Prostate cancer(PCa)accounted for over 300000 deaths world-wide in 2018.Most of the PCa deaths occurred due to the aggressive castration-resistant PCa(CRPC).Since the androgen receptor(AR)and its ligands contribute to...Prostate cancer(PCa)accounted for over 300000 deaths world-wide in 2018.Most of the PCa deaths occurred due to the aggressive castration-resistant PCa(CRPC).Since the androgen receptor(AR)and its ligands contribute to the continued growth of androgendependent PCa(ADPCa)and CRPC,AR has become a well-characterized and pivotal therapeutic-target.Although AR signaling was identified as therapeutic-target in PCa over five-decades ago,there remains several practical issues such as lack of antagonist-bound AR crystal structure,stabilization of the AR in the presence of agonists due to N-terminus and C-terminus interaction,unfavorable large-molecule accommodation of the ligand-binding domain(LBD),and generation of AR splice variants that lack the LBD that impede the discovery of highly potent fail-safe drugs.This review summarizes the AR-signaling pathway targeted therapeutics currently used in PCa and the approaches that could be used in future ARtargeted drug development of potent next-generation molecules.The review also outlines the discovery of molecules that bind to domains other than the LBD and those that inhibit both the full length and splice variant of ARs.展开更多
In order to investigate the neuroendocrine mechanism of the mating behavior in the adult male mandarin voles Microtus mandarinus,the radioimmunoassay(RIA)and immunohistochemistry methods were used to investigate the d...In order to investigate the neuroendocrine mechanism of the mating behavior in the adult male mandarin voles Microtus mandarinus,the radioimmunoassay(RIA)and immunohistochemistry methods were used to investigate the differences in plasma testosterone(T)concentrations and distribution of T immunoreactive neurons(T-IRs),androgen receptor immunoreactive neurons(AR-IRs)and Fos protein immunoreactive neurons(Fos-IRs)in the accessory olfactory bulb(AOB)and the main olfactory bulb(MOB)following exposure to clean hard-wood shavings(control group),soiled bedding(exposure group)or contact with an estrous female(mating group).Results showed that plasma T concentration was significantly higher in the mating group than that in the exposure group,and both the mating group and the exposure group displayed significantly higher plasma T concentration than the control group.T-IRs,AR-IRs and Fos-IRs were investigated with the immunohistochemistry method in granule cell(GC)and mitral cell(MC)of the MOB and the AOB in the three groups.There were significantly more T-IRs,AR-IRs and Fos-IRs in MC and GC of the AOB in the mating group than that in the exposure group or the control group.T-IRs,AR-IRs and Fos-IRs did not show significant differences between the exposure group and the control group.Furthermore,obvious differences in MC and GC of the MOB were not found among the three groups.The results confirm that both changes of T and AR in the AOB might be underlying mating behavior in the adult male mandarin voles.展开更多
Population studies have suggested an association between diabetes and the symptoms of testosterone deficiency. Recently, the expression of the androgen receptor （AR） has been shown to be decreased in diabetic patien...Population studies have suggested an association between diabetes and the symptoms of testosterone deficiency. Recently, the expression of the androgen receptor （AR） has been shown to be decreased in diabetic patients. Furthermore, diabetes has been shown to induce global methylation. In this study, we used an animal model to investigate whether diabetes results in increased methylation of the AR promoter and whether these changes are associated with the decreased expression of AR in penile cavernosal smooth muscle tissue. Twenty C57BL/6J mice were divided into two groups, receiving either high- （mature diabetic） or low- （mature control） caloric meals for 14 weeks. Another 10 mice were killed at 1 week （young control）. Animals in the mature diabetic group showed decreased testosterone levels, although this was not statistically significant. In both control groups, no significant methylation was observed in the AR promoter region CpG island （-85 to ＋339）. In the mature diabetic group, significant methylation was observed at ＋ 185 and ＋200 of the AR promoter. These changes were associated with increased homeostatic model assessment for insulin resistance （HOMA-IR） and decreased corpus cavernosal tissue mass and expression of AR mRNA and protein. We conclude that in these animals, insulin resistance increased the methylation of the GC-rich regions of the AR promoter, leading to decreased AR expression.展开更多
基金supported by a grant from National Cancer Institute(NCI)1R01CA229164-01A1.
