Reduced mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor contributes to neurodegeneration in a model of spinal and bulbar muscular atrophy pathology

Spinal and bulbar muscular atrophy is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor gene,which encodes a ligand-dependent transcription facto r.The mutant androgen receptor protein,characterized by polyglutamine expansion,is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in spinal and bulbar muscular atrophy patients.These aggregates alter protein-protein interactions and compromise transcriptional activity.In this study,we reported that in both cultured N2a cells and mouse brain,mutant androgen receptor with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-de rived neurotrophic factor.Overexpressio n of mesencephalic astrocyte-derived neurotrophic factor amelio rated the neurotoxicity of mutant androgen receptor through the inhibition of mutant androgen receptor aggregation.Conversely.knocking down endogenous mesencephalic astrocyte-derived neurotrophic factor in the mouse brain exacerbated neuronal damage and mutant androgen receptor aggregation.Our findings suggest that inhibition of mesencephalic astrocyte-derived neurotrophic factor expression by mutant androgen receptor is a potential mechanism underlying neurodegeneration in spinal and bulbar muscular atrophy.

Androgen Receptor Promotes Lung Cancer Metastasis by Modifying the miR23a-3p/EPHB2 Pathway

Objective This study aimed to investigate the reasons behind the lower survival rates in male lung cancer patients than in female lung cancer patients.Methods Through various techniques,such as Argonaute immunoprecipitation,luciferase assays,and ChIP,this study confirmed the positive effects of androgen receptor(AR)on lung cancer cell invasion across different in vitro cell lines and in vivo mouse models.Results The findings suggest that AR enhanced the invasion of lung cancer cells by modifying EPHB2 signals at the protein expression level,which in turn required changes in miRNA-23a-3p.Restoring miRNA-23a-3p could counteract the intensified invasion of lung cancer cells mediated by AR.Conclusion This study revealed that AR may facilitate the lung cancer matastasis by modulating miRNA-23a-3p/EPHB2 signaling and that targeting this signaling pathway could provide new approaches to inhibit lung cancer metastasis.

Olfactory receptors in neural regeneration in the central nervous system

Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring.The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous system.Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent deficits.Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's disease.Olfa ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian body.This ectopic expression provides insights into the chemical structures that can activate olfactory receptors.In addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota.The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation mechanisms.This review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative processes.Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries.

P2Y1 receptor in Alzheimer’s disease

Alzheimer’s disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau.Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer’s disease treatments in the last decades.However,existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic,necessitating the exploration of alternative therapeutic strategies.Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer’s disease patients,with dysregulated astrocytic purinergic receptors,particularly the P2Y1 receptor,all of which constitute the pathophysiology of Alzheimer’s disease.These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer’s disease.This review delves into recent insights into the association between P2Y1 receptor and Alzheimer’s disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer’s disease by mitigating neuroinflammation,thus offering promising avenues for developing drugs for Alzheimer’s disease and potentially contributing to the development of more effective treatments.

C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 pathway as a therapeutic target and regulatory mechanism for spinal cord injury

Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.

Hypidone hydrochloride(YL-0919)ameliorates functional deficits after traumatic brain injury in mice by activating the sigma-1 receptor for antioxidation

Traumatic brain injury involves complex pathophysiological mechanisms,among which oxidative stress significantly contributes to the occurrence of secondary injury.In this study,we evaluated hypidone hydrochloride(YL-0919),a self-developed antidepressant with selective sigma-1 receptor agonist properties,and its associated mechanisms and targets in traumatic brain injury.Behavioral experiments to assess functional deficits were followed by assessment of neuronal damage through histological analyses and examination of blood-brain barrier permeability and brain edema.Next,we investigated the antioxidative effects of YL-0919 by assessing the levels of traditional markers of oxidative stress in vivo in mice and in vitro in HT22 cells.Finally,the targeted action of YL-0919 was verified by employing a sigma-1 receptor antagonist(BD-1047).Our findings demonstrated that YL-0919 markedly improved deficits in motor function and spatial cognition on day 3 post traumatic brain injury,while also decreasing neuronal mortality and reversing blood-brain barrier disruption and brain edema.Furthermore,YL-0919 effectively combated oxidative stress both in vivo and in vitro.The protective effects of YL-0919 were partially inhibited by BD-1047.These results indicated that YL-0919 relieved impairments in motor and spatial cognition by restraining oxidative stress,a neuroprotective effect that was partially reversed by the sigma-1 receptor antagonist BD-1047.YL-0919 may have potential as a new treatment for traumatic brain injury.

