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1.
Prostate ; 81(1): 81-88, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33022763

RESUMO

BACKGROUND: Recent genomic profiling has identified a subtype of prostate cancer (PCa) characterized by two key genetic alterations: missense mutation of speckle-type POZ protein (SPOP) and homozygous deletion of chromodomain helicase DNA-binding protein 1 (CHD1). Mutually exclusive with E26 transformation-specific (ETS) rearrangements, this subtype displays high genomic instability. Previous studies indicate that deficient SPOP or CHD1 alone leads to feeble prostate abnormalities and each protein is involved in DNA damage response (DDR). It remains to be determined whether CHD1 and SPOP cooperate to suppress prostate tumorigenesis and DDR. METHODS: Prostate-specific single or double knockout of Spop and Chd1 was generated with the Cre/loxP system in mice. Wild-type or mutant SPOP (F102C, F133V) overexpression and CHD1 knockdown with short hairpin RNA were created in human benign prostatic hyperplasia cell line BPH1. The levels of DNA damage and homologous recombination repair were measured by immunofluorescence staining of γH2AX and RAD51, respectively. RESULTS: Spop/Chd1 double-knockout mice displayed prostatic intraepithelial neoplasia at both young (3 months) and old (12 months) ages and failed to generate prostate adenocarcinoma. Compared with wild-type or single-knockout mice, the double-knockout prostate harbored moderately higher proliferating cells and dramatically augmented the level of γH2AX staining, although androgen receptor-positive cells and apoptotic cells remained at a similar level. In BPH1 cell line, SPOP mutant overexpression and CHD1 silencing synergistically sensitized the cells to DNA damage by camptothecin, an inducer of double-strand breaks. CONCLUSIONS: Our results indicate that SPOP and CHD1 can synergistically promote repair of naturally occurring or chemically induced DNA damages in prostate epithelial cells. Regarding the progression of the SPOP/CHD1 subtype of PCa, other functionally complementary drivers warrant further identification. The clinical implication is that this subtype of PCa may be particularly sensitive to poly(ADP-ribose) polymerase inhibitors or DNA-damaging agents.


Assuntos
DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Proteínas Nucleares/genética , Próstata/fisiologia , Neoplasias da Próstata/genética , Proteínas Repressoras/genética , Complexos Ubiquitina-Proteína Ligase/genética , Animais , Dano ao DNA , Células Epiteliais/patologia , Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Próstata/patologia , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologia
2.
Science ; 368(6490): 497-505, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32355025

RESUMO

Androgen deprivation is the cornerstone of prostate cancer treatment. It results in involution of the normal gland to ~90% of its original size because of the loss of luminal cells. The prostate regenerates when androgen is restored, a process postulated to involve stem cells. Using single-cell RNA sequencing, we identified a rare luminal population in the mouse prostate that expresses stemlike genes (Sca1 + and Psca +) and a large population of differentiated cells (Nkx3.1 +, Pbsn +). In organoids and in mice, both populations contribute equally to prostate regeneration, partly through androgen-driven expression of growth factors (Nrg2, Rspo3) by mesenchymal cells acting in a paracrine fashion on luminal cells. Analysis of human prostate tissue revealed similar differentiated and stemlike luminal subpopulations that likewise acquire enhanced regenerative potential after androgen ablation. We propose that prostate regeneration is driven by nearly all persisting luminal cells, not just by rare stem cells.


Assuntos
Androgênios/metabolismo , Próstata/fisiologia , Próstata/cirurgia , Neoplasias da Próstata/cirurgia , Regeneração , Antagonistas de Androgênios/uso terapêutico , Proteína de Ligação a Androgênios/genética , Animais , Antígenos de Neoplasias/genética , Ataxina-1/genética , Diferenciação Celular/genética , Proteínas Ligadas por GPI/genética , Expressão Gênica , Proteínas de Homeodomínio/genética , Humanos , Masculino , Células-Tronco Mesenquimais/fisiologia , Camundongos , Proteínas de Neoplasias/genética , Fatores de Crescimento Neural/genética , Tamanho do Órgão , Organoides/metabolismo , Organoides/fisiologia , Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Regeneração/genética , Análise de Sequência de RNA , Análise de Célula Única , Trombospondinas/genética , Fatores de Transcrição/genética
3.
Prostate ; 80(11): 831-849, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32449814

