receptors despite that NRs share similar domain organizations. Here, we present cryoelectron microscopy (cryo-EM) structures of DNA-bound full-length AR and its complex structure with key coactivators, SRC-3 and p300. AR dimerization follows a unique head-to-head and tail-to-tail manner. Unlike ERα, AR directly contacts a single SRC-3 and p300. The AR NTD is the primary site for coactivator recruitment. The structures provide a basis for understanding assembly of the AR:coactivator complex and its domain contributions for coactivator assembly and transcriptional regulation.
Xinzhe Yu, Ping Yi, Ross A Hamilton, Hong Shen, Muyuan Chen, Charles E Foulds, Michael A Mancini, Steven J Ludtke, Zhao Wang, Bert W O'Malley

1609 related Products with: Structural Insights of Transcriptionally Active, Full-Length Androgen Receptor Coactivator Complexes.

5 x 50 ug100ug/vial1mg50 ug200ul1 ml100 µg100ug200ug50 ug 100ul100ug

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#32392092   2020/05/11 To Up

A Mechanistic High-Content Analysis Assay Using a Chimeric Androgen Receptor That Rapidly Characterizes Androgenic Chemicals.

Human health is at risk from environmental exposures to a wide range of chemical toxicants and endocrine-disrupting chemicals (EDCs). As part of understanding this risk, the U.S. Environmental Protection Agency (EPA) has been pursuing new high-throughput in vitro assays and computational models to characterize EDCs. EPA models have incorporated our high-content analysis-based green fluorescent protein estrogen receptor (GFP-ER): PRL-HeLa assay, which allows direct visualization of ER binding to DNA regulatory elements. Here, we characterize a modified functional assay based on the stable expression of a chimeric androgen receptor (ARER), wherein a region containing the native AR DNA-binding domain (DBD) was replaced with the ERα DBD (amino acids 183-254). We demonstrate that the AR agonist dihydrotestosterone induces GFP-ARER nuclear translocation, PRL promoter binding, and transcriptional activity at physiologically relevant concentrations (<1 nM). In contrast, the AR antagonist bicalutamide induces only nuclear translocation of the GFP-ARER receptor (at μM concentrations). Estradiol also fails to induce visible chromatin binding, indicating androgen specificity. In a screen of reference chemicals from the EPA and the Agency for Toxic Substances and Disease Registry, the GFP-ARER cell model identified and mechanistically grouped activity by known (anti-)androgens based on the ability to induce nuclear translocation and/or chromatin binding. Finally, the cell model was used to identify potential (anti-)androgens in environmental samples in collaboration with the Houston Ship Channel/Galveston Bay Texas A&M University EPA Superfund Research Program. Based on these data, the chromatin-binding, in vitro assay-based GFP-ARER model represents a selective tool for rapidly identifying androgenic activity associated with drugs, chemicals, and environmental samples.
Adam T Szafran, Michael J Bolt, Caroline E Obkirchner, Maureen G Mancini, Christine Helsen, Frank Claessens, Fabio Stossi, Michael A Mancini

1752 related Products with: A Mechanistic High-Content Analysis Assay Using a Chimeric Androgen Receptor That Rapidly Characterizes Androgenic Chemicals.

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#32277850   2020/04/11 To Up

Testosterone-androgen receptor: The steroid link inhibiting TRPM8-mediated cold sensitivity.

