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  1. Tan JSJ, Ong KC, Ong DBL, Wu YS, Razack A, Kuppusamy S, et al.
    Malays J Pathol, 2019 Dec;41(3):243-251.
    PMID: 31901908
    INTRODUCTION: Polymorphic expression of a CAG repeat sequence in the androgen receptor (AR) gene may influence the activity of the AR and the occurrence of prostate cancer and the TMPRSS2-ERG fusion event. Furthermore, this polymorphism may be responsible for the ethnic variation observed in prostate cancer occurrence and expression of the ERG oncogene. We investigate the expression of AR and ERG in the biopsies of Malaysian men with prostate cancer and in the same patients relate this to the length of the CAG repeat sequence in their AR gene.

    MATERIALS AND METHODS: From a PSA screening initiative, 161 men were shown to have elevated PSA levels in their blood and underwent prostatic tissue biopsy. DNA was extracted from the blood, and exon 1 of the AR gene amplified by PCR and sequenced. The number of CAG repeat sequences were counted and compared to the immunohistochemical expression of ERG and AR in the matched tumour biopsies.

    RESULTS: Of men with elevated PSA, 89 were diagnosed with prostate cancer, and 72 with benign prostatic hyperplasia (BPH). There was no significant difference in the length of the CAG repeat in men with prostate cancer and BPH. The CAG repeat length was not associated with; age, PSA or tumour grade, though a longer CAG repeat was associated with tumour stage. ERG and AR were expressed in 36% and 86% of the cancers, respectively. There was no significant association between CAG repeat length and ERG or AR expression. However, there was a significant inverse relationship between ERG and AR expression. In addition, a significantly great proportion of Indian men had ERG positive tumours, compared to men of Malay or Chinese descent.

    CONCLUSIONS: CAG repeat length is not associated with prostate cancer or expression of ERG or AR. However, ERG appears to be more common in the prostate cancers of Malaysian Indian men than in the prostate cancers of other Malaysian ethnicities and its expression in this study was inversely related to AR expression.

