Search Results (161)

Background: The androgen receptor (AR) is a ligand-dependent transcription factor of the nuclear steroid receptor superfamily, implicated in the pathogenesis of various solid tumors. The AR gene, located on chromosome Xq11–12, is accompanied by several X-linked genes that modulate AR expression and function, including FLNA, UXT, and members of the melanoma antigen gene (MAGE) family (MAGEA1, MAGEA11, MAGEC1, MAGEC2). While the AR has been investigated in multiple tumor types, its role in adult-type diffuse gliomas remains largely unexplored. Here, we characterized AR protein expression and the promoter methylation status of the AR and associated regulatory genes in adult-type diffuse gliomas. Methods: A retrospective analysis was conducted on 50 patients with adult-type diffuse gliomas, including IDH-mutant gliomas (grades 2–4) and IDH-wildtype glioblastomas (GBMs), classified according to the 2021 WHO criteria. AR nuclear expression was assessed by immunohistochemistry (IHC). Methylation-specific PCR and quantitative DNA methylation analyses were employed to evaluate promoter methylation of the AR and selected co-regulatory genes. Results: AR nuclear positivity correlated significantly with male sex (p = 0.04) and higher tumor grade, with the highest expression in IDH-wildtype GBMs (p = 0.04). In IDH-mutant gliomas, AR immunoreactivity was more prevalent in astrocytomas than in 1p/19q codeleted oligodendrogliomas (p = 0.02). AR expression was associated with unmethylated MGMT promoter status (p = 0.02). DNA methylation analysis revealed AR gene hypomethylation in tumors displaying nuclear AR positivity and in IDH-wildtype GBMs (Kruskal–Wallis p < 0.05). Additionally, methylation patterns of AR co-regulators located on the X chromosome suggest epigenetic regulation of AR signaling in gliomas. Conclusions: The findings reveal distinct AR pathway activation patterns in adult-type diffuse gliomas, particularly IDH-wildtype GBMs, suggesting that further exploration of antiandrogen therapies is warranted. Full article

The androgen receptor (AR) signaling pathway is the primary driver of prostate cancer initiation and progression, including the development of castration-resistant prostate cancer (CRPC). Because current AR-targeted therapies inevitably encounter drug resistance, novel strategies to suppress AR signaling are urgently needed. Natural products represent a rich and structurally diverse source of bioactive compounds capable of targeting AR at multiple regulatory levels. This review overviews the interactions between natural products and the AR signaling axis through distinct mechanisms, including inhibition of testosterone production and 5α-reductase activity, direct antagonism of AR, and induction of AR degradation. In addition, several compounds disrupt AR nuclear translocation, downregulate AR splice variants, or suppress AR signaling indirectly through epigenetic regulation, microRNA modulation, or interference with co-regulator networks. Preclinical studies provide compelling evidence that these agents can effectively interrupt AR signaling, thereby suppressing prostate cancer growth. However, challenges remain, particularly the limited pharmacokinetic characterization, lack of in vivo validation, and scarcity of clinical studies. Future research should focus on improving bioavailability, exploring synergistic combinations with existing therapies, and advancing well-designed in vivo and clinical investigations. Collectively, these efforts may establish natural products as lead compounds to modulate AR signaling for prostate cancer prevention and treatment. Full article

Background/Objectives: Benign prostatic hyperplasia (BPH) is a prevalent urological disorder in aging men, characterized by the enlargement of prostate epithelial and stromal cells, which leads to lower urinary tract symptoms. Paeonol, a bioactive compound derived from Moutan Cortex (Paeonia suffruticosa), exhibits multiple pharmacological properties; however, its therapeutic potential in BPH remains unclear. This study aimed to elucidate the mechanisms of paeonol in BPH treatment using network pharmacology and in vivo experiments. Methods: Network pharmacology and molecular docking were conducted to identify potential targets of paeonol against BPH. For the in vivo study, testosterone-induced BPH rat models were employed, and efficacy was evaluated through prostate weight assessment, histological examination, and the quantitative real-time polymerase chain reaction (qRT-PCR) analysis of prostate tissues. Results: In silico analysis revealed key signaling pathways involved in apoptosis, proliferation, phosphatidylinositol 3-kinase (PI3K)–protein kinase B (Akt), and inflammation. Paeonol administration significantly reduced prostate weight, volume, and histological hyperplasia in BPH rats. qRT-PCR analysis demonstrated that paeonol may suppress dihydrotestosterone production by inhibiting 5α-reductase 2 (5AR2) and the androgen receptor (AR), while also downregulating local growth factors, alpha serine/threonine-protein kinase (Akt1), nuclear factor-κB (NF-κB), and glutathione reductase (GR) expression. Conclusions: These findings provide novel insights into the multitargeted therapeutic potential of paeonol in BPH by inhibiting 5AR and AR and suppressing proliferation via NF-κB and Akt pathway modulation. Full article