RESUMO

INTRODUCTION: Prostate smooth muscle contraction is critical for etiology and treatment of lower urinary tract symptoms in benign prostatic hyperplasia (BPH). Integrins connect the cytoskeleton to membranes and cells to extracellular matrix, what is essential for force generation in smooth muscle contraction. Integrins are composed of different subunits and may cooperate with integrin-linked kinase (ILK). Here, we examined effects of inhibitors for different integrin heterodimers and ILK on contraction of human prostate tissues. METHODS: Prostate tissues were obtained from radical prostatectomy. Integrins and ILK were detected by Western blot, real-time polymerase chain reaction (RT-PCR), and double fluorescence staining. Smooth muscle contractions of prostate strips were studied in an organ bath. Contractions were compared after application of solvent (controls), the ILK inhibitor Cpd22 (N-methyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide), the integrin α2ß1 inhibitor BTT-3033 (1-(4-fluorophenyl)-N-methyl-N-[4[[(phenylamino)carbonyl]amino]phenyl]-1H-pyrazole-4-sulfonamide), or the integrin α4ß1/α9ß1 inhibitor BOP (N-(benzenesulfonyl)- l-prolyl- l-O-(1-pyrrolidinylcarbonyl)tyrosine sodium salt). RESULTS: Western blot analyses of prostate tissues using antibodies raised against integrins α2b, α4, α9, ß1, and ILK revealed bands matching the expected sizes of corresponding antigens. Expression of integrins and ILK was confirmed by RT-PCR. Individual variations of expression levels occurred independently from divergent degree of BPH, reflected by different contents of prostate-specific antigen. Double fluorescence staining of prostate sections using antibodies raised against integrins α2 and ß1, or against ILK resulted in immunoreactivity colocalizing with calponin, suggesting localization in prostate smooth muscle cells. Electric field stimulation (EFS) induced frequency-dependent contractions, which were inhibited by Cpd22 (3 µM) and BTT-3033 (1 µM) (inhibition around 37% by Cpd22 and 46% by BTT-3033 at 32 Hz). The thromboxane A2 analog U46619-induced concentration-dependent contractions, which were inhibited by Cpd22 and BTT-3033 (around 67% by Cpd22 and 39% by BTT-3033 at 30 µM U46619). Endothelin-1 induced concentration-dependent contractions, which were not affected by Cpd22 or BTT-3033. Noradrenaline and the α1 -adrenergic agonists methoxamine and phenylephrine-induced concentration-dependent contractions, which were not or very slightly inhibited by Cpd22 and BTT-3033. BOP did not change EFS- or agonist-induced contraction. CONCLUSIONS: Integrin α2ß1 and ILK inhibitors inhibit neurogenic and thromboxane A2 -induced prostate smooth muscle contraction in human BPH. A role for these targets for prostate smooth muscle contraction may appear possible.


Assuntos
Integrina alfa2beta1/antagonistas & inibidores , Músculo Liso/efeitos dos fármacos , Próstata/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Dipeptídeos/farmacologia , Humanos , Masculino , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Músculo Liso/metabolismo , Músculo Liso/fisiologia , Piperazinas/farmacologia , Próstata/metabolismo , Próstata/fisiologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Sulfonas/farmacologia , Tromboxano A2/metabolismo , Vasoconstritores/farmacologia
4.
Nihon Yakurigaku Zasshi ; 155(2): 74-79, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32115481

RESUMO

Recently, hydrogen sulfide (H2S) has been recognized as the third gasotransmitter besides nitric oxide and carbon monoxide, and it has been reported that H2S exhibits various physiological functions such as neuromodulation and vasorelaxation. In the lower urinary tract (bladder and prostate), it is reported that donors of H2S induce contraction of the rat detrusor and relaxation of the pig bladder neck. These reports suggest a possibility that H2S may have site-specific effects on the bladder. However, the detailed functions of H2S in each part of the bladder are still unclear. In addition, there is no report showing physiological roles of H2S in the prostate. In this article, we will review the distribution of enzymes related to H2S biosynthesis and physiological roles of H2S in the lower urinary tract based on reports from our and other groups. We will also introduce a possibility that H2S can be a new therapeutic target against lower urinary tract symptoms (LUTS) based on our data from spontaneously hypertensive rats (SHRs), which develop hypertension-mediated LUTS.