    Matched MeSH terms: Receptors, Androgen/genetics*
  2. Thevendran R, Tang TH, Citartan M
    Biotechnol J, 2023 Apr;18(4):e2200092.
    PMID: 36735817 DOI: 10.1002/biot.202200092
    Aptamers are a class of single-stranded (ss) nucleic acid molecules generated through Systematic Evolution of Ligands by Exponential Enrichment (SELEX) that involves iterations of time-consuming and tedious selection, amplification, and enrichment steps. To compensate for the drawbacks of conventional SELEX, we have devised an in-silico methodology that facilitates a cost-effective and facile manner of aptamer selection. Here, we report the isolation of DNA aptamers against androgen receptors (ARs) using androgen response elements (ARE) that possess natural affinity toward AR. A virtual library of ARE sequences was prepared and subjected to a stringent selection criterion to generate a sequence pool having stable hairpin conformations and high GC content. The 3D-structures of the selected ss AREs were modeled and screened through rigid docking and molecular dynamic (MD) simulation to examine their potency as potential AR binders. The predicted sequences were further validated using direct enzyme-linked aptasorbent assay (ELASA), which includes the measurement of their binding affinity, specificity, and target discrimination properties under complex biological enviroments. A short, 15 nucleotides (nts), ssDNA aptamer, termed ARapt1 with the estimated Kd value of 5.5 ± 3 nm, was chosen as the most prominent aptamer against AR based on the coherence of both the in-silico and in-vitro evaluation results. The high target-binding affinity and selectivity of ARapt1 signify its potential use as a versatile tool in diagnostic applications relevant to prostate cancer and related diseases.
    Matched MeSH terms: Receptors, Androgen/genetics
  3. Azmahani A, Nakamura Y, Felizola SJ, Ozawa Y, Ise K, Inoue T, et al.
    J Steroid Biochem Mol Biol, 2014 Oct;144 Pt B:268-79.
    PMID: 25090634 DOI: 10.1016/j.jsbmb.2014.07.010
    The sebaceous gland is a major site of steroid synthesis in human skin, but details of the status of steroidogenic enzymes and their regulation in human sebaceous glands under normal and pathological conditions have rarely been reported. Therefore, in this study, we examined the status of steroidogenic enzymes, sex steroid receptors and transcription factors in human sebaceous glands under normal and pathological conditions to explore their possible roles in in situ steroid production in human skin. Immunohistochemical analysis was performed in a total of 59 human skin specimens, including 22 normal human sebaceous glands, 12 with sebaceous nevus, 12 with sebaceous gland hyperplasia, 3 with sebaceoma and 10 with sebaceous carcinoma. Immortalised human SZ95 sebocytes were treated with forskolin or vehicle for 3h, 6h, 12h or 24h, and the mRNA levels of steroidogenic enzymes were evaluated at each time point using quantitative RT-PCR (qPCR). The results of immunohistochemistry demonstrated the immunoreactivity of 3β-HSD1, CYP11A1, StAR, 17β-HSD5, CYP17A1, 5α-red1, PRB, AR and NGFI-B in normal human sebaceous gland, with lower levels of expression in pathological sebaceous glands. The results of the in vitro study also indicated that the expression levels of 3β-HSD1, CYP11A1, StAR, 5α-red1 and NGFI-B were elevated by forskolin. 3β-HSD1 and other steroidogenic enzymes were expressed in sebaceous glands resulting in in situ androgen and progesterone synthesis and their functions.
    Matched MeSH terms: Receptors, Androgen/genetics
  4. Albujja MH, Messaudi SA, Vasudevan R, Al Ghamdi S, Chong PP, Ghani KA, et al.
    Asian Pac J Cancer Prev, 2020 08 01;21(8):2271-2280.
    PMID: 32856855 DOI: 10.31557/APJCP.2020.21.8.2271
    BACKGROUND: The X-chromosome has been suggested to play a role in prostate cancer (PrCa) since epidemiological studies have provided evidence for an X-linked mode of inheritance for PrCa based on the higher relative risk among men who report an affected brother(s) as compared to those reporting an affected father. The aim of this study was to examine the potential association between the forensic STR markers located at four regions Xp22.31, Xq11.2-12, Xq26.2, and Xq28 and the risk of BPH and PrCa to confirm the impact of ChrX in the PrCa incidence. This may be helpful in the incorporation of STRs genetic variation in the early detection of men population at risk of developing PrCa.

    METHODS: DNA samples from 92 patients and 156 healthy controls collected from two medical centers in Riyadh, Saudi Arabia were analyzed for four regions located at X-chromosome using the Investigator® Argus X-12 QS Kit.

    RESULTS: The results demonstrated that microvariant alleles of (DXS7132, DXS10146, HPRTB, DXS10134, and DXS10135) are overrepresented in the BPH group (p < 0.00001). Allele 28 of DXS10135 and allele 15 of DXS7423 could have a protective effect, OR 0.229 (95%CI, 0.066-0.79); and OR 0.439 (95%CI, 0.208-0.925). On the other hand, patients carrying allele 23 of DXS10079 and allele 26 of DXS10148 presented an increased risk to PrCa OR 4.714 (95%CI, 3.604-6.166).

    CONCLUSION: The results are in concordance with the involvement of the X chromosome in PrCa and BPH development. STR allele studies may add further information from the definition of a genetic profile of PrCa resistance or susceptibility. As TBL1, AR, LDOC1, and RPL10 genes are located at regions Xp22.31, Xq11.2-12, Xq26.2, and Xq28, respectively, these genes could play an essential role in PrCa or BPH.

