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Peter Thomas - One of the best experts on this subject based on the ideXlab platform.
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membrane Androgen receptors unrelated to Nuclear steroid receptors
Endocrinology, 2019Co-Authors: Peter ThomasAbstract:Rapid (nongenomic) membrane-initiated Androgen actions have been described in Nuclear Androgen receptor-null cells. Four distinct proteins have been proposed as membrane Androgen receptors (mARs) or sensors. Transient receptor potential melastatin 8 (TRPM8) is a calcium channel that acts as a pain receptor and mediates Androgen- and menthol-induced increases in calcium levels and survival of prostate cancer cells. Testosterone (T) directly interacts with TRPM8, but extensive Androgen receptor binding studies to confirm its role as an mAR are lacking. Oxoeicosanoid receptor 1 (OXER1) is highly expressed in prostate cancer tissues, and its major ligand, 5-oxoeicosatretraenoic acid (5-oxo-ETE), is a potent inducer of prostate cancer cell proliferation and survival. T competes for 5-oxo-ETE binding to OXER1 and antagonizes 5-oxo-ETE-mediated inhibition of cAMP production. However, OXER1 does not meet a traditional criterion for its designation as an mAR because T treatment alone does not alter cAMP signaling. GPRC6A is a class C G protein-coupled receptor activated by l-α-amino acids and is modulated by calcium. Although there has been controversy over the proposed role of T as a GPRC6A ligand, Androgen induction of GPRC6A signaling has recently been confirmed by several researchers. ZIP9 belongs to the zinc transporter ZIP (SLC39A) family and displays specific T binding characteristic of an mAR. ZIP9 mediates Androgen-dependent intracellular signaling and apoptosis of breast and prostate cancer cells through activation of G proteins. Androgen-signaling functions of ZIP9 have been confirmed in other cells, but the overall importance of ZIP9 in Androgen physiology remains unclear. Here, the current status of these four proteins as mARs or sensors is critically reviewed.
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zip9 a novel membrane Androgen receptor and zinc transporter protein
General and Comparative Endocrinology, 2018Co-Authors: Peter Thomas, Aubrey Converse, Hakan BergAbstract:Rapid, Androgen actions initiated at the cell surface have been reported in a variety of vertebrate cells, including several macrophage and prostate cancer cell lines that lack the Nuclear Androgen receptor. However, until recently the identity of the novel membrane Androgen receptor (mAR) mediating these nonclassical Androgen actions remained unknown. In 2014, a novel mAR unrelated to Nuclear Androgen receptors was identified in Atlantic croaker ovaries as the zinc transporter protein, ZIP9. ZIP9 is one of the 14 members of the ZIP (ZRT-and Irt-like Protein, SLC39A) family that regulates zinc homeostasis by transporting zinc across cell and organelle membranes into the cytoplasm. Zinc is a micronutrient critical for the maintenance of physiological and cellular processes, such as development, growth, protein assembly and activity, signaling, and apoptosis. Both croaker ZIP9 and human ZIP9 proteins have the binding characteristics of high affinity, specific mARs, and are coupled to G proteins. Testosterone induces apoptosis through ZIP9 in croaker granulosa cells and in human breast and prostate cancer cells by a unique mechanism involving increases in both second messengers and intracellular free zinc concentrations. ZIP9 also mediates testosterone regulation of tight junction formation in Sertoli cells and nonclassical testosterone signaling in spermatogenic cells. ZIP9 acts through several signal transduction pathways, a stimulatory G protein (Gs) in granulosa cells, an inhibitory one (Gi) in cancer cells, and a Gq11 one (Gnα11) in spermatogenic cells. ZIP9 has a very broad tissue distribution and is predicted to mediate numerous and diverse nonclassical Androgen actions in vertebrates.
