Effects of Taraxaci Herba (Dandelion) on Testosterone Propionate-Induced Benign Prostatic Hyperplasia in Rats.

Benign prostatic hyperplasia (BPH) is the non-malignant enlargement of the prostate, associated with lower urinary tract symptoms (LUTSs). Taraxaci Herba (TH), commonly known as dandelion, has traditionally been utilized in East Asia to treat symptoms related to LUTSs. Based on this traditional use, our study aimed to explore the inhibitory effects of TH on BPH progression using a testosterone propionate-induced rat model. To induce BPH, male Sprague Dawley rats were castrated and injected subcutaneously with testosterone propionate (3 mg/kg/day) for 28 days. Concurrently, TH extract was administered orally at doses of 100 and 300 mg/kg/day throughout the four-week period of testosterone propionate injections. The TH extract significantly reduced both the absolute and relative weights of the prostate, along with histopathological changes in the gland. Moreover, it lowered serum levels of testosterone and dihydrotestosterone and reduced the expression of the androgen receptor in the prostate. Additionally, the TH extract modulated the protein expressions of Bax and Bcl-2, which are key regulators of apoptosis in prostate cells. Collectively, our findings suggest that TH inhibits BPH development partially by modulating androgen signaling and inducing apoptosis within the prostate.

In silico investigation of the role of miRNAs in a possible developmental origin of prostate cancer in F1 and F2 offspring of mothers exposed to a phthalate mixture.

A previous study using miRNA sequencing revealed that exposure to a mixture of phthalates during pregnancy and lactation dysregulated rno-miR-184 and rno-miR-141-3p in the ventral prostate (VP) of offspring. Here, rno-miR-184 and rno-miR-141-3 expressions were obtained by RT-qPCR in the VP of F1 males as well as in F2 offspring, aiming to establish a relationship with possible oncogenic targets through in silico analyses with multigenerational approach. Additionally, some targets were measured by western blots to highlight a possible relationship between the deregulated miRNAs and some of their targets. VP samples from rats exposed to a mixture of phthalates maternally during pregnancy and lactation (GD10 to PND21-F1) and VP from offspring (F2) were examined. The phthalate mixture at both concentrations (20 µg and 200 mg/kg/day) increased the expression of both miRNAs in the F1 (PND22 and 120) and F2 (descendants of F1-treated males) prostate. Target prediction analysis revealed that both microRNAs are responsible for modulating the expression and synthesis of 40 common targets. A phthalate target association analysis and the HPA database showed an interesting relationship among these possible miRNAs modulated targets with prostate adenocarcinoma and other oncogenic processes. Western blots showed alteration in P63, P53, WNT5, and STAT3 expression, which are targeted by the miRNAs, in the VP of F1/F2 males. The data draw attention to the epigenetic modulation in the prostate of descendants exposed to phthalates and adds to one of the few currently found in the literature to point to microRNAs signature as biomarkers of exposure to plasticizers.

Effect of nonsteroidal anti-inflammatory drugs (aspirin and naproxen) on inflammation-associated proteomic profiles in mouse plasma and prostate during TMPRSS2-ERG (fusion)-driven prostate carcinogenesis.

Recent preclinical studies have shown that the intake of nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin and naproxen could be an effective intervention strategy against TMPRSS2-ERG fusion-driven prostate tumorigenesis. Herein, as a follow-up mechanistic study, employing TMPRSS2-ERG (fusion) positive tumors and plasma from TMPRSS2-ERG. Ptenflox/flox mice, we profiled the stage specific proteomic changes (focused on inflammatory circulating and prostate tissue/tumor-specific cytokines, chemokines, and growth factors/growth signaling-associated molecules) that contribute to prostate cancer (PCa) growth and progression in the TMPRSS2-ERG fusion-driven mouse model of tumorigenesis. In addition, the association of the protective effects of NSAIDs (aspirin 1400 ppm and naproxen 400 ppm) with the modulation of these specific molecular pathways was determined. A sandwich Elisa based membrane array-proteome profiler identifying 111 distinct signaling molecules was employed. Overall, the plasma and prostate tissue sample analyses identified 54 significant and differentially expressed cytokines, chemokines, and growth factors/growth signaling-associated molecules between PCa afflicted mice (TMPRSS2-ERG. Ptenflox/flox, age-matched noncancerous controls, NSAIDs-supplemented and no-drug controls). Bioinformatic analysis of the array outcomes indicated that the protective effect of NSAIDs was associated with reduced expression of (a) tumor promoting inflammatory molecules (M-CSF, IL-33, CCL22, CCL12, CX3CL1, CHI3L1, and CD93), (b) growth factors- growth signaling-associated molecules (Chemerin, FGF acidic, Flt-3 ligand, IGFBP-5, and PEDF), and (c) tumor microenvironment/stromal remodeling proteins MMP2 and MMP9. Overall, our findings corroborate the pathological findings that protective effects of NSAIDs in TMPSS2-ERG fusion-driven prostate tumorigenesis are associated with antiproliferative and anti-inflammatory effects and possible modulation of the immune cell enriched microenvironment.