Assuntos
Sulfeto de Hidrogênio/metabolismo , Próstata/fisiologia , Bexiga Urinária/fisiologia , Animais , Masculino , Ratos , Ratos Endogâmicos SHR , Suínos
5.
Prostate ; 80(6): 471-480, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32049374

RESUMO

BACKGROUND: The shape and function of the longitudinal muscular column (LMC) of the prostate have not been established in detail. The present study was undertaken to elucidate the roles of the LMC of the posterior wall of the prostatic urethra (PSU) in the emission phase of ejaculation by investigating the form and muscular arrangement of the LMC. METHODS: Prostates and urinary bladders were obtained from 14 Korean adult cadavers. Nine specimens were histologically analyzed using hematoxylin and eosin, Masson's trichrome, and Verhoeff-van Gieson staining. Two specimens were scanned using microcomputed tomography (micro-CT), and all scanned images were reconstructed into a three-dimensional model. RESULTS: At the proximal level of the prostate, the ejaculatory ducts (EDs) and prostatic utricle (PU) together were surrounded by circular smooth-muscle fibers. However, at the seminal colliculus (SC) where the EDs and PU opened, they were mainly surrounded by an abundance of longitudinal fibers. The longitudinal fibers posterior to the EDs and PU formed a distinctive LMC in the posterior urethral wall. In histologic sections and micro-CT images, the LMC extended distally from the level of the SC to the level of the membranous urethra (MBU). We simulated a potential mechanism of LMC using a mathematical model of its movements. CONCLUSIONS: Comprehensive analyses based on in-depth assessment of histologic characteristics and micro-CT images demonstrated extension of the LMC from the level of the SC to the level of the MBU, enabling a better understanding of ejaculation physiology involving the LMC. These results suggest that the LMC in the posterior wall of the PSU is a critical component of ejaculation by facilitating the ejection of seminal vesicle fluid into the PSU via well-coordinated contractions.


Assuntos
Ejaculação/fisiologia , Modelos Biológicos , Próstata/anatomia & histologia , Próstata/fisiologia , Idoso , Idoso de 80 Anos ou mais , Cadáver , Elastina/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Anatômicos , Músculo Liso/anatomia & histologia , Músculo Liso/citologia , Músculo Liso/fisiologia , Próstata/citologia , Próstata/diagnóstico por imagem , Uretra/anatomia & histologia , Uretra/citologia , Uretra/fisiologia , Microtomografia por Raio-X/métodos
6.
PLoS Genet ; 16(1): e1008588, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31929563

RESUMO

Prostate embryonic development, pubertal and adult growth, maintenance, and regeneration are regulated through androgen signaling-mediated mesenchymal-epithelial interactions. Specifically, the essential role of mesenchymal androgen signaling in the development of prostate epithelium has been observed for over 30 years. However, the identity of the mesenchymal cells responsible for this paracrine regulation and related mechanisms are still unknown. Here, we provide the first demonstration of an indispensable role of the androgen receptor (AR) in sonic hedgehog (SHH) responsive Gli1-expressing cells, in regulating prostate development, growth, and regeneration. Selective deletion of AR expression in Gli1-expressing cells during embryogenesis disrupts prostatic budding and impairs prostate development and formation. Tissue recombination assays showed that urogenital mesenchyme (UGM) containing AR-deficient mesenchymal Gli1-expressing cells combined with wildtype urogenital epithelium (UGE) failed to develop normal prostate tissue in the presence of androgens, revealing the decisive role of AR in mesenchymal SHH responsive cells in prostate development. Prepubescent deletion of AR expression in Gli1-expressing cells resulted in severe impairment of androgen-induced prostate growth and regeneration. RNA-sequencing analysis showed significant alterations in signaling pathways related to prostate development, stem cells, and organ morphogenesis in AR-deficient Gli1-expressing cells. Among these altered pathways, the transforming growth factor ß1 (TGFß1) pathway was up-regulated in AR-deficient Gli1-expressing cells. We further demonstrated the activation of TGFß1 signaling in AR-deleted prostatic Gli1-expressing cells, which inhibits prostate epithelium growth through paracrine regulation. These data demonstrate a novel role of the AR in the Gli1-expressing cellular niche for regulating prostatic cell fate, morphogenesis, and renewal, and elucidate the mechanism by which mesenchymal androgen-signaling through SHH-responsive cells elicits the growth and regeneration of prostate epithelium.