Glucocorticoid receptor signaling in the brain and its involvement in cognitive function

The hypothalamic-pituitary-adrenal axis regulates the secretion of glucoco rticoids in response to environmental challenges.In the brain,a nuclear receptor transcription fa ctor,the glucocorticoid recepto r,is an important component of the hypothalamicpituitary-a d renal axis's negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity.The glucoco rticoid receptor influences cognitive processes,including glutamate neurotransmission,calcium signaling,and the activation of brain-derived neurotrophic factor-mediated pathways,through a combination of genomic and non-genomic mechanisms.Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor,there by affecting the hypothalamic-pituitary-a d renal axis and stress-related cognitive functions.An appropriate level of glucocorticoid receptor expression can improve cognitive function,while excessive glucocorticoid receptors or long-term exposure to glucoco rticoids may lead to cognitive impairment.Patients with cognitive impairment-associated diseases,such as Alzheimer's disease,aging,depression,Parkinson's disease,Huntington's disease,stroke,and addiction,often present with dysregulation of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor expression.This review provides a comprehensive overview of the functions of the glucoco rticoid receptor in the hypothalamic-pituitary-a d renal axis and cognitive activities.It emphasizes that appropriate glucocorticoid receptor signaling fa cilitates learning and memory,while its dysregulation can lead to cognitive impairment.This provides clues about how glucocorticoid receptor signaling can be targeted to ove rcome cognitive disability-related disorders.

Overexpression of low-density lipoprotein receptor prevents neurotoxic polarization of astrocytes via inhibiting NLRP3 inflammasome activation in experimental ischemic stroke

Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.

Pan-TRK positive uterine sarcoma in immunohistochemistry without neurotrophic tyrosine receptor kinase gene fusions:A case report

BACKGROUND The classification of uterine sarcomas is based on distinctive morphological and immunophenotypic characteristics,increasingly supported by molecular genetic diagnostics.Data on neurotrophic tyrosine receptor kinase(NTRK)gene fusionpositive uterine sarcoma,potentially aggressive and morphologically similar to fibrosarcoma,are limited due to its recent recognition.Pan-TRK immunohistochemistry(IHC)analysis serves as an effective screening tool with high sensitivity and specificity for NTRK-fusion malignancies.CASE SUMMARY We report a case of a malignant mesenchymal tumor originating from the uterine cervix,which was pan-TRK IHC-positive but lacked NTRK gene fusions,accompanied by a brief literature review.A 55-year-old woman presented to the emergency department with abdominal pain and distension,exhibiting significant ascites and multiple solid pelvic masses.Pelvic examination revealed a tumor encompassing the uterine cervix,extending to the vagina and uterine corpus.A punch biopsy of the cervix indicated NTRK sarcoma with positive immunochemical pan-TRK stain.However,subsequent next generation sequencing revealed no NTRK gene fusion,leading to a diagnosis of poorly differentiated,advanced-stage sarcoma.CONCLUSION The clinical significance of NTRK gene fusion lies in potential treatment with TRK inhibitors for positive sarcomas.Identifying such rare tumors is crucial due to the potential applicability of tropomyosin receptor kinase inhibitor treatment.

Cortico-striatal gamma oscillations are modulated by dopamine D3 receptors in dyskinetic rats

Long-term levodopa administration can lead to the development of levodopa-induced dyskinesia.Gamma oscillations are a widely recognized hallmark of abnormal neural electrical activity in levodopa-induced dyskinesia.Currently,studies have reported increased oscillation power in cases of levodopa-induced dyskinesia.However,little is known about how the other electrophysiological parameters of gamma oscillations are altered in levodopa-induced dyskinesia.Furthermore,the role of the dopamine D3 receptor,which is implicated in levodopa-induced dyskinesia,in movement disorder-related changes in neural oscillations is unclear.We found that the cortico-striatal functional connectivity of beta oscillations was enhanced in a model of Parkinson’s disease.Furthermore,levodopa application enhanced cortical gamma oscillations in cortico-striatal projections and cortical gamma aperiodic components,as well as bidirectional primary motor cortex(M1)↔dorsolateral striatum gamma flow.Administration of PD128907(a selective dopamine D3 receptor agonist)induced dyskinesia and excessive gamma oscillations with a bidirectional M1↔dorsolateral striatum flow.However,administration of PG01037(a selective dopamine D3 receptor antagonist)attenuated dyskinesia,suppressed gamma oscillations and cortical gamma aperiodic components,and decreased gamma causality in the M1→dorsolateral striatum direction.These findings suggest that the dopamine D3 receptor plays a role in dyskinesia-related oscillatory activity,and that it has potential as a therapeutic target for levodopa-induced dyskinesia.