Selective Androgen Receptor Modulators-Transformative Drugs or Heralds of the Next Drug Epidemic?

This Viewpoint examines whether selective androgen receptor modulators have the potential to be transformative drugs or whether they herald the next drug epidemic.

Enhanced Chemoprevention of Prostate Cancer by Combining Arctigenin with Green Tea and Quercetin in Prostate-Specific Phosphatase and Tensin Homolog Knockout Mice.

The low bioavailability of most phytochemicals limits their anticancer effects in humans. The present study was designed to test whether combining arctigenin (Arc), a lignan mainly from the seed of Arctium lappa, with green tea (GT) and quercetin (Q) enhances the chemopreventive effect on prostate cancer. We performed in vitro proliferation studies on different cell lines. We observed a strong synergistic anti-proliferative effect of GT+Q+Arc in exposing androgen-sensitive human prostate cancer LNCaP cells. The pre-malignant WPE1-NA22 cell line was more sensitive to this combination. No cytotoxicity was observed in normal prostate epithelial PrEC cells. For an in vivo study, 3-week-old, prostate-specific PTEN (phosphatase and tensin homolog) knockout mice were treated with GT+Q, Arc, GT+Q+Arc, or the control daily until 16 weeks of age. In vivo imaging using prostate-specific membrane antigen (PSMA) probes demonstrated that the prostate tumorigenesis was significantly inhibited by 40% (GT+Q), 60% (Arc at 30 mg/kg bw), and 90% (GT+Q+Arc) compared to the control. A pathological examination showed that all control mice developed invasive prostate adenocarcinoma. In contrast, the primary lesion in the GT+Q and Arc alone groups was high-grade prostatic intraepithelial neoplasia (PIN), with low-grade PIN in the GT+Q+Arc group. The combined effect of GT+Q+Arc was associated with an increased inhibition of the androgen receptor, the PI3K/Akt pathway, Ki67 expression, and angiogenesis. This study demonstrates that combining Arc with GT and Q was highly effective in prostate cancer chemoprevention. These results warrant clinical trials to confirm the efficacy of this combination in humans.

Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance.

Inflammation is a hallmark of cancer1. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities2-5. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11b+HLA-DRloCD15+CD14- myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.

Bisphenol A modulates proliferation, apoptosis, and wound healing process of normal prostate cells: Involvement of G2/M-phase cell cycle arrest, MAPK signaling, and transcription factor-mediated MMP regulation.

Bisphenol A (BPA) is commonly used to produce epoxy resins and polycarbonate plastics. BPA is an endocrine-disrupting chemical that is leaked from the polymer and absorbed into the body to disrupt the endocrine system. Although BPA may cause cytotoxicity in the prostate, a hormone-dependent reproductive organ, its underlying mechanism has not yet been elucidated. Here, we investigated the effects of BPA on cell proliferation, apoptosis, and the wound healing process using prostate epithelial cells (RWPE-1) and stromal cells (WPMY-1). Observations revealed that BPA induced G2/M cell cycle arrest in both cell types through the ATM-CHK1/CHK2-CDC25c-CDC2 signaling pathway, and the IC50 values were estimated to be 150 µM. Furthermore, BPA was found to induce caspase-dependent apoptosis through initiator (caspase-8 and -9) and executioner (caspase-3 and -7) caspase cascades. In addition, BPA interfered with the wound healing process through inhibition of MMP-2 and - 9 expression, accompanied by reductions in the binding activities of AP-1 as well as NF-κB motifs. Phosphorylation of MAPKs was associated with the BPA-mediated toxicity of prostate cells. These results suggest that BPA exhibits prostate toxicity by inhibiting cell proliferation, inducing apoptosis, and interfering with the wound healing process. Our study provided new insights into the precise molecular mechanisms of BPA-induced toxicity in human prostate cells.