Background: The outgrowth of castration-resistant prostate cancer (CRPC) dictates patient morbidity and mortality. Recurrence of prostate cancer (PC) following androgen-deprivation therapy (ADT) often occurs due to constitutively active androgen receptor (AR) splice variants (AR-Vs), primarily AR-V7. Therefore, safe and effective therapies enabling the suppression of both full-length AR (AR-FL) and AR-Vs are urgently needed. The natural compound dimethyl sulfoxide (DMSO) has negligible cytotoxicity at concentrations below 5% and has anticancer potential. DMSO has been broadly used in biomedical research as a solvent for pharmaceuticals, as a cryoprotectant for cells, and as a topical treatment to suppress pain and inflammation. We investigated the effect of low-dose DMSO on AR expression, cell viability, and metastatic ability in PC cell lines expressing both AR-FL and AR-V7 (e.g., 22Rv1) and those expressing only AR-FL (e.g., C4-2B). Methods: MTT cell viability assays were performed to measure DMSO-induced cytotoxicity. Wound-healing assays were conducted to monitor the effect of DMSO on the migratory phenotype of cancer cells. Western blot analyses were performed to study the efficacy of DMSO in suppressing the protein levels of AR-FL and AR-V7, and expression of heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) was measured as a possible mechanism. Results: At concentrations of 0.1–1% (v/v), DMSO treatment showed minimal cytotoxicity, whereas the highest concentration used (2.5%) showed approximately 20% cytotoxicity at 96 h. Interestingly, however, DMSO treatment at concentrations of 1.0 and 2.5% significantly inhibited the migration of PC cells. Treatment with DMSO led to a dose-dependent inhibition of both AR-FL and AR-V7. Notably, in 22Rv1 cells, DMSO potently downregulated the expression of hnRNPH1, a splicing factor often associated with AR expression and signaling. Conclusions: Our findings suggest that low concentrations of DMSO may have potential as an effective anticancer agent, both at the initial and later stages when PC cells become castration resistant. Full article

This study investigated whether the Endocrine Disruptome and VirtualToxLab in silico platforms are suitable for predicting the endocrine disrupting effects of per- and polyfluoroalkyl substances (PFASs)—in particular, for interactions with oestrogen receptors (ERs) and androgen receptor (AR). Compounds included in the U.S. Environmental Protection Agency’s PFAS working list were analysed with both models, and the results were compared with the available in vitro data regarding their modulation of nuclear receptors. Based on the identified prediction parameters, such as sensitivity, specificity, accuracy, and Mathews’ correlation coefficient, VirtualToxLab was found to be a reliable model for predicting the reactivity of PFASs with AR, while a positive consensus approach of both platforms provided reliable predictions of the PFAS reactivity with ERα and ERβ. This study provides the evidence that Endocrine Disruptome and VirtualToxLab can be used as a tier 1 screening tool for assessment of the endocrine disrupting effect of PFASs. Furthermore, it demonstrates that the likelihood of endocrine disrupting properties increases with the lipophilicity of PFASs and identifies the understudied PFHpS, PFNS, PFDS, 9-Cl, NMeFOSAA, NEtFOSAA, 4:2 FTS, 6:2 FTS, 8:2 FTS, 6:2 monoPAP, 8:2 monoPAP, and 5:3 acid as potential ligands of AR and/or ERs. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and currently is the second-leading cause of cancer-related mortality globally. Current front-line systemic therapies for advanced HCC offer only modest improvements in patient overall survival. HCC is a sexually dimorphic disease, and cancer progression is driven in part by AR activity. Here, we present novel niclosamide pro-drugs for use in advanced HCC based upon niclosamide’s known anti-AR activity and additional anti-cancer pathway efficacy. Methods: Niclosamide analogs were evaluated for their impacts on the AR protein in two HCC cell lines with different AR phenotypes. Amino acid conjugates of niclosamide were developed, and pharmacokinetic (PK) analyses were conducted to determine improvements in clearance and oral exposure. Finally, niclosamide analogs and amino acid conjugates were evaluated in an in vivo model of HCC. Results: Niclosamide analogs maintained anti-AR properties in HCC. Valine-conjugated niclosamide showed improved oral exposure, positioning it as a potential therapeutic in advanced HCC. Conclusions: Valine–niclosamide improves upon niclosamide’s poor solubility and oral bioavailability, increasing its utility for a variety of therapeutic uses. Further study of valine–niclosamide in advanced HCC and in other cancers or diseases is warranted. Full article