Recent studies have revealed gender differences in cold perception, and pointed to a possible direct action of testosterone (TST) on the cold-activated TRPM8 (Transient Receptor Potential Melastatin Member 8) channel. However, the mechanisms by which TST influences TRPM8-mediated sensory functions remain elusive. Here, we show that TST inhibits TRPM8-mediated mild-cold perception through the noncanonical engagement of the Androgen Receptor (AR). Castration of both male rats and mice increases sensitivity to mild cold, and this effect depends on the presence of intact TRPM8 and AR. TST in nanomolar concentrations suppresses whole-cell TRPM8-mediated currents and single-channel activity in native dorsal root ganglion (DRG) neurons and HEK293 cells co-expressing recombinant TRPM8 and AR, but not TRPM8 alone. AR cloned from rat DRGs shows no difference from standard AR. However, biochemical assays and confocal imaging reveal the presence of AR on the cell surface and its interaction with TRPM8 in response to TST, leading to an inhibition of channel activity.
Dimitra Gkika, Stéphane Lolignier, Guillaume P Grolez, Alexis Bavencoffe, Georges Shapovalov, Dmitri Gordienko, Artem Kondratskyi, Mathieu Meleine, Laetitia Prival, Eric Chapuy, Monique Etienne, Alain Eschalier, Yaroslav Shuba, Roman Skryma, Jérôme Busserolles, Natalia Prevarskaya

2014 related Products with: Testosterone-androgen receptor: The steroid link inhibiting TRPM8-mediated cold sensitivity.

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#32057540   2020/02/11 To Up

Deep androgen receptor suppression in prostate cancer exploits sexually dimorphic renal expression for systemic glucocorticoid exposure.

Enzalutamide and apalutamide are potent next-generation androgen receptor (AR) antagonists used in metastatic and non-metastatic prostate cancer. Metabolic, hormonal and immunologic effects of deep AR suppression are unknown. We hypothesized that enzalutamide and apalutamide suppress 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2), which normally converts cortisol to cortisone, leading to elevated cortisol concentrations, increased ratio of active to inactive glucocorticoids and possibly suboptimal response to immunotherapy. On-treatment glucocorticoid changes might serve as an indicator of active glucocorticoid exposure and resultant adverse consequences.
M Alyamani, J Li, M Patel, S Taylor, F Nakamura, M Berk, C Przybycin, E M Posadas, R A Madan, J L Gulley, B Rini, J A Garcia, E A Klein, N Sharifi

1416 related Products with: Deep androgen receptor suppression in prostate cancer exploits sexually dimorphic renal expression for systemic glucocorticoid exposure.



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#31873151   2019/12/23 To Up

Disordered region of cereblon is required for efficient degradation by proteolysis-targeting chimera.

Proteolysis targeting chimeras (PROTACs) are an emerging strategy for promoting targeted protein degradation by inducing the proximity between targeted proteins and E3 ubiquitin ligases. Although successful degradation of numerous proteins by PROTACs has been demonstrated, the elements that determine the degradability of PROTAC-targeted proteins have not yet been explored. In this study, we developed von Hippel-Lindau-Cereblon (VHL-CRBN) heterodimerizing PROTACs that induce the degradation of CRBN, but not VHL. A quantitative proteomic analysis further revealed that VHL-CRBN heterodimerizing PROTACs induced the degradation of CRBN, but not the well-known immunomodulatory drug (IMiD) neo-substrates, IKAROS family zinc finger 1 (IKZF1) and -3 (IZKF3). Moreover, truncation of disordered regions of CRBN and the androgen receptor (AR) attenuated their PROTAC-induced degradation, and attachment of the disordered region to stable CRBN or AR facilitated PROTAC-induced degradation. Thus, these results suggest that the intrinsically disordered region of targeted proteins is essential for efficient proteolysis, providing a novel criterion for choosing degradable protein targets.
Kidae Kim, Dong Ho Lee, Sungryul Park, Seung-Hyun Jo, Bonsu Ku, Sung Goo Park, Byoung Chul Park, Yeong Uk Jeon, Sunjoo Ahn, Chung Hyo Kang, Daehee Hwang, Sehyun Chae, Jae Du Ha, Sunhong Kim, Jong Yeon Hwang, Jeong-Hoon Kim

1142 related Products with: Disordered region of cereblon is required for efficient degradation by proteolysis-targeting chimera.

100 μg100 μg100 μg100 μg0.1 ml25 μg25 µg100 μg100 μg0.1 mg0.25 mg1 ml

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