Fermented rape pollen powder can alleviate benign prostatic hyperplasia in rats by reducing hormone content and changing gut microbiota.

Benign prostatic hyperplasia (BPH) can cause urethral compression, bladder stone formation, and renal function damage, which may endanger the life of patients. Therefore, we aimed to develop plant-based preparations for BPH treatment with no side effects. In this study, the Lactiplantibacillus plantarum 322Hp, Lactobacillus acidophilus 322Ha, and Limosilactobacillus reuteri 322Hr were used to ferment rape pollen. The fermented rape pollen was subsequently converted into fermented rape pollen powder (FRPP) through vacuum freeze-drying technology. After fermenting and drying, the bioactive substances and antioxidant capacity of FRPP were significantly higher than those of unfermented rapeseed pollen, and FRPP had a longer storage duration, which can be stored for over one year. To investigate the therapeutic effect of FRPP on BPH, a BPH rat model was established by hypodermic injection of testosterone propionate. The BPH rats were treated differently, with the model group receiving normal saline, the positive control group receiving finasteride, and the low, medium, and high dose FRPP group receiving FRPP at doses of 0.14 g/kg/d, 0.28 g/kg/d, and 0.56 g/kg/d, respectively. The results indicate that medium dose FRPP reduced the levels of hormone such as testosterone, dihydrotestosterone, and oestradiol in rats with BPH by about 32%, thus bringing the prostate tissue of BPH rats closer to normal. More importantly, medium dose FRPP treatment had a significant effect on the composition of gut microbiota in rats with BPH, increasing the levels of beneficial genera (such as Coprococcus and Jeotgalicoccus), and decreasing the levels of harmful pathogens (such as Turicibacter and Clostridiaceae_Clostridium) in the gut. This study showed that medium dose FRPP reduced the hormone level and regulated the unbalanced gut microbiota in BPH rats, thereby alleviating BPH.

Chronic coexposure to arsenic and estrogen potentiates genotoxic estrogen metabolic pathway and hypermethylation of DNA glycosylase MBD4 in human prostate epithelial cells.

BACKGROUND: Previously we reported that arsenic and estrogen cause synergistic effects in the neoplastic transformation of human prostate epithelial cells. In addition to receptor-mediated pathways, DNA-reactive estrogen metabolites have also been shown to play a critical role in mutagenicity and carcinogenicity. Both estrogen and arsenic are known prostate carcinogens, however, the effect of coexposure to these two chemicals on genes involved in estrogen metabolism is not known. Therefore, the objective of this study was to evaluate the role of arsenic and estrogen coexposure on the expression of estrogen receptors and estrogen metabolism-associated genes. Earlier, we also reported the synergistic effect of arsenic and estrogen on decreased expression of MBD4 genes that play an important role in DNA repair through its DNA glycosylase activity. To further understand the mechanism, the promoter methylation of this gene was also analyzed. METHODS: Total RNA and protein were isolated from RWPE-1 human prostate epithelial cells that were coexposed to arsenic and estrogen for a chronic duration (6 months). The expression of estrogen receptors, estrogen metabolism associated phase I genes (CYP 1A1, 1A2, 3A4, and 1B1) and phase II gene catechol-O-methyltransferase (COMT), as well as antioxidant MnSOD, were analyzed either at the RNA level by quantitative reverse transcriptase-polymerase chain reaction or at the protein level by western blot. Promoter methylation of MBD4 was analyzed by pyrosequencing. RESULTS: Expression of MnSOD and phase I genes that convert E2 into genotoxic metabolites 2-OH-E2 and 4-OH-E2 were significantly increased, whereas the expression of phase II gene COMT that detoxifies estrogen metabolites was significantly decreased in arsenic and estrogen coexposed cells. MBD4 promoter was hypermethylated in arsenic and estrogen coexposed cells. Coexposure to arsenic and estrogen has synergistic effects on the expression of these genes as well as in MBD4 promoter hypermethylation. CONCLUSIONS: These novel findings suggest that coexposure to arsenic and estrogen acts synergistically in the activation of not only the estrogen receptors but also the genes associated with genotoxic estrogen metabolism and epigenetic inactivation of DNA glycosylase MBD4. Together, these genetic and epigenetic aberrations provide the molecular basis for the potentiation of carcinogenicity of arsenic and estrogen coexposure in prostate epithelial cells.