Phenotypic heterogeneity of mutations in androgen receptor gene

Androgen receptor （AR） gene has been extensively studied in diverse clinical conditions. In addition to the point mutations, trinucleotide repeat （CAG and GGN） length polymorphisms have been an additional subject of interest and controversy among geneticists. The polymorphic variations in triplet repeats have been associated with a number of disorders, but at the same time contradictory findings have also been reported. Further, studies on the same disorder in different populations have generated different results. Therefore, combined analysis or review of the published studies has been of much value to extract information on the significance of variations in the gene in various clinical conditions. AR genetics has been reviewed extensively but until now review articles have focused on individual clinical categories such as androgen insensitivity, male infertility, prostate cancer, and so on. We have made the first effort to review most the aspects of AR genetics. The impact of androgens in various disorders and polymorphic variations in the AR gene is the main focus of this review. Additionally, the correlations observed in various studies have been discussed in the light of in vitro evidences available for the effect of AR gene variations on the action of androgens.

Androgen receptor signaling and mutations in prostate cancer

Normal and neoplastic growth of the prostate gland are dependent on androgen receptor （AR） expression and function. Androgenic activation of the AR, in association with its coregulatory factors, is the classical pathway that leads to transcriptional activity of AR target genes. Alternatively, cytoplasmic signaling crosstalk of AR by growth factors, neurotrophic peptides, cytokines or nonandrogenic hormones may have important roles in prostate carcinogenesis and in metastatic or androgen-independent （AI） progression of the disease. In addition, cross-modulation by various nuclear transcription factors acting through basal transcriptional machinery could positively or negatively affect the AR or AR target genes expression and activity. Androgen ablation leads to an initial favorable response in a significant number of patients; however, almost invariably patients relapse with an aggressive form of the disease known as castration-resistant or hormone-refractory prostate cancer （PCa）. Understanding critical molecular events that lead PCa cells to resist androgen-deprivation therapy is essential in developing successful treatments for hormone-refractory disease. In a significant number of hormone-refractory patients, the AR is overexpressed, mutated or genomically amplified. These genetic alterations maintain an active presence for a highly sensitive AR, which is responsive to androgens, antiandrogens or nonandrogenic hormones and collectively confer a selective growth advantage to PCa cells. This review provides a brief synopsis of the AR structure, AR coregulators, posttranslational modifications of AR, duality of AR function in prostate epithelial and stromal cells, AR-dependent signaling, genetic changes in the form of somatic and germline mutations and their known functional significance in PCa cells and tissues.

nfluence of immune inflammation on androgen receptor expression in benign prostatic hyperplasia tissue

This study was designed to investigate the association between immune inflammation and androgen receptor （AR） expression in benign prostatic hyperplasia （BPH）. We retrospectively analyzed 105 prostatectomy specimens. An immune inflammation score for each specimen was defined by combining three immunohistochemical markers （CD4, CD8 and CD20）. The immunohistochemical markers were CD4 and CD8 for T lymphocytes, CD20 for B lymphocytes and AR antibody for the AR in BPH samples. Rates of CD4, CD8, CD20 and AR expression in BPH were 20 （19.0%）, 21 （20.0%）, 101 （96.2%） and 48 （45.7%）, respectively. Total prostate volume （TPV） was higher in the immune inflammation group than in the non-immune inflammation group （62.7 ml vs. 49.2 ml, t=-2.482, P〈0.05）. Patients in the immune inflammation group had a higher serum prostate-specific antigen （PSA） than those in the non-inflammation group （7.5 ng m1-1 vs. 5.4 ng m1-1, t=-2.771, P〈0.05）. Specifically, the immune inflammation group showed a higher rate of AR expression than the non-inflammation group （56.1% vs. 28.2%, χ2=7.665, P〈0.05）. Our study revealed a strong association between immune inflammation and TPV, serum PSA and AR expression in BPH tissue. Prostate hyperplasia caused by an immune inflammatory process may contribute to BPH progression over time. Therefore, the inflammatory response involved in BPH may be a prime therapeutic target.