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regulation of Androgen receptors in atlantic croaker brains by testosterone and estradiol
General and Comparative Endocrinology, 2002Co-Authors: D Joakim G Larsson, Todd S Sperry, Peter ThomasAbstract:A Nuclear Androgen receptor (AR1), distinctly different from the mammalian AR, has previously been identified in the brain of the Atlantic croaker, Micropogonias undulatus. Interestingly, brain AR1 levels were higher in gonadally recrudesced than in regressed fish. Therefore, the possible involvement of gonadal steroids in the regulation of brain AR1 levels was investigated in the present study. Saturation analysis of [3H]testosterone binding showed that brain AR1 levels were significantly reduced (2-3-fold) in either the Nuclear or cytosolic fractions of both males and females three weeks after gonadectomy. Implantation of gonadectomized females with testosterone or estradiol-17beta one week prior to sampling resulted in physiological plasma steroid concentrations and restored brain AR1 levels to 60-105% of those in intact or sham-operated fish. These results suggest that gonadal factors, including both Androgens and estrogens, are involved in the physiological regulation of brain Androgen receptors in a teleost species during the reproductive cycle.
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characterization of two Nuclear Androgen receptors in atlantic croaker comparison of their biochemical properties and binding specificities
Endocrinology, 1999Co-Authors: Todd S Sperry, Peter ThomasAbstract:Two distinct Androgen receptors (ARs) with different characteristics were identified in the brain and ovary of Atlantic croaker, Micropogonias undulatus. A Nuclear AR, AR1, was identified in the brain that had high affinity binding sites for testosterone (T; Kd, 1.1 ± 0.15 nm; binding capacity, 1.4 ± 0.14 pmol/g tissue; n = 16). A second Nuclear AR, AR2, was found in the ovary that had high affinity binding sites for 5α-dihydrotestosterone (DHT; Kd, 0.62 ± 0.1 nm; binding capacity, 0.38 ± 0.06 pmol/g tissue; n = 14). AR2 has physiochemical properties similar to those of other vertebrate ARs. AR2 has high affinity binding for a broad spectrum of natural and synthetic Androgens, including 17α-methyl-5α-dihydrotestosterone, which has a relative binding affinity of DHT = 100% > T > mibolerone > 11-ketotestosterone = 16%, a rapid association (t1/2, 44 min) and a slow dissociation (t1/2, 45 h) rate, as well as specific binding to purified DNA. The cytosolic AR2 interacts with heat shock proteins in a manner sim...
Luciano Sturmer De Fraga - One of the best experts on this subject based on the ideXlab platform.
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epitestosterone and testosterone replacement in immature castrated rats changes main testicular developmental characteristics
Molecular and Cellular Endocrinology, 2017Co-Authors: Fernanda Carvalho Cavalari, Tadeu Dourado, Alexandre Luz De Castro, Maria Beatriz Kohek, Maria Flavia Marques Ribeiro, Wania Aparecida Partata, Luciana Abreu Da Rosa, Gustavo Monteiro Escott, Luciano Sturmer De FragaAbstract:Abstract Epitestosterone is the 17α-epimer of testosterone and has been described as an anti-Androgen, since it inhibits the effects produced by testosterone and dihydrotestosterone via the Nuclear Androgen receptor (nAR). However, epitestosterone also displays an effect which is similar to the non-classical effect of testosterone, depolarizing the membrane potential of Sertoli cells and inducing a rapid Ca2+ uptake. This study aimed to investigate the effects of a treatment with epitestosterone on developmental parameters of immature rats. Animals were chemically castrated by using the gonadotropin-releasing hormone (GnRH) antagonist cetrorelix and then received a replacement of 7 days with epitestosterone or testosterone. Replacement with either epitestosterone or testosterone restored the anogenital distance (AGD) and testicular weight which had been reduced by chemical castration. The immunocontent of nAR and the nAR-immunoreactivity were reduced by epitestosterone treatment in the testis of both castrated and non-castrated animals. Furthermore, testosterone was unable of changing the membrane potential of Sertoli cells through its non-classical action in the group of animals castrated and replaced with epitestosterone. In conclusion, in relation to the level of protein expression of nAR epitestosterone acts as an anti-Androgen. However, it acts in the same way as testosterone when genital development parameters are evaluated. Moreover, in castrated rats epitestosterone suppressed the non-classical response of testosterone, changing the pattern of testosterone signalling via a membrane mechanism in Sertoli cells.