Nanoparticles of Costus speciosus Ameliorate Diabetes-Induced Structural Changes in Rat Prostate through Mediating the Pro-Inflammatory Cytokines IL 6, IL1ß and TNF-α.

Diabetes mellitus is a common global health problem. Among the complications that are frequently associated with DM are the alternation of sexual function and fertility, especially in young men. This study aimed to assess the efficacy of nanoparticles of Costus speciosus (C. speciosus) in preserving the prostatic structure of diabetic rats and to explore the mechanism behind this effect. A model of DM was induced in male albino rats by a single intraperitoneally injection of streptozotocin (STZ, 60 mg/kg body weight). Five groups (n = 10 each) of rats were included in this study: the control, C. speciosus gold nanoparticles-treated (150 mg/kg body weight through gastric intubation for 30 days), untreated diabetic, metformin-treated diabetic (500 mg/kg/day gastric intubation for 30 days) and the C. speciosus-treated diabetic group. The blood glucose, insulin and testosterone levels as well as oxidants/antioxidants status were assessed in the serum. Gene expression of proinflammatory cytokines TNF-α, IL1ß and IL-6 were assessed in the prostate homogenate. At the end of the experiment, the rats were sacrificed and the prostate was dissected out and prepared for histopathological and immunohistochemistry study using Ki67 and Bcl-2. C. Speciosus nanoparticles significantly decreased (p = 0.03) the blood glucose level while significantly increasing insulin (p = 0.01) and testosterone (p = 0.04) levels compared to the untreated diabetic rats. Oxidants/antioxidants status was markedly improved after administration of C. speciosus. Prostatic expression of the mRNA of pro-inflammatory cytokines IL-6, IL1ß and TNF-α was down-regulated in metformin- and C. speciosus-treated rats. The histological structure of the ventral prostate was preserved in metformin- and C. speciosus-treated diabetic rats with a significantly thicker epithelial cell layer and significant increase immunoexpression in Bcl-2 and Ki67. In conclusion, the protective effect induced by C. speciosus nanoparticles on the prostate of diabetic rats might be directly mediated through the down-regulation of inflammatory cytokines and the up-regulation of antioxidant activity and indirectly mediated through the anti-hyperglycemic effect through enhancing insulin secretion.

A mass spectrometric method for in-depth profiling of phosphoinositide regioisomers and their disease-associated regulation.

Phosphoinositides are a family of membrane lipids essential for many biological and pathological processes. Due to the existence of multiple phosphoinositide regioisomers and their low intracellular concentrations, profiling these lipids and linking a specific acyl variant to a change in biological state have been difficult. To enable the comprehensive analysis of phosphoinositide phosphorylation status and acyl chain identity, we develop PRMC-MS (Phosphoinositide Regioisomer Measurement by Chiral column chromatography and Mass Spectrometry). Using this method, we reveal a severe skewing in acyl chains in phosphoinositides in Pten-deficient prostate cancer tissues, extracellular mobilization of phosphoinositides upon expression of oncogenic PIK3CA, and a unique profile for exosomal phosphoinositides. Thus, our approach allows characterizing the dynamics of phosphoinositide acyl variants in intracellular and extracellular milieus.

Overcoming resistance to immune checkpoint therapy in PTEN-null prostate cancer by intermittent anti-PI3Kα/ß/δ treatment.