Assuntos
Proteínas Hedgehog/metabolismo , Morfogênese , Próstata/metabolismo , Receptores Androgênicos/metabolismo , Regeneração , Transdução de Sinais , Animais , Células Cultivadas , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Próstata/citologia , Próstata/crescimento & desenvolvimento , Próstata/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo
7.
Lab Invest ; 100(5): 670-681, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31857695

RESUMO

The normal prostate epithelial structure is maintained by homeostatic interactions with smooth muscle cells. However, structural alterations of the stroma are commonly observed in prostatic proliferative diseases, leading to the abnormalities of prostate epithelial structure. A decrease in the androgen level experimentally induces stromal remodeling, i.e., replacement of smooth muscle cells with fibroblasts or myofibroblasts. In this study, we investigated the effects of castration-induced stromal remodeling and subsequent aberrant activation of epithelial-stromal interactions on the reconstituted human prostate-like epithelial structure. We performed in vivo experiments using the human prostate epithelial cell line BPH-1 and fetal rat urogenital sinus mesenchyme to generate heterotypic tissue recombinants that form human prostate-like epithelial structure (i.e., solid- and canalized-epithelial cords). Host mice were castrated at 12 weeks post transplantation (castration) and implanted with a dihydrotestosterone pellet at 14 days post castration (androgen replacement treatment; ART). In the castration group, the percentages of fibrotic area and disrupted prostate epithelial structure without the basement membrane (BM) increased proportionally in a time-dependent manner, but were suppressed by ART. In the castration group, tenascin-C (TNC)-positive fibroblasts were abundant in the stroma surrounding disrupted prostate epithelial structure without the BM. TGF-ß1 secretion from BPH-1 cells was increased by co-culturing with human primary cultured prostate fibroblasts. TNC mRNA expression was increased in fibroblasts co-culturing with BPH-1 cells and was suppressed by treatment with a TGF-ß RI kinase inhibitor. Moreover, in the castration group, the percentage of p-Smad2-positive cells was significantly higher in the stroma surrounding disrupted prostate epithelial structure without the BM. Our results demonstrate that castration-induced stromal remodeling disrupted the reconstituted human prostate-like epithelial structure and induced the appearance of TNC-positive fibroblasts accompanied by activation of TGF-ß signaling. The alteration of prostate stromal structure may be responsible for loss of the BM and epithelial cell polarity.


Assuntos
Orquiectomia , Próstata , Células Estromais , Animais , Linhagem Celular , Di-Hidrotestosterona/farmacologia , Epitélio/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos SCID , Próstata/citologia , Próstata/efeitos dos fármacos , Próstata/fisiologia , Ratos , Células Estromais/citologia , Células Estromais/fisiologia , Tenascina/genética , Tenascina/metabolismo
8.
Sci Rep ; 9(1): 19192, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844133

RESUMO

Pelvic floor muscles (PFMs) play a crucial role in urinary continence. Therefore, training the PFMs remains the most popular conservative treatment for urinary incontinence (UI). The effect of training other body muscles on the PFMs is unclear and mostly hypothetical. The objective of our study was to evaluate the effectiveness of postoperative diaphragm muscle, abdominal muscle and PFM training on PFM strength (PFMS) and endurance (PFME) as well as on UI in men after radical prostatectomy (RP). Per-protocol PFMS, PFME and urine loss measurements were performed at 1, 3, and 6 months postoperatively. The primary endpoints were PFMS and PFME differences among the study groups. The secondary endpoint was the correlation between UI and PFMS and PFME. In total, 148 men were randomized to the treatment groups. An increase in PFMS and PFME was observed in all groups compared to baseline (p < 0.001). The greatest difference in PFMS was in the PFM training group, but diaphragm training had the best effect on PFME. The highest (from moderate to strong) correlation between UI and PFME and PFMS (r = -0.61 and r = -0.89, respectively) was observed in the diaphragm training group. Despite different but significant effects on PFMS and PFME, all rehabilitation-training programmes decreased UI in men after RP.


Assuntos
Músculos Abdominais/fisiologia , Diafragma/fisiologia , Força Muscular/fisiologia , Músculo Esquelético/fisiologia , Diafragma da Pelve/fisiologia , Idoso , Educação/métodos , Terapia por Exercício/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Próstata/fisiologia , Prostatectomia/métodos , Resultado do Tratamento , Incontinência Urinária/fisiopatologia
9.
Am J Physiol Renal Physiol ; 317(4): F996-F1009, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31390231