The role of the androgen receptor in prostate development and benign prostatic hyperplasia:A review

Benign prostatic hyperplasia(BPH)is a benign enlargement of the prostate in which incidence increases linearly with age,beginning at about 50 years old.BPH is a significant source of morbidity in aging men by causing lower urinary tract symptoms and acute urinary retention.Unfortunately,the etiology of BPH incidence and progression is not clear.This review highlights the role of the androgen receptor(AR)in prostate development and the evidence for its involvement in BPH.The AR is essential for normal prostate development,and individuals with defective AR signaling,such as after castration,do not experience prostate enlargement with age.Furthermore,decreasing dihydrotestosterone availability through therapeutic targeting with 5a-reductase inhibitors diminishes AR activity and results in reduced prostate size and symptoms in some BPH patients.While there is some evidence that AR expression is elevated in certain cellular compartments,how exactly AR is involved in BPH progression has yet to be elucidated.It is possible that AR signaling within stromal cells alters intercellular signaling and a“reawakening”of the embryonic mesenchyme,loss of epithelial AR leads to changes in paracrine signaling interactions,and/or chronic inflammation aids in stromal or epithelial proliferation evident in BPH.Unfortunately,a subset of patients fails to respond to current medical approaches,forcing surgical treatment even though age or associated co-morbidities make surgery less attractive.Fundamentally,new therapeutic approaches to treat BPH are not currently forthcoming,so a more complete molecular understanding of BPH etiology is necessary to identify new treatment options.

dentification of testosterone-/androgen receptor-regulated genes in mouse Sertoli cells

Androgen and androgen receptor （AR） play important roles in male spermatogenesis and fertility, yet detailed androgen/AR signals in Sertoli cells remain unclear. To identify AR target genes in Sertoli cells, we analyzed the gene expression profiles of testis between mice lacking AR in Sertoli cells （S-AR-/y） and their littermate wild-type （WT） mice. Digital gene expression analysis identified 2276 genes downregulated and 2865 genes upregulated in the S-AR-/y mice testis compared to WT ones. To further nail down the difference within Sertoli cells, we first constructed Sertoli cell line TM4 with stably transfected AR （named as TM4/AR） and found androgens failed to transactivate AR in Sertoli TM4 and TM4/AR cells. Interestingly, additional transient transfection of AR-cDNA resulted in significant androgen responsiveness with TM4/AR cells showing 10 times more androgen sensitivity than TM4 cells. In the condition where maximal androgen response was demonstrated, we then analyzed gene expression and found the expression levels of 2313 genes were changed more than twofold by transient transfection of AR-cDNA in the presence of testosterone. Among these genes, 603 androgen-/ AR-regulated genes, including 164 upregulated and 439 downregulated, were found in both S-AR-/y mice testis and TM4/AR cells. Using informatics analysis, the gene ontology was applied to analyze these androgen-/AR-regulated genes to predict the potential roles of androgen/AR in the process of spermatogenesis. Together, using gene analysis in both S-AR-/y mice testis and TM4/AR cells may help us to better understand the androeen/AR signals in Sertoli cells and their influences in spermatogenesis.

Androgen receptor signaling in hepatocellular carcinoma and pancreatic cancers

Hepatocellular carcinoma (HCC) and pancreatic cancer remain difficult to treat, and despite the ongoing development of new treatments, the overall survival rate has only modestly improved over the past decade. Liver and pancreatic progenitors commonly develop from endoderm cells in the embryonic foregut. A previous study showed that HCC and pancreatic cancer cell lines variably express androgen receptor (AR), and these cancers and the surrounding tissues also express AR. AR is a ligand-dependent transcription factor that belongs to the nuclear receptor superfamily. Androgen response element is present in regulatory elements on the AR-responsive target genes, such as transforming growth factor beta-1 (TGF beta-1) and vascular endothelial growth factor (VEGF). It is well known that the activation of AR is associated with human carcinogenesis in prostate cancer as well as HCC and pancreatic cancer and that GRP78, TGF beta, and VEGF all play important roles in carcinogenesis and cancer development in these cancers. HCC is a male-dominant cancer irrespective of its etiology. Previous work has reported that vertebrae forkhead box A 1/2 are involved in estrogen receptors and/or AR signaling pathways, which may contribute to the gender differences observed with HCC. Our recent work also showed that AR has a critical role in pancreatic cancer development, despite pancreatic cancer not being a male dominant cancer. Aryl hydrocarbon (or dioxin) receptor is also involved in both HCC and pancreatic cancer through the formation of complex with AR. It is possible that AR might be involved in their carcinogenesis through major histocompatibility complex class I chain-related gene A/B. This review article describes AR and its role in HCC and pancreatic cancer and suggests that more specific AR signaling-inhibitors may be useful in the treatment of these “difficult to treat” cancers.