Combining immune checkpoint therapy (ICT) and targeted therapy holds great promises for broad and long-lasting anti-cancer therapies. However, combining ICT with anti-PI3K inhibitors have been challenging because the multifaceted effects of PI3K on both cancer cells and immune cells within the tumor microenvironment. Here we find that intermittent but not daily dosing of a PI3Kα/ß/δ inhibitor, BAY1082439, on Pten-null prostate cancer models could overcome ICT resistance and unleash CD8+ T cell-dependent anti-tumor immunity in vivo. Mechanistically, BAY1082439 converts cancer cell-intrinsic immune-suppression to immune-stimulation by promoting IFNα/IFNγ pathway activation, ß2-microglubin expression and CXCL10/CCL5 secretion. With its preferential regulatory T cell inhibition activity, BAY1082439 promotes clonal expansion of tumor-associated CD8+ T cells, most likely via tertiary lymphoid structures. Once primed, tumors remain T cell-inflamed, become responsive to anti-PD-1 therapy and have durable therapeutic effect. Our data suggest that intermittent PI3K inhibition can alleviate Pten-null cancer cell-intrinsic immunosuppressive activity and turn "cold" tumors into T cell-inflamed ones, paving the way for successful ICT.

Statin Use and Lower Urinary Tract Symptoms Incidence and Progression in Reduction by Dutasteride of Prostate Cancer Events (REDUCE) Trial.

PURPOSE: Benign prostatic hyperplasia (BPH) is a common disease often manifested by lower urinary tract symptoms (LUTS). We previously found statins were associated with modest attenuations in prostate growth over time in REDUCE. We tested whether statins were associated with LUTS incidence in asymptomatic men and LUTS progression in symptomatic men. MATERIALS AND METHODS: We performed a post-hoc analysis of REDUCE in 3,060 "asymptomatic" men with baseline International Prostate Symptom Score (IPSS) <8 and in 2,198 symptomatic men with baseline IPSS ≥8 not taking α-blockers or 5α-reductase inhibitors. We used multivariable Cox regression models to assess associations between statin use at baseline and LUTS incidence and progression. Among asymptomatic men, incident LUTS was defined as the first reported medical or surgical treatment for BPH or sustained clinically significant LUTS (2 reports of IPSS >14). Among symptomatic men, LUTS progression was defined as IPSS increase ≥4 points from baseline, any surgical procedure for BPH, or initiation of a BPH drug. RESULTS: Among asymptomatic and symptomatic men, 550 (18%) and 392 (18%) used statins at baseline, respectively. On multivariable analysis, statin use was not associated with LUTS incidence (HR 1.05; 95% CI 0.78-1.41, p=0.74) in asymptomatic men, or with LUTS progression (HR 1.13; 95% CI 0.96-1.33, p=0.15) in symptomatic men. Similar results were seen in the dutasteride and placebo arms when stratified by treatment assignment. CONCLUSIONS: In REDUCE, statin use was not associated with either incident LUTS in asymptomatic men or LUTS progression in symptomatic men. These data do not support a role for statins in LUTS prevention or management.

Do commonly used prostate medications alter prostate MRI and fusion biopsy performance?

AIMS: To determine whether phosphodiesterase inhibitors (PDEi) or α-antagonists (AA) were associated with differences in region of interest (ROI) characteristics or prostate cancer detection on fusion biopsy (FB). MATERIALS AND METHODS: Records from 847 consecutive patients undergoing FB at three separate institutions over a period of 2 years were retrospectively reviewed. Associations between medication use, Prostate Imaging Reporting & Data System (PIRADS) scores, and ROI locations were assessed with ordinal logistic regression. Associations with lesion size and International Society of Urologic Pathology (ISUP) grade group (GG) on biopsy were tested using multivariate regression. RESULTS: Medication use included PDEi in 14.2% and AA in 23.0%. PDEi use was associated with 19.3% smaller lesion diameter (-2.8 mm; CI from -4.8 to -0.7; p < 0.01) and lower PIRADS scores on MRI (OR 0.60; CI 0.40 - 1.00; p = 0.05). AA use was associated with higher PIRADS scores (OR 1.43; CI 0.97 - 2.11; p = 0.06), fewer positive fusion-directed biopsy cores (-28.6%, CI from -57.9 to 0.01%, p = 0.05), and downgrading on final pathology (-19%; CI from -40 to 2%; p = 0.06). CONCLUSION: For PIRADS scores ≥ 3, PDEi use is associated with smaller ROI and lower PIRADS scores, while AA use is associated with higher PIRADS scores. Neither medication was associated with differences in biopsy GG. Prospective studies are needed to investigate the discordance between multi-parametric magnetic resonance imaging (mpMRI) results and oncologic outcomes associated with PDEi and AA use.