Androgenetic alopecia (AGA) is associated with dihydrotestosterone (DHT)-induced apoptosis in human dermal papilla cells (HDPCs) via androgen receptor (AR) upregulation. This study aimed to evaluate the potential of Cucumis melo var. makuwa leaf extract (CLE) to attenuate these DHT-mediated effects in HDPCs. HDPCs were treated with CLE, and DHT-induced apoptosis and AR expression were assessed. High-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (HPLC–ESI–MS) identified Meloside A as the principal bioactive constituent within CLE. CLE significantly attenuated DHT-induced apoptosis in HDPCs, demonstrating a 57.74% reduction at 1000 ppm. Mechanistically, Meloside A inhibited DHT-stimulated AR nuclear translocation and reduced AR protein expression. Furthermore, Meloside A decreased the expression of downstream target genes at 100 ppm, showing a 16.27% reduction in IL-6, a 26.55% reduction in TGF-β1, and a 35.38% reduction in DKK-1. Additionally, Meloside A significantly inhibited ROS generation within DHT-stimulated HDPCs by 45.45% at 100 ppm. These findings suggest that Meloside A, isolated from CLE, exerts anti-AGA effects by modulating AR nuclear translocation and gene expression. This highlights its potential as a therapeutic agent for AGA and provides a basis for developing novel therapeutic strategies for hair loss. Full article

The protective potentials of Tribulus terrestris (TT) and L-arginine (L-Arg) against reproductive toxicity induced by fipronil (FPN) in male rats were investigated. A total of 36 male rats were allocated into six groups: control, TT, L-Arg, FPN, FPN + TT, and FPN + L-Arg groups. The body and sex organ weights, semen criteria, serum testosterone levels, and testicular oxidative stress were determined. Sexual behavior, testicular and penile androgen receptor (AR), penile nitric oxide synthase (NOS), immunohistochemistry of proliferating cell nuclear antigen (PCNA), and histopathology were also assessed. FPN disrupted reproductive health by influencing the expression and activity of NOS and AR, leading to compromised erectile function, sexual dysfunction, and hormonal imbalance. Significant improvements in body weight, reproductive organ weights, the expression of NOS and AR, and testosterone levels were observed in the TT- and L-Arg-treated groups. Behavioral assessments indicated improved sexual performance in the TT- and L-Arg-treated groups. Histopathological studies of the testes and penis tissue, immunohistochemical expression of PCNA in testicular tissues, and biochemical analyses further confirmed the protective effects of TT and L-Arg. Collectively, these findings highlighted the potential of TT and L-Arg in counteracting FPN-induced reproductive impairments. Full article

Background: The optimal diagnostic and therapeutic strategies for prostate cancer (PCa) in patients aged ≥75 years (mild-old and oldest-old) are still contentious. Resource allocation and ideal treatment for older patients are challenges, mainly due to their comorbidities and reduced life expectancy. This survey aims to assess current clinical practices and the experiences of healthcare providers in the diagnosis and management of elderly patients with PCa. Materials and Methods: In Northeast Italy, members of the Gruppo Uro-Oncologico del Nord-Est (GUONE) conducted a survey involving 104 physicians of different specialties (Nuclear Medicine, Medical Oncology, Radiation Oncology, Radiology, Urology) between 1 November 2024 and 30 November 2024. The survey encompassed 51 questions, evaluating various diagnostic and therapeutic scenarios. Results: Digital rectal exam (DRE) was recommended by 35.9% of physicians for patients aged 75 or older at risk of PCa. PSA testing was continued in 76.3% of these patients. For 36.5% of the physicians, there should be no age limit for prostate biopsy. Moreover, 42.6% of physicians recommended a magnetic resonance imaging (MRI)-guided prostate biopsy regardless of age. A prostate biopsy was deemed mandatory before initiating any form of hormonal therapy by 57.7% of the participants. For 22.3% and 34.7% of physicians, there should be no age limit for prostate MRI and PET/CT for staging purposes. Interestingly, PET/CT was not recommended in 52% of cases as a staging tool for patients older than 85 years. For patients without comorbidities, the age limit to consider radical prostatectomy (RP) was 75, with 58.6% of physicians in favor. There were no definitive limits for radiotherapy (RT). Chemotherapy had an age limit for 81.6% of the respondents; for 18.4%, 22.5%, and 26.5% of physicians, age limits were 75, 80, and 85 years, respectively. The use of androgen receptor pathway inhibitors (ARPIs) had no definitive age limits for 46.5% of respondents. For patients with no comorbidities and low-volume metastatic PCa, the preferred option was androgen deprivation therapy + ARPIs + RT. The follow-up schedule after RP or RT exhibited heterogeneity with no consensus regarding the frequency of PSA testing or the age at which it should be discontinued. Conclusions: This survey highlights the need for consensus guidelines in diagnosing and managing mild-old and oldest-old elderly PCa patients. With the aging population, standardized protocols are essential to ensure optimal care. Full article