文摘Prostate cancer(PCa)accounted for over 300000 deaths world-wide in 2018.Most of the PCa deaths occurred due to the aggressive castration-resistant PCa(CRPC).Since the androgen receptor(AR)and its ligands contribute to the continued growth of androgendependent PCa(ADPCa)and CRPC,AR has become a well-characterized and pivotal therapeutic-target.Although AR signaling was identified as therapeutic-target in PCa over five-decades ago,there remains several practical issues such as lack of antagonist-bound AR crystal structure,stabilization of the AR in the presence of agonists due to N-terminus and C-terminus interaction,unfavorable large-molecule accommodation of the ligand-binding domain(LBD),and generation of AR splice variants that lack the LBD that impede the discovery of highly potent fail-safe drugs.This review summarizes the AR-signaling pathway targeted therapeutics currently used in PCa and the approaches that could be used in future ARtargeted drug development of potent next-generation molecules.The review also outlines the discovery of molecules that bind to domains other than the LBD and those that inhibit both the full length and splice variant of ARs.
基金funded by theNatural Science Foundation of China(30670273)Natural Science Foundation of ShaanXi(2008C269)+1 种基金Science and Technology Plan Project of Xi'an Burea of Science and Technology(YF07194)Special Science Research Fund for Xi'an University of Arts and Science(KY200520)
文摘In order to investigate the neuroendocrine mechanism of the mating behavior in the adult male mandarin voles Microtus mandarinus,the radioimmunoassay(RIA)and immunohistochemistry methods were used to investigate the differences in plasma testosterone(T)concentrations and distribution of T immunoreactive neurons(T-IRs),androgen receptor immunoreactive neurons(AR-IRs)and Fos protein immunoreactive neurons(Fos-IRs)in the accessory olfactory bulb(AOB)and the main olfactory bulb(MOB)following exposure to clean hard-wood shavings(control group),soiled bedding(exposure group)or contact with an estrous female(mating group).Results showed that plasma T concentration was significantly higher in the mating group than that in the exposure group,and both the mating group and the exposure group displayed significantly higher plasma T concentration than the control group.T-IRs,AR-IRs and Fos-IRs were investigated with the immunohistochemistry method in granule cell(GC)and mitral cell(MC)of the MOB and the AOB in the three groups.There were significantly more T-IRs,AR-IRs and Fos-IRs in MC and GC of the AOB in the mating group than that in the exposure group or the control group.T-IRs,AR-IRs and Fos-IRs did not show significant differences between the exposure group and the control group.Furthermore,obvious differences in MC and GC of the MOB were not found among the three groups.The results confirm that both changes of T and AR in the AOB might be underlying mating behavior in the adult male mandarin voles.
文摘Population studies have suggested an association between diabetes and the symptoms of testosterone deficiency. Recently, the expression of the androgen receptor （AR） has been shown to be decreased in diabetic patients. Furthermore, diabetes has been shown to induce global methylation. In this study, we used an animal model to investigate whether diabetes results in increased methylation of the AR promoter and whether these changes are associated with the decreased expression of AR in penile cavernosal smooth muscle tissue. Twenty C57BL/6J mice were divided into two groups, receiving either high- （mature diabetic） or low- （mature control） caloric meals for 14 weeks. Another 10 mice were killed at 1 week （young control）. Animals in the mature diabetic group showed decreased testosterone levels, although this was not statistically significant. In both control groups, no significant methylation was observed in the AR promoter region CpG island （-85 to ＋339）. In the mature diabetic group, significant methylation was observed at ＋ 185 and ＋200 of the AR promoter. These changes were associated with increased homeostatic model assessment for insulin resistance （HOMA-IR） and decreased corpus cavernosal tissue mass and expression of AR mRNA and protein. We conclude that in these animals, insulin resistance increased the methylation of the GC-rich regions of the AR promoter, leading to decreased AR expression.