Per- and polyfluoroalkyl substances target and alter human prostate stem-progenitor cells.

Per- and polyfluorinated alkyl substances (PFAS) are a large family of widely used synthetic chemicals that are environmentally and biologically persistent and present in most individuals. Chronic PFAS exposure have been linked to increased prostate cancer risk in occupational settings, however, underlying mechanisms have not been interrogated. Herein we examined exposure of normal human prostate stem-progenitor cells (SPCs) to 10 nM PFOA or PFOS using serial passage of prostasphere cultures. Exposure to either PFAS for 3-4 weeks increased spheroid numbers and size indicative of elevated stem cell self-renewal and progenitor cell proliferation. Transcriptome analysis using single-cell RNA sequencing (scRNA-seq) showed 1) SPC expression of PPARs and RXRs able to mediate PFAS effects, 2) the emergence of a new cell cluster of aberrantly differentiated luminal progenitor cells upon PFOS/PFOA exposure, and 3) enrichment of cancer-associated signaling pathways. Metabolomic analysis of PFAS-exposed prostaspheres revealed increased glycolytic pathways including the Warburg effect as well as strong enrichment of serine and glycine metabolism which may promote a pre-malignant SPC fate. Finally, growth of in vivo xenografts of tumorigenic RWPE-2 human prostate cells, shown to contain cancer stem-like cells, was markedly enhanced by daily PFOS feeding to nude mice hosts. Together, these findings are the first to identify human prostate SPCs as direct PFAS targets with resultant reprogrammed transcriptomes and metabolomes that augment a preneoplastic state and may contribute to an elevated prostate cancer risk with chronic exposures.

Zonal Growth Pattern of the Prostate Is Affected by Age and Body Mass Index.

PURPOSE: As men age, the prostate continues to grow on average 2.5% per year. While the variable growth rate of the total prostate gland is recognized, the growth rate of different prostate zones remains largely unclear. We evaluated the growth patterns of the prostate zones and identified clinical parameters contributing to the zonal growth rates. MATERIALS AND METHODS: Prostate magnetic resonance imaging (MRI) data and clinical information were obtained retrospectively on 156 patients who had at least 3 prostate MRIs between 2003 and 2018. Different prostate zonal volumes were measured and analyzed. The outcome was analyzed using linear regression. RESULTS: We observed that prostate growth rates vary depending on body mass index (BMI), transition zone index (TZI), the prostate zone and 5-alpha reductase inhibitor (5ARI) use. The peripheral zone volume growth rates increased with age and peaked at 60-70 years of age (p=0.047), while the transition zone volume demonstrates continuous growth without a peak through all ages. BMI and TZI are associated with the growth rate of the peripheral zone (p=0.026, p <0.001, respectively) but not the transition zone growth rate. 5ARI use is significantly associated with the reduction in the transition zone growth rate (p=0.033), not the peripheral zone. In addition, patients with TZI greater than 60% had the most significant reduction in the transition zone growth rate while taking 5ARI (p <0.001). CONCLUSIONS: Transition and peripheral zones of the prostate grow at variable rates. BMI and TZI affect peripheral zone growth rate, while 5ARI use reduces the transition zone growth rate.

Enzalutamide-induced and PTH1R-mediated TGFBR2 degradation in osteoblasts confers resistance in prostate cancer bone metastases.

Enzalutamide resistance has been observed in approximately 50% of patients with prostate cancer (PCa) bone metastases. Therefore, there is an urgent need to investigate the mechanisms and develop strategies to overcome resistance. We observed enzalutamide resistance in bone lesion development induced by PCa cells in mouse models. We found that the bone microenvironment was indispensable for enzalutamide resistance because enzalutamide significantly inhibited the growth of subcutaneous C4-2B tumors and the proliferation of C4-2B cells isolated from the bone lesions, and the resistance was recapitulated only when C4-2B cells were co-cultured with osteoblasts. In revealing how osteoblasts contribute to enzalutamide resistance, we found that enzalutamide decreased TGFBR2 protein expression in osteoblasts, which was supported by clinical data. This decrease was possibly through PTH1R-mediated endocytosis. We showed that PTH1R blockade rescued enzalutamide-mediated decrease in TGFBR2 levels and enzalutamide responses in C4-2B cells that were co-cultured with osteoblasts. This is the first study to reveal the contribution of the bone microenvironment to enzalutamide resistance and identify PTH1R as a feasible target to overcome the resistance in PCa bone metastases.