Prostate cancer (PCa) is ranked as one of the top cancers affecting men in Western societies. BRCA1-associated protein 1 (BAP1) expression significance has been observed in various cancers, including prostate cancer. The search for prognostic models allowing better risk stratification and prediction of disease progression in prostate cancer patients is still of major clinical need. Our data showed that nuclear BAP1 expression is the most associated with cancer clinical outcomes and other biomarkers. The data confirmed that decreased BAP1 nuclear expression is linked to aggressive tumors and poorer prognosis. We assessed BAP1 expression in 202 cases, including advanced and castrate-resistant PCa (CRPCa). Our data indicated low BAP1 nuclear expression in advanced and castrate-resistant disease (CRPCa). Furthermore, there was a significant difference between high and low BAP1 nuclear expression relative to the patient’s clinical outcome. In the present cohort, decreased BAP1 intensity exhibited a significant association with unfavorable overall survival (OS) (HR 2.31, CI: 1.38–3.86, p = 0.001) and cause-specific survival (CSS) (HR 2.44, CI: 1.24–4.78, p = 0.01). Additionally, this association was more pronounced when low BAP1 expression (high risk) was combined with other common PCa genomic alterations such as phosphatase and tensin homolog (PTEN) loss or ETS-related gene (ERG)-positive cases, resulting in higher unfavorable OS and CSS. Conversely, high BAP1 nuclear expression (moderate and high intensity) combined with no ERG expression or PTEN (moderate or high expression), p53 (wild type), and androgen receptor (AR) (low/moderate intensity) showed better association with higher survival rates. All these data support the notion that BAP1 functions as a tumor suppressor. Integrating BAP1 status with other genomic alterations offers a more comprehensive understanding of disease aggressiveness. Full article

Sex steroids and the neurotrophin brain-derived neurotrophic factor (BDNF) participate in neural tissue formation, phenotypic differentiation, and neuroplasticity. These processes are essential for the health and maintenance of the central nervous system. Aim: The aim of our review is to elucidate the interaction mechanisms between BDNF and sex steroids in neuronal function. Method: A series of searches were performed using Mesh terms for androgen/receptors, estrogen/receptors, and BDNF/receptors, and a collection of the scientific data available on PubMed up to February 2025 about mechanical interactions between BDNF and sex steroids was included in this literature review. Discussion: This review discussed the influence of sex steroids on the formation and/or maintenance of neural circuits via different mechanisms, including the regulation of BDNF expression and signaling. Estrogens exert a time- and region-specific effect on BDNF synthesis. The nuclear estrogen receptor can directly regulate BDNF expression, independently of the presence of estrogen, in neuronal cells, whereas progesterone and testosterone upregulate BDNF expression via their specific nuclear receptors. In addition, testosterone has a positive effect on BDNF release by glial cells, which lack androgen receptors. Full article

Benign prostatic hyperplasia (BPH) is a noncancerous urinary disorder that is common in older adult men; however, its underlying mechanisms remain unclear. Fenugreek has some biological effects, including hyperglycemia regulation, immune response modulation, and anti-cancer properties; In this study, we investigated the ameliorative effects of fenugreek seed extract (Forceterone^® [FCT]) in a testosterone propionate (TP)-induced BPH animal model and its mechanisms in BPH-1 human prostate epithelial cells. Sprague Dawley (SD) rats were injected subcutaneously with TP (3 mg/kg) for 8 weeks to induce BPH while FCT was administered orally at 25, 50, and 100 mg/kg. In addition, BPH-1 cells were used to evaluate the inhibitory effects on cell proliferation and examine inflammatory cytokine expression. Treating rats with FCT decreased prostate weight, dihydrotestosterone (DHT) level, and proliferating cell nuclear antigen (PCNA) expression in the prostate. Furthermore, it decreased androgen receptor (AR), 5α-reductase 2, B-cell lymphoma 2 (Bcl-2), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and NF-κB expression in vitro and in vivo and increased Bcl-2-associated X protein (Bax) expression. FCT also inhibited cell proliferation dose dependently in BPH-1 cells. These findings showed the potential use of FCT as an alternative treatment for BPH. Full article