    Matched MeSH terms: Receptors, Androgen/genetics*
  5. Sabetian S, Shamsir MS
    Int J Mol Sci, 2016 Nov 10;17(11).
    PMID: 27834916
    Non-obstructive azoospermia is a severe infertility factor. Currently, the etiology of this condition remains elusive with several possible molecular pathway disruptions identified in the post-meiotic spermatozoa. In the presented study, in order to identify all possible candidate genes associated with azoospermia and to map their relationship, we present the first protein-protein interaction network related to azoospermia and analyze the complex effects of the related genes systematically. Using Online Mendelian Inheritance in Man, the Human Protein Reference Database and Cytoscape, we created a novel network consisting of 209 protein nodes and 737 interactions. Mathematical analysis identified three proteins, ar, dazap2, and esr1, as hub nodes and a bottleneck protein within the network. We also identified new candidate genes, CREBBP and BCAR1, which may play a role in azoospermia. The gene ontology analysis suggests a genetic link between azoospermia and liver disease. The KEGG analysis also showed 45 statistically important pathways with 31 proteins associated with colorectal, pancreatic, chronic myeloid leukemia and prostate cancer. Two new genes and associated diseases are promising for further experimental validation.
    Matched MeSH terms: Receptors, Androgen/genetics
  6. Nna VU, Bakar ABA, Ahmad A, Mohamed M
    Andrology, 2019 01;7(1):110-123.
    PMID: 30515996 DOI: 10.1111/andr.12567
    BACKGROUND: Metformin has long been used for glycemic control in diabetic state. Recently, other benefits of metformin beyond blood glucose regulation have emerged.

    OBJECTIVES: To investigate the effect of metformin on the expression of testicular steroidogenesis-related genes, spermatogenesis, and fertility of male diabetic rats.

    MATERIALS AND METHODS: Eighteen adult male Sprague Dawley rats were divided into three groups, namely normal control (NC), diabetic control (DC), and metformin-treated (300 mg/kg body weight/day) diabetic rats (D+Met). Diabetes was induced using a single intraperitoneal injection of streptozotocin (60 mg/kg b.w.), followed by oral treatment with metformin for four weeks.

    RESULTS: Diabetes decreased serum and intratesticular testosterone levels and increased serum but not intratesticular levels of luteinizing hormone. Sperm count, motility, viability, and normal morphology were decreased, while sperm nuclear DNA fragmentation was increased in DC group, relative to NC group. Testicular mRNA levels of androgen receptor, luteinizing hormone receptor, cytochrome P450 enzyme (CYP11A1), steroidogenic acute regulatory (StAR) protein, 3β-hydroxysteroid dehydrogenase (HSD), and 17β-HSD, as well as the level of StAR protein and activities of CYP11A1, 3β-HSD, and 17β-HSD, were decreased in DC group. Similarly, decreased activities of epididymal antioxidant enzymes and increased lipid peroxidation were observed in DC group. Consequently, decreased litter size, fetal weight, mating and fertility indices, and increased pre- and post-implantation losses were recorded in DC group. Following intervention with metformin, we observed increases in serum and intratesticular testosterone levels, Leydig cell count, improved sperm parameters, and decreased sperm nuclear DNA fragmentation. Furthermore, mRNA levels and activities of steroidogenesis-related enzymes were increased, with improved fertility outcome.

    DISCUSSION AND CONCLUSION: Diabetes mellitus is associated with dysregulation of steroidogenesis, abnormal spermatogenesis, and fertility decline. Controlling hyperglycemia is therefore crucial in preserving male reproductive function. Metformin not only regulates blood glucose level, but also preserves male fertility in diabetic state.

    Matched MeSH terms: Receptors, Androgen/genetics
  7. Hata S, Ise K, Azmahani A, Konosu-Fukaya S, McNamara KM, Fujishima F, et al.
    Life Sci, 2017 Dec 01;190:15-20.
    PMID: 28947209 DOI: 10.1016/j.lfs.2017.09.029
    AIMS: Bladder urothelial carcinoma is increasing in incidence with age and its prognosis could become worse when accompanied with metastasis. Effective treatment of these advanced patients is required and it becomes important to understand its underlying biology of this neoplasm, especially with regard to its biological pathways. A potential proposed pathway is androgen receptor (AR)-mediated intracellular signaling but the details have remained relatively unexplored.

    MAIN METHODS: The expression of AR, 5α-reductase type1 (5αR1) and 5α-reductase type2 (5αR2) were examined in the bladder cancer cell line T24 and surgical pathology specimens. We also evaluated the status of androgen related cell proliferation and migration using the potent, non-aromatizable androgen agonist 5α-dihydrotestosterone (DHT).

    KEY FINDINGS: DHT treatment significantly increased AR mRNA expression level, but not those of 5αR1 and 5αR2 in T24 cells. DHT also suppressed cellular migration with weaker and opposite effects on cell proliferation. A significant inverse correlation was detected between pT stage and AR, 5αR1 and 5αR2 immunoreactivity.