Human androgen deficiency： insights gained from androgen receptor knockout mouse models

The mechanism of androgen action is complex. Recently, significant advances have been made into our understanding of how androgens act via the androgen receptor （AR） through the use of genetically modified mouse models. A number of global and tissue-specific AR knockout （ARKO） models have been generated using the Cre-loxP system which allows tissue- and/or cell-specific deletion. These ARKO models have examined a number of sites of androgen action including the cardiovascular system, the immune and hemopoetic system, bone, muscle, adipose tissue, the prostate and the brain. This review focuses on the insights that have been gained into human androgen deficiency through the use of ARKO mouse models at each of these sites of action, and highlights the strengths and limitations of these Cre-loxP mouse models that should be considered to ensure accurate interpretation of the phenotype.

Chimeric molecules facilitate the degradation of androgen receptors and repress the growth of LNCaP cells

Post-translational degradation of protein plays an important role in cell life. We employed chimeric molecules （dihydrotestosterone-based proteolysis-targeting chimeric molecule [DHT-PROTAC]） to facilitate androgen receptor （AR） degradation via the ubiquitin-proteasome pathway （UPP） and to investigate the role of AR in cell proliferation and viability in androgen-sensitive prostate cancer cells. Western blot analysis and immunohistochemistry were applied to analyse AR levels in LNCaP cells after DHT-PROTAC treatment. Cell counting and the 3-（4,5-dimethylthiazol-2-yl）-2,5- diphenyl tetrazolium bromide （MTT） cell viability assay were used to evaluate cell proliferation and viability after AR elimination in both LNCaP and PC-3 cells. AR was tagged for elimination via the UPP by DHT-PROTAC, and this could be blocked by proteasome inhibitors. Degradation of AR depended on DHT-PROTAC concentration, and either DHT or an ALAPYIP-（arg）8 peptide could compete with DHT-PROTAC. Inhibition of cell proliferation and decreased viability were observed in LNCaP cells, but not in PC-3 or 786-0 cells after DHT-PROTAC treatment. These data indicate that AR elimination is facilitated via the UPP by DHT-PROTAC, and that the growth of LNCaP cells is repressed after AR degradation.

Androgen receptor isoforms in human and rat prostate

Aim: To investigate the androgen receptor (AR) isoforms and its variability of expression in human and rat prostatictissues. Methods: Human benign prostatic hyperplasia (BPH) and prostatic cancer tissues were obtained from pa-tients undergoing prostatectomy, and rat ventral prostate was incised 3 days after castration. Forty-one AR-positive BPHspecimens, 3 prostatic cancer specimens, and 6 rat prostates were used. After processing at 4℃, the tissues were ex-amined by means of high resolution isoelectric focusing (IEF) technique to determine their AR isoforms. Results:From the prostatic specimens, 3 types of AR isoforms were detected with pI values at 6.5, 6.0, and 5.3. In humanBPH tissues, 15/41 (36.6%) specimens showed all the three types of isoforms, while 19/41 (46.3%) showed 2 iso-fora at various combinations and 7/41 (17.1%), 1 isoform. For the 3 prostatic cancer specimens, one showed 3 iso-forms, one, 2 isoforms, and the other failed to show any isoform. All rat prostatic tissues showed 2 isoforms at differ-ent combinations. Binding of ~3H-dihydrotestosterone (DHT) to the isoforms was inhibited by the addition of 100-foldexcess of DHT or testosterone, but not progesterone, oestradiol or diethylstilboestrol. Conclusion: AR isoforms aredifferent in different patients. Although their genesis is not clear, the therapeutic implication of the present observationappears to be interesting, that may help clarifying the individual differences in the response to hormonal therapy.(Asian J Androl 2000 Dec; 2: 307-310)

Androgen receptor isoforms in human prostatic cancer tissue and LNCaP cell line

Aim: To investigate the androgen receptor (AR) isoform expressions in human prostatic cancer tissue and LNCaPcell line. Methods: With high resolution isoelectric focusing (IEF) method we demonstrated the different expres-sions of AR isoforms in human prostatic cancer tissues and LNCaP cell line. Results; Data were obtained from threeprostatic cancer specimens and the LNCaP cell line. Three types of AR isoforms were detected with pI values at 6.5,6.0, and 5.3. For the 3 prostatic cancer specimens, 1 sample showed all the three types of AR isoforms, the secondspecimen expressed at 6.5 and 6.0, and the third failed to show any type of isoforms. The LNCaP cell line expressedall the three AR isoforms. Binding of ~3H-dihydrotestosterone (~3H-DHT) to these three isoforms was inhibited by the ad-dition of 100-fold excess of DHT or testosterone, while not by progesterone, oestradiol and diethylstilboestrol. Conclu-sion : The expression of AR isoforms is different in different prostate cancer tissues, which may be related to the dif-ference in the effect of anti-androgen therapy in different patients. (Asian J Androl 2001 Sep; 3: 223 - 225)