RESUMO

Laboratory mice are used to identify causes of urinary dysfunction including prostate-related mechanisms of lower urinary tract symptoms. Effective use of mice for this purpose requires a clear understanding of molecular, cellular, anatomic, and endocrine contributions to voiding function. Whether the prostate influences baseline voiding function has not been specifically evaluated, in part because most methods that alter prostate mass also change circulating testosterone concentrations. We performed void spot assay and cystometry to establish a multiparameter "baseline" of voiding function in intact male and female 9-wk-old (adult) C57BL/6J mice. We then compared voiding function in intact male mice to that of castrated male mice, male (and female) mice treated with the steroid 5α-reductase inhibitor finasteride, or male mice harboring alleles (Pbsn4cre/+; R26RDta/+) that significantly reduce prostate lobe mass by depleting prostatic luminal epithelial cells. We evaluated aging-related changes in male urinary voiding. We also treated intact male, castrate male, and female mice with exogenous testosterone to determine the influence of androgen on voiding function. The three methods used to reduce prostate mass (castration, finasteride, and Pbsn4cre/+; R26RDta/+) changed voiding function from baseline but in a nonuniform manner. Castration feminized some aspects of male urinary physiology (making them more like intact female mice) while exogenous testosterone masculinized some aspects of female urinary physiology (making them more like intact male mice). Our results provide evidence that circulating testosterone is responsible in part for baseline sex differences in C57BL/6J mouse voiding function while prostate lobe mass in young, healthy adult mice has a lesser influence.


Assuntos
Androgênios/fisiologia , Próstata/anatomia & histologia , Próstata/fisiologia , Fenômenos Fisiológicos do Sistema Urinário , Inibidores de 5-alfa Redutase/farmacologia , Envelhecimento , Animais , Células Epiteliais/fisiologia , Feminino , Finasterida/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Orquiectomia , Próstata/citologia , Caracteres Sexuais , Testosterona/farmacologia , Fenômenos Fisiológicos do Sistema Urinário/efeitos dos fármacos , Fenômenos Fisiológicos do Sistema Urinário/genética , Urodinâmica
10.
Med Phys ; 46(7): 3034-3043, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31049993

RESUMO

PURPOSE: Assessment of urethral dynamics is clinically regarded to be important in analyzing the functional impact of pathological features like urethral obstruction, albeit it is difficult to perform directly in vivo. To facilitate such an assessment, urethra phantoms may serve well as investigative tools by reconstructing urethral dynamics based on anthropomorphic factors. Here, our aim is to design a new class of anatomically realistic, deformable urethra phantoms that can simulate the geometric, mechanical, and hydrodynamic characteristics of the male prostatic urethra. METHODS: A new lost-core tube casting protocol was devised. It first involved the drafting of urethra geometry in computer-aided design software. Next, 3D printing was used to fabricate the urethra geometry and an outer mold. These parts were then used to cast a urinary tract using a polyvinyl alcohol (PVA)-based material (with 26.6 ± 4.0 kPa Young's elastic modulus). After forming a surrounding tissue-mimicking slab using an agar-gelatin mixture (with 17.4 ± 3.4 kPa Young's modulus), the completed urethra phantom was connected to a flow circuit that simulates voiding. To assess the fabricated phantoms' morphology, ultrasound imaging was performed over different planes. Also, color Doppler imaging was performed to visualize the flow profile within the urinary tract. RESULTS: Deformable phantoms were devised for the normal urethra and a diseased urethra with obstruction due to benign prostatic hyperplasia (BPH). During voiding, the short-axis lumen diameter at the verumontanum of the BPH-featured phantom (0.91 ± 0.08 mm) was significantly smaller than that for the normal phantom (2.49 ± 0.20 mm). Also, the maximum flow velocity of the BPH-featured phantom (59.3 ± 5.8 cm/s; without Doppler angle correction) was found to be higher than that of the normal phantom (22.7 ± 9.0 cm/s). CONCLUSION: The fabricated phantoms were effective in simulating urethra deformation resulting from urine passage during voiding. They can be used for mechanistic studies of urethral dynamics and for the testing of urodynamic diagnostic techniques in urology.