    SIGNIFICANCE: Inverse correlations detected between tumor grade and AR/androgen metabolizing enzyme also suggested that the loss of AR and androgen-producing enzymes could be associated with tumor progression. Effects of DHT on cells also suggest that androgens may regulate cellular behavior.

    Matched MeSH terms: Receptors, Androgen/genetics*
  8. Soga T, Wong DW, Putteeraj M, Song KP, Parhar IS
    Neuroscience, 2012 Dec 6;225:172-84.
    PMID: 22960312 DOI: 10.1016/j.neuroscience.2012.08.061
    Postnatal treatment with selective serotonin reuptake inhibitors (SSRIs) has been found to affect brain development and the regulation of reproduction in rodent models. The normal masculinization process in the brain requires a transient decrease in serotonin (5-HT) levels in the brain during the second postnatal week. Strict regulation of androgen receptor (AR) and gonadotropin-releasing hormone (GnRH) expression is important to control male reproductive activity. Therefore, this study was designed to examine the effects of a potent SSRI (citalopram) on male sexual behavior and expression levels of AR and GnRH in adult male mice receiving either vehicle or citalopram (10mg/kg) daily during postnatal days 8-21. The citalopram-treated male mice showed altered sexual behavior, specifically a significant reduction in the number of intromissions preceding ejaculation compared with the vehicle-treated mice. The citalopram-treated male mice displayed elevated anxiety-like behavior in an open field test and lower locomotor activity in their home cage during the subjective night. Although there was no change in GnRH and AR mRNA levels in the preoptic area (POA), quantified by real-time polymerase chain reaction, immunostained AR cell numbers in the medial POA were decreased in the citalopram-treated male mice. These results suggest that the early-life inhibition of 5-HT transporters alters the regulation of AR expression in the medial POA, likely causing decreased sexual behavior and altered home cage activity in the subjective night.
    Matched MeSH terms: Receptors, Androgen/genetics
  9. Kitahashi T, Ogawa S, Soga T, Sakuma Y, Parhar I
    Endocrinology, 2007 Dec;148(12):5822-30.
    PMID: 17823257
    The role of steroid/thyroid hormones in the regulation of endocrine cells at the level of the pituitary has remained unclear. Therefore, using single-cell quantitative real-time PCR, we examined absolute amounts of transcripts for nuclear receptors [estrogen receptors (ERs) alpha, beta, and gamma; androgen receptors (ARs) a and b; glucocorticoid receptors (GRs) 1, 2a, and 2b; and thyroid hormone receptors (TRs) alpha1, alpha2, and beta] in pituitary cells of immature (IM) and mature (M) male tilapia, Oreochromis niloticus. In the two reproductive stages, ACTH cells expressed only ERbeta, whereas all other pituitary cell types expressed ERalpha + beta, and a subpopulation coexpressed ARa, ARb, GR1, GR2b, and TRbeta but lacked ERgamma, GR2a, TRalpha1, and TRalpha2. IM males had high percentages of LH cells (IM 46.0% vs. M 10.0%), GH cells (IM 23.3% vs. M 7.9%), and prolactin cells (IM 68.8% vs. M 6.0%) with ERbeta, and TSH cells (IM 19.2% vs. M 0.0%) and MSH cells (IM 25.6% vs. M 0.0%) with ERalpha + TRbeta. A high percentage of FSH cells in IM males expressed ERbeta (IM 46.9% vs. M 18.8%), and FSH cells in M males showed significantly high GR1 transcripts (IM 76.0 +/- 5.0 vs. M 195.0 +/- 10.7 copies per cell; P < 0.05), suggesting that FSH cells are regulated differently in the two reproductive stages. Coexpression of ERalpha + beta in high percentages of cells of the GH family (GH, IM 43.8% vs. M 14.3%; prolactin, IM 8.3% vs. M 59.7%; somatolactin, IM 22.2% vs. M 42.2%) suggests that the expression of both ERs is important for functionality. Thus, differential coexpression of genes for nuclear receptors in subpopulations of pituitary cell types suggests multiple steroid/thyroid hormone regulatory pathways at the level of the pituitary during the two reproductive stages.
    Matched MeSH terms: Receptors, Androgen/genetics
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