Inhibitory Effect of Astaxanthin on Testosterone-Induced Benign Prostatic Hyperplasia in Rats.

This study investigates the inhibitory effect of astaxanthin (AST) on testosterone-induced benign prostatic hyperplasia (BPH) in rats. Except for the sham operation, BPH model rats were randomly assigned to five groups: the BPH model control rats, AST-treated BPH model rats (20 mg/kg, 40 mg/kg, and 80 mg/kg), and epristeride (EPR)-treated BPH model rats. After treatment, as compared with the BPH model control rats, the prostate and ventral prostate weights of the AST-treated rats decreased, while there was a marked decline in the 80 mg/kg AST-treated rats. The same effect was also observed in the prostate index and ventral prostate index. The proliferation characteristics of epithelia observed in the BPH model control group were gradually alleviated in the AST-treated rats. As compared with the BPH model control rats, lower epithelial thicknesses of prostates and fewer secretory granules in epithelia were observed in the AST-treated rats. The superoxide dismutase (SOD) activity of prostates increased in all the AST-treated rats with a significant increase in the 40 mg/kg and 80 mg/kg AST-treated rats. The testosterone (T) and dihydrotestosterone (DHT) levels of prostates in the AST-treated groups were lower than those in the BPH model control group, and a significant decline was found in the T level of prostates in the 40 g/kg and 80 mg/kg AST-treated rats and the DHT level of prostates in the 40 mg/kg AST-treated rats. These results indicate that AST might have an inhibitory effect on T-induced BPH in rats, possibly due to SOD activity regulation and T and DHT levels.

Clearing-induced tisssue shrinkage: A novel observation of a thickness size effect.

The use of clearing agents has provided new insights in various fields of medical research (developmental biology, neurology) by enabling examination of tissue architecture in 3D. One of the challenges is that clearing agents induce tissue shrinkage and the shrinkage rates reported in the literature are incoherent. Here, we report that for a classical clearing agent, benzyl-alcohol benzyl-benzoate (BABB), the shrinkage decreases significantly with increasing sample size, and present an analytical formula describing this.

Berberine ameliorates testosterone-induced benign prostate hyperplasia in rats.

INTRODUCTION: Benign prostatic hyperplasia (BPH) is a major urologic problem that mostly develops in older males. Oxidative stress and inflammation influence the occurrence of BPH. Berberine (BBR) is a natural ingredient that has antioxidant and anti-inflammatory properties. The current research aims at examining the effects of BBR on testosterone-stimulated BPH in rats. METHODS: Animals were randomly categorized to six groups. In the control group, normal saline and olive oil were injected as the vehicle. BPH group: received testosterone (3 mg/kg, subcutaneous, 28 days), BPH + BBR groups; received BBR (25 and 50 mg/kg, p.o, 28 days), BPH + finasteride groups: received finasteride (1 mg/kg, p.o, 28 days), BBR (50 mg/kg, p.o, alone) was administered for subjects in the BBR group. On the 29th day, after anesthesia, cervical dislocation was used to kill the subjects. Serum concentration of testosterone and dihydrotestosterone was measured and prostate tissues were excised and used for biochemical, inflammation, and histological analysis. RESULTS: BBR prevented increased serum concentrations of testosterone and dihydrotestosterone. BBR considerably reduced BPH-stimulated oxidative stress and inflammation through preventing the rise in lipid peroxidation and nitrite concentration and declined the accumulations of pro-inflammatory cytokines (e.g. interleukin 1ß and tumor necrosis factor α) and declining the depletion rate of GSH and the function of catalase and superoxide dismutase. Histopathological investigations reported that administration of BBR could suppress testosterone-stimulated BPH. CONCLUSION: This study demonstrated that BBR could significantly prevent the development of BPH in rats.