Assuntos
Imagens de Fantasmas , Próstata/fisiologia , Urodinâmica , Fenômenos Biomecânicos , Humanos , Masculino , Próstata/diagnóstico por imagem , Próstata/fisiopatologia , Hiperplasia Prostática/diagnóstico por imagem , Hiperplasia Prostática/patologia , Hiperplasia Prostática/fisiopatologia , Ultrassonografia , Uretra/diagnóstico por imagem , Uretra/patologia , Uretra/fisiopatologia , Sistema Urinário/anatomia & histologia , Sistema Urinário/diagnóstico por imagem , Sistema Urinário/patologia
11.
Chemotherapy ; 64(1): 8-16, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31112957

RESUMO

BACKGROUND: Mounting worldwide resistance trends make the use of fluoroquinolone (FQ) antibacterial agents increasingly difficult. This is felt more acutely in the case of urogenital infections, which are mainly caused by Gram-negative pathogens. For years, levofloxacin and other FQs have been the first-line drugs for treating National Institutes of Health (NIH) category II chronic bacteria prostatitis (CBP). Eradication rates achieved by levofloxacin in the frame of randomized trials vary greatly, ranging between 71 and 86%. OBJECTIVES: This was a retrospective observational study to investigate the efficacy of levofloxacin against CBP in a real-life setting (urological outpatient wards). METHODS: A database including the clinical records of >2,500 CBP patients was reviewed. Patients were selected based on strict inclusion criteria. They were treated for 4 weeks with 500 mg levofloxacin per day, alone or combined with other antibacterials. Besides standard urological procedures including the 4-glass test for pathogen isolation, international symptom questionnaires (the NIH Chronic Prostatitis Symptom Index [NIH-CPSI] and International Prostate Symptom Score [IPSS]) were administered. RESULTS: Pathogen eradication was achieved in 79% of the cases treated with levofloxacin as a single agent and 87.8% of patients who received a combination of levofloxacin and azithromycin. The 11% increase in the eradication rate in the latter group is statistically significant. In addition, the levofloxacin-azithromycin combination caused a significant decrease in prostate volume and significantly increased the bladder-voided volume. IPSS and NIH-CPSI values and the urinary peak flow rate decreased to a similar extent in both treatment groups. No adverse effects were reported by patients belonging to either treatment group. CONCLUSION: Levofloxacin retained its therapeutic efficacy in patients assessed in a real-life setting, and high eradication rates were attained when it was administered as a single agent. A combination of an FQ with azithromycin induced a significant improvement of eradication rates. This strategy may be an interesting option in both first-referral and relapsing cases, although caution should be exercised when patients are at risk of developing arrhythmias, tendinitis, or other adverse effects.


Assuntos
Antibacterianos/uso terapêutico , Levofloxacino/uso terapêutico , Prostatite/tratamento farmacológico , Adulto , Idoso , Antibacterianos/farmacologia , Azitromicina/farmacologia , Azitromicina/uso terapêutico , Candida albicans/efeitos dos fármacos , Candida albicans/isolamento & purificação , Quimioterapia Combinada , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/isolamento & purificação , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/isolamento & purificação , Humanos , Levofloxacino/farmacologia , Masculino , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Próstata/fisiologia , Antígeno Prostático Específico/sangue , Prostatite/diagnóstico , Estudos Retrospectivos , Resultado do Tratamento , Estados Unidos , Adulto Jovem
12.
Reprod Domest Anim ; 54(8): 1064-1068, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31095788

RESUMO

Current knowledge about the composition of the prostate fluid in healthy male dogs is limited and restricted to small case numbers. Furthermore, published data often vary significantly regarding sample processing and analytical methods. Therefore, we aimed to provide data on the composition of electrolytes and minerals in the canine prostatic fluid in a larger population (n = 30 dogs/samples) and to compare these results with the existing literature. Concentrations of sodium, potassium and copper analysed in our population were most consistent with those in the literature. Different to this, concentrations of total calcium, magnesium, zinc and inorganic phosphate varied. Whereas magnesium, zinc and inorganic phosphate seemed to depend on the analysis method, total calcium concentrations differed if centrifugation was performed or not. Our results clearly indicate a need for standardization of methods for analysis of seminal plasma components.


Assuntos
Cães/fisiologia , Eletrólitos/química , Minerais/química , Próstata/fisiologia , Sêmen/química , Animais , Masculino , Sêmen/fisiologia
13.
J Cancer Res Ther ; 15(Supplement): S69-S75, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30900624