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epitestosterone and testosterone replacement in immature castrated rats changes main testicular developmental characteristics
Molecular and Cellular Endocrinology, 2017Co-Authors: Fernanda Carvalho Cavalari, Tadeu Dourado, Alexandre Luz De Castro, Maria Beatriz Kohek, Maria Flavia Marques Ribeiro, Wania Aparecida Partata, Luciana Abreu Da Rosa, Gustavo Monteiro Escott, Luciano Sturmer De FragaAbstract:Abstract Epitestosterone is the 17α-epimer of testosterone and has been described as an anti-Androgen, since it inhibits the effects produced by testosterone and dihydrotestosterone via the Nuclear Androgen receptor (nAR). However, epitestosterone also displays an effect which is similar to the non-classical effect of testosterone, depolarizing the membrane potential of Sertoli cells and inducing a rapid Ca2+ uptake. This study aimed to investigate the effects of a treatment with epitestosterone on developmental parameters of immature rats. Animals were chemically castrated by using the gonadotropin-releasing hormone (GnRH) antagonist cetrorelix and then received a replacement of 7 days with epitestosterone or testosterone. Replacement with either epitestosterone or testosterone restored the anogenital distance (AGD) and testicular weight which had been reduced by chemical castration. The immunocontent of nAR and the nAR-immunoreactivity were reduced by epitestosterone treatment in the testis of both castrated and non-castrated animals. Furthermore, testosterone was unable of changing the membrane potential of Sertoli cells through its non-classical action in the group of animals castrated and replaced with epitestosterone. In conclusion, in relation to the level of protein expression of nAR epitestosterone acts as an anti-Androgen. However, it acts in the same way as testosterone when genital development parameters are evaluated. Moreover, in castrated rats epitestosterone suppressed the non-classical response of testosterone, changing the pattern of testosterone signalling via a membrane mechanism in Sertoli cells.
Alexandre Luz De Castro - One of the best experts on this subject based on the ideXlab platform.
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epitestosterone and testosterone replacement in immature castrated rats changes main testicular developmental characteristics
Molecular and Cellular Endocrinology, 2017Co-Authors: Fernanda Carvalho Cavalari, Tadeu Dourado, Alexandre Luz De Castro, Maria Beatriz Kohek, Maria Flavia Marques Ribeiro, Wania Aparecida Partata, Luciana Abreu Da Rosa, Gustavo Monteiro Escott, Luciano Sturmer De FragaAbstract:Abstract Epitestosterone is the 17α-epimer of testosterone and has been described as an anti-Androgen, since it inhibits the effects produced by testosterone and dihydrotestosterone via the Nuclear Androgen receptor (nAR). However, epitestosterone also displays an effect which is similar to the non-classical effect of testosterone, depolarizing the membrane potential of Sertoli cells and inducing a rapid Ca2+ uptake. This study aimed to investigate the effects of a treatment with epitestosterone on developmental parameters of immature rats. Animals were chemically castrated by using the gonadotropin-releasing hormone (GnRH) antagonist cetrorelix and then received a replacement of 7 days with epitestosterone or testosterone. Replacement with either epitestosterone or testosterone restored the anogenital distance (AGD) and testicular weight which had been reduced by chemical castration. The immunocontent of nAR and the nAR-immunoreactivity were reduced by epitestosterone treatment in the testis of both castrated and non-castrated animals. Furthermore, testosterone was unable of changing the membrane potential of Sertoli cells through its non-classical action in the group of animals castrated and replaced with epitestosterone. In conclusion, in relation to the level of protein expression of nAR epitestosterone acts as an anti-Androgen. However, it acts in the same way as testosterone when genital development parameters are evaluated. Moreover, in castrated rats epitestosterone suppressed the non-classical response of testosterone, changing the pattern of testosterone signalling via a membrane mechanism in Sertoli cells.