Background: Cytochromes P450 (CYPs) are heme-containing oxidoreductase enzymes with mono-oxygenase activity. Human CYPs catalyze the oxidation of a great variety of chemicals, including xenobiotics, steroid hormones, vitamins, bile acids, procarcinogens, and drugs. Findings: In our review article, we discuss recent data evidencing that the same CYP isoform can be involved in both bioactivation and detoxification reactions and convert the same substrate to different products. Conversely, different CYP isoforms can convert the same substrate, xenobiotic or procarcinogen, into either a more or less toxic product. These phenomena depend on the type of catalyzed reaction, substrate, tissue type, and biological species. Since the CYPs involved in bioactivation (CYP3A4, CYP1A1, CYP2D6, and CYP2C8) are primarily expressed in the liver, their metabolites can induce hepatotoxicity and hepatocarcinogenesis. Additionally, we discuss the role of drugs as CYP substrates, inducers, and inhibitors as well as the implication of nuclear receptors, efflux transporters, and drug–drug interactions in anticancer drug resistance. We highlight the molecular mechanisms underlying the development of hormone-sensitive cancers, including breast, ovarian, endometrial, and prostate cancers. Key players in these mechanisms are the 2,3- and 3,4-catechols of estrogens, which are formed by CYP1A1, CYP1A2, and CYP1B1. The catechols can also produce quinones, leading to the formation of toxic protein and DNA adducts that contribute to cancer progression. However, 2-hydroxy- and 4-hydroxy-estrogens and their O-methylated derivatives along with conjugated metabolites play cancer-protective roles. CYP17A1 and CYP11A1, which are involved in the biosynthesis of testosterone precursors, contribute to prostate cancer, whereas conversion of testosterone to 5α-dihydrotestosterone as well as sustained activation and mutation of the androgen receptor are implicated in metastatic castration-resistant prostate cancer (CRPC). CYP enzymatic activities are influenced by CYP gene polymorphisms, although a significant portion of them have no effects. However, CYP polymorphisms can determine poor, intermediate, rapid, and ultrarapid metabolizer genotypes, which can affect cancer and drug susceptibility. Despite limited statistically significant data, associations between CYP polymorphisms and cancer risk, tumor size, and metastatic status among various populations have been demonstrated. Conclusions: The metabolic diversity and dual character of biological effects of CYPs underlie their implications in, preliminarily, hormone-sensitive cancers. Variations in CYP activities and CYP gene polymorphisms are implicated in the interindividual variability in cancer and drug susceptibility. The development of CYP inhibitors provides options for personalized anticancer therapy. Full article

This review focuses on the pivotal roles of nuclear receptors (NRs) in driving endocrine resistance in prostate and breast cancers. In prostate cancer (PCa), androgen receptor (AR) amplification, mutations, and altered coactivator interactions sustain tumor growth under androgen deprivation therapy (ADT), leading to castration-resistant prostate cancer (CRPC). Orphan NRs like RORβ, TLX, and COUP-TFII further contribute to CRPC by regulating stemness and therapeutic resistance mechanisms. In breast cancer, NRs, including estrogen receptor alpha (ERα), androgen receptor (AR), glucocorticoid receptor (GR), and liver receptor homolog-1 (LRH-1), modulate estrogen signaling pathways and alternative survival mechanisms like PI3K/AKT/mTOR and NFκB, promoting resistance to endocrine therapies such as tamoxifen. Understanding these NR-mediated mechanisms is critical for developing targeted therapies to overcome endocrine resistance and improve patient outcomes in hormone-dependent cancers. Full article

The androgen receptor (AR), a member of the nuclear steroid hormone receptor family of transcription factors, plays a crucial role not only in the development of the male phenotype but also in the development and growth of prostate cancer. While AR structure and AR interactions with coregulators and chromatin have been studied in detail, improving our understanding of AR function in gene transcription regulation, the spatio-temporal organization and the role of microscopically discernible AR foci in the nucleus are still underexplored. This review delves into the molecular mechanisms underlying AR foci formation, focusing on liquid–liquid phase separation and its role in spatially organizing ARs and their binding partners within the nucleus at transcription sites, as well as the influence of 3D-genome organization on AR-mediated gene transcription. Full article