RESUMO

Purpose: Prostate motion during the radiotherapy course is an important issue. This study investigated the inter-fraction prostate motion in controlled rectal filling condition. Methods: 10 prostate cancer patients underwent image-guided radiotherapy (IGRT) using a cone-beam computed tomography (CBCT) system, after the insertion of fiducial markers (FMs). The planning CT was the reference CT (CTref) used to estimate the reference intermarker distances, and CBCTs were used for off-line comparison with CTref. We evaluated the influence of rectal and bladder volume on prostate shifts. We calculated the required planning target volume (PTV) margins in this patient population. Results: 120 CBCTs were analyzed. Mean prostate displacements (± SD) along the 3 axes (x, y, z) averaged over the 10 patients, were: 0.90 ± 0.84 mm in x, 0.00 ± 2.07 mm in y, -0.80 ± 1.28 mm in z. There is a statistically significant anti-correlation between prostate displacements and: bladder volume variations (P < 0.001) in the y-axis, and rectal volume variations (P < 0.05) in the z-axis. PTV margins obtained for the directions x, y and z are respectively 2.5, 5.6 and 3.9 mm. Conclusion: IGRT in reproducible empty rectum condition allow a high reduction of daily treatment uncertainties.


Assuntos
Próstata/fisiologia , Neoplasias da Próstata/radioterapia , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia Guiada por Imagem/métodos , Tomografia Computadorizada de Feixe Cônico/instrumentação , Tomografia Computadorizada de Feixe Cônico/métodos , Marcadores Fiduciais , Humanos , Masculino , Movimento/fisiologia , Tamanho do Órgão , Próstata/diagnóstico por imagem , Próstata/efeitos da radiação , Planejamento da Radioterapia Assistida por Computador/instrumentação , Radioterapia Guiada por Imagem/instrumentação , Reto/anatomia & histologia , Reto/diagnóstico por imagem , Bexiga Urinária/anatomia & histologia , Bexiga Urinária/diagnóstico por imagem
14.
Differentiation ; 107: 1-10, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30927641

RESUMO

Androgen signaling is essential for prostate development, morphogenesis, and regeneration. Emerging evidence also indicates a regulatory role of Notch signaling in prostate development, differentiation, and growth. However, the collaborative regulatory mechanisms of androgen and Notch signaling during prostate development, growth, and regeneration are largely unknown. Hairy and Enhancer of Split 1 (Hes1) is a transcriptional regulator of Notch signaling pathways, and its expression is responsive to Notch signaling. Hes1-expressing cells have been shown to possess the regenerative capability to repopulate a variety of adult tissues. In this study, we developed new mouse models to directly assess the role of the androgen receptor in prostatic Hes1-expressing cells. Selective deletion of AR expression in embryonic Hes1-expressing cells impeded early prostate development both in vivo and in tissue xenograft experiments. Prepubescent deletion of AR expression in Hes1-expressing cells resulted in prostate glands containing abnormalities in cell morphology and gland architecture. A population of castration-resistant Hes1-expressing cells was revealed in the adult prostate, with the ability to repopulate prostate epithelium following androgen supplementation. Deletion of AR in Hes1-expressing cells diminishes their regenerative ability. These lines of evidence demonstrate a critical role for the AR in Notch-responsive cells during the course of prostate development, morphogenesis, and regeneration, and implicate a mechanism underlying interaction between the androgen and Notch signaling pathways in the mouse prostate.


Assuntos
Próstata/fisiologia , Receptores Notch/metabolismo , Regeneração , Fatores de Transcrição HES-1 , Androgênios/metabolismo , Animais , Masculino , Camundongos , Modelos Animais , Próstata/embriologia , Receptores Androgênicos/metabolismo , Transdução de Sinais , Fatores de Transcrição HES-1/biossíntese , Fatores de Transcrição HES-1/genética
15.
J Vis Exp ; (143)2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30735176

RESUMO

This paper describes a detailed protocol for three-dimensional (3D) culturing, handling, and evaluation of human primary prostate organoids. The process involves seeding of epithelial cells sparsely in a 3D matrix gel on a 96-well microplate with media changes to cultivate expansion into organoids. Morphology is then assessed by whole-well capturing of z-stack images. Compression of z-stacks creates a single in-focus image from which organoids are measured to quantify a variety of outputs, including circularity, roundness, and area.DNA, RNA, and protein can be collected from organoids recovered from the matrix gel. Cell populations of interest can be assessed by organoid dissociation and flow cytometry. Formalin-fixation-paraffin-embedding (FFPE) followed by sectioning is used for the histological assessment and antibody staining. Whole-mount immunofluorescent staining preserves organoid morphology and facilitates observation of protein localization in organoids in situ. Commercial assays that are traditionally used for 2D monolayer cells can be modified for 3D organoids. Used together, the techniques in this protocol provide a robust toolbox to quantify prostate organoid growth, morphologic characteristics, and expression of differentiation markers.