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epitestosterone and testosterone replacement in immature castrated rats changes main testicular developmental characteristics
Molecular and Cellular Endocrinology, 2017Co-Authors: Fernanda Carvalho Cavalari, Tadeu Dourado, Alexandre Luz De Castro, Maria Beatriz Kohek, Maria Flavia Marques Ribeiro, Wania Aparecida Partata, Luciana Abreu Da Rosa, Gustavo Monteiro Escott, Luciano Sturmer De FragaAbstract:Abstract Epitestosterone is the 17α-epimer of testosterone and has been described as an anti-Androgen, since it inhibits the effects produced by testosterone and dihydrotestosterone via the Nuclear Androgen receptor (nAR). However, epitestosterone also displays an effect which is similar to the non-classical effect of testosterone, depolarizing the membrane potential of Sertoli cells and inducing a rapid Ca2+ uptake. This study aimed to investigate the effects of a treatment with epitestosterone on developmental parameters of immature rats. Animals were chemically castrated by using the gonadotropin-releasing hormone (GnRH) antagonist cetrorelix and then received a replacement of 7 days with epitestosterone or testosterone. Replacement with either epitestosterone or testosterone restored the anogenital distance (AGD) and testicular weight which had been reduced by chemical castration. The immunocontent of nAR and the nAR-immunoreactivity were reduced by epitestosterone treatment in the testis of both castrated and non-castrated animals. Furthermore, testosterone was unable of changing the membrane potential of Sertoli cells through its non-classical action in the group of animals castrated and replaced with epitestosterone. In conclusion, in relation to the level of protein expression of nAR epitestosterone acts as an anti-Androgen. However, it acts in the same way as testosterone when genital development parameters are evaluated. Moreover, in castrated rats epitestosterone suppressed the non-classical response of testosterone, changing the pattern of testosterone signalling via a membrane mechanism in Sertoli cells.
Fernanda Carvalho Cavalari - One of the best experts on this subject based on the ideXlab platform.
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epitestosterone and testosterone replacement in immature castrated rats changes main testicular developmental characteristics
Molecular and Cellular Endocrinology, 2017Co-Authors: Fernanda Carvalho Cavalari, Tadeu Dourado, Alexandre Luz De Castro, Maria Beatriz Kohek, Maria Flavia Marques Ribeiro, Wania Aparecida Partata, Luciana Abreu Da Rosa, Gustavo Monteiro Escott, Luciano Sturmer De FragaAbstract:Abstract Epitestosterone is the 17α-epimer of testosterone and has been described as an anti-Androgen, since it inhibits the effects produced by testosterone and dihydrotestosterone via the Nuclear Androgen receptor (nAR). However, epitestosterone also displays an effect which is similar to the non-classical effect of testosterone, depolarizing the membrane potential of Sertoli cells and inducing a rapid Ca2+ uptake. This study aimed to investigate the effects of a treatment with epitestosterone on developmental parameters of immature rats. Animals were chemically castrated by using the gonadotropin-releasing hormone (GnRH) antagonist cetrorelix and then received a replacement of 7 days with epitestosterone or testosterone. Replacement with either epitestosterone or testosterone restored the anogenital distance (AGD) and testicular weight which had been reduced by chemical castration. The immunocontent of nAR and the nAR-immunoreactivity were reduced by epitestosterone treatment in the testis of both castrated and non-castrated animals. Furthermore, testosterone was unable of changing the membrane potential of Sertoli cells through its non-classical action in the group of animals castrated and replaced with epitestosterone. In conclusion, in relation to the level of protein expression of nAR epitestosterone acts as an anti-Androgen. However, it acts in the same way as testosterone when genital development parameters are evaluated. Moreover, in castrated rats epitestosterone suppressed the non-classical response of testosterone, changing the pattern of testosterone signalling via a membrane mechanism in Sertoli cells.
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epitestosterone and testosterone replacement in immature castrated rats changes main testicular developmental characteristics
Molecular and Cellular Endocrinology, 2017Co-Authors: Fernanda Carvalho Cavalari, Tadeu Dourado, Alexandre Luz De Castro, Maria Beatriz Kohek, Maria Flavia Marques Ribeiro, Wania Aparecida Partata, Luciana Abreu Da Rosa, Gustavo Monteiro Escott, Luciano Sturmer De FragaAbstract:Abstract Epitestosterone is the 17α-epimer of testosterone and has been described as an anti-Androgen, since it inhibits the effects produced by testosterone and dihydrotestosterone via the Nuclear Androgen receptor (nAR). However, epitestosterone also displays an effect which is similar to the non-classical effect of testosterone, depolarizing the membrane potential of Sertoli cells and inducing a rapid Ca2+ uptake. This study aimed to investigate the effects of a treatment with epitestosterone on developmental parameters of immature rats. Animals were chemically castrated by using the gonadotropin-releasing hormone (GnRH) antagonist cetrorelix and then received a replacement of 7 days with epitestosterone or testosterone. Replacement with either epitestosterone or testosterone restored the anogenital distance (AGD) and testicular weight which had been reduced by chemical castration. The immunocontent of nAR and the nAR-immunoreactivity were reduced by epitestosterone treatment in the testis of both castrated and non-castrated animals. Furthermore, testosterone was unable of changing the membrane potential of Sertoli cells through its non-classical action in the group of animals castrated and replaced with epitestosterone. In conclusion, in relation to the level of protein expression of nAR epitestosterone acts as an anti-Androgen. However, it acts in the same way as testosterone when genital development parameters are evaluated. Moreover, in castrated rats epitestosterone suppressed the non-classical response of testosterone, changing the pattern of testosterone signalling via a membrane mechanism in Sertoli cells.
Yuichi Hashimoto - One of the best experts on this subject based on the ideXlab platform.
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4 anilino pyrrole 2 carboxamides novel non steroidal non anilide type Androgen antagonists effective upon human prostate tumor lncap cells with mutated Nuclear Androgen receptor
Bioorganic & Medicinal Chemistry, 2008Co-Authors: Kenichi Wakabayashi, Keisuke Imai, Hiroyuki Miyachi, Yuichi Hashimoto, Aya TanataniAbstract:Various 4-(anilino)pyrrole-2-carboxamides were designed and synthesized as novel Androgen receptor (AR) antagonists without steroidal or anilide structure, based on our strategy for developing full antagonists of Nuclear receptors. Introduction of a bulky N-alkyl group, such as a cyclohexylmethyl or benzyl group, increased the binding affinity for wild-type AR and the potency for growth inhibition of Androgen-dependent SC-3 cells. Among the compounds obtained, N-[4-[(benzyl)(4-nitrophenyl)amino]-1-methylpyrrole-2-carbonyl]pyrrolidine (22) is as potent an AR antagonist as the typical anilide-type AR antagonists hydroxyflutamide and bicalutamide. Further, compound 22 had potent binding affinity for T877A mutated AR, and dose-dependently inhibited the testosterone-induced production of prostate-specific antigen in LNCaP cells bearing T877A AR.
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ligands with a 3 3 diphenylpentane skeleton for Nuclear vitamin d and Androgen receptors dual activities and metabolic activation
Bioorganic & Medicinal Chemistry, 2006Co-Authors: Shinnosuke Hosoda, Aya Tanatani, Kenichi Wakabayashi, Makoto Makishima, Keisuke Imai, Hiroyuki Miyachi, Kazuo Nagasawa, Yuichi HashimotoAbstract:Abstract Ligands possessing dual vitamin D 3 (VD 3 )-agonistic and Androgen–antagonistic activities with various activity spectra were prepared based on a substituted 3,3-diphenylpentane (DPP) skeleton. Among the compounds, ( R , S )-DPP-1023 [( R , S )- 7b ] and ( S , S )-DPP-0123 [( S , S )- 7c ] showed the most potent vitamin D 3 -agonistic activity [with potency comparable to that of 1α,25-dihydroxyvitamin D 3 (1,25-VD 3 )] and Nuclear Androgen receptor (AR)-binding activity (with higher affinity than that of hydroxyflutamide), respectively. Metabolic activation (reduction of the carbonyl group) of pivaloyl analogs [DPP-1113 ( 3a ), DPP-1013 ( 3b ), DPP-0113 ( 3c ), and DPP-0013 ( 3d )] in HL-60 cells was found to be necessary for binding to Nuclear vitamin D 3 receptor (VDR).
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novel non steroidal non anilide type Androgen antagonists with an isoxazolone moiety
ChemInform, 2002Co-Authors: Toshiyasu Ishioka, Kazuo Nagasawa, Asako Kubo, Yukiko Koiso, Akiko Itai, Yuichi HashimotoAbstract:3-Substituted (Z)-4-(4-N,N-dialkylaminophenylmethylene)-5(4H)-isoxazolones and related compounds were designed and prepared as candidates for structurally novel Androgen antagonists. Several compounds showed potent anti-Androgenic activity as assessed by Nuclear Androgen receptor binding assay and growth inhibition assay using Androgen-dependent Shionogi carcinoma cells SC-3. They were approximately 10--220 times more potent than flutamide in these assay systems. They also showed anti-Androgenic activity toward prostate tumor cell line LNCaP, which has an aberrant Nuclear Androgen receptor.