Assuntos
Organoides/fisiologia , Próstata/fisiologia , Técnicas de Cultura de Tecidos/métodos , Células Epiteliais/citologia , Humanos , Masculino
16.
Prostate ; 79(2): 115-125, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30225866

RESUMO

BACKGROUND: Direct mechanical characterization of tissue is the application of engineering techniques to biological tissue to ascertain stiffness or elasticity, which can change in response to disease states. A number of papers have been published on the application of these techniques to prostate tissue with a range of results reported. There is a marked variability in the results depending on testing techniques and disease state of the prostate tissue. We aimed to clarify the utility of direct mechanical characterization of prostate tissue in identifying disease states. METHODS: A systematic review of the published literature regarding direct mechanical characterization of prostate tissue was undertaking according to PRISMA guidelines. RESULTS: A variety of testing methods have been used, including compression, indentation, and tensile testing, as well as some indirect testing techniques, such as shear-wave elastography. There is strong evidence of significant stiffness differences between cancerous and non-cancerous prostate tissue, as well as correlations with prostate cancer stage. There is a correlation with increasing prostate stiffness and increasing lower urinary tract symptoms in patients with benign prostate hyperplasia. There is a wide variation in the testing methods and protocols used in the literature making direct comparison between papers difficult. Most studies utilise ex-vivo or cadaveric tissue, while none incorporate in vivo testing. CONCLUSION: Direct mechanical assessment of prostate tissue permits a better understanding of the pathological and physiological changes that are occurring within the tissue. Further work is needed to include prospective and in vivo data to aid medical device design and investigate non-surgical methods of managing prostate disease.


Assuntos
Próstata/citologia , Neoplasias da Próstata/patologia , Fenômenos Biomecânicos , Humanos , Masculino , Próstata/fisiologia , Neoplasias da Próstata/fisiopatologia
17.
J Ethnopharmacol ; 233: 115-122, 2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-30508623

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ulmus macrocarpa Hance (UMH), of the family Ulmaceae, is a deciduous tree, widely distributed throughout Korea. UMH has been used as a traditional oriental medicine in Korea for the treatment of urological disorders, including bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), diuresis, and hematuria. To date, its possible protective effects against benign prostatic hyperplasia (BPH) have not been analyzed. AIM OF THE STUDY: This study investigated the effects of UMH on the development of BPH using a rat model of testosterone propionate (TP)-induced BPH. MATERIALS AND METHODS: BPH was induced by daily subcutaneous injections of testosterone propionate (TP) for four weeks. UMH was administrated daily by oral gavage at a dose of 150 mg/kg during the four weeks of TP injections. Animals were sacrificed, and their prostates were weighed and subjected to histopathological examination, TUNEL assay, and western blot analysis. RESULTS: Treatment of BPH-model rats with UMH significantly reduced prostate weight, serum testosterone concentration and dihydrotestosterone (DHT) concentration in prostate tissue. TP-induced prostatic hyperplasia and the expression of proliferating cell nuclear antigen (PCNA) were significantly attenuated in UMH-treated rats. In addition, UMH administration markedly induced the activation of caspases-3, - 8, and - 9 in prostate tissues of BPH rats, accompanied by upregulation of expression of Fas, Fas-associated protein with death domain (FADD), and Fas ligand (FasL) and a reduction in the ratio of B-cell lymphoma 2 (Bcl-2) to Bcl-2-associated X protein (Bax). CONCLUSIONS: UMH effectively inhibited the proliferation and promoted the apoptosis of prostate cells, suggesting it may be useful for the treatment of BPH.


Assuntos
Extratos Vegetais/uso terapêutico , Hiperplasia Prostática/tratamento farmacológico , Ulmus , Animais , Apoptose/efeitos dos fármacos , Di-Hidrotestosterona/metabolismo , Masculino , Fitoterapia , Extratos Vegetais/farmacologia , Próstata/efeitos dos fármacos , Próstata/patologia , Próstata/fisiologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Ratos Sprague-Dawley , Testosterona/sangue , Propionato de Testosterona
18.
Prostate ; 79(2): 183-194, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30298636

RESUMO

BACKGROUND: Serum folate concentrations in the United States have risen since dietary folic acid fortification was first mandated in 1998. Although maternal folic acid offers protection against neural tube defects in conceptuses, its impact on other organ systems and life stages have not been fully examined. Here, we used a mouse model to investigate the impact of a Folic acid (FA) enriched diet on prostate homeostasis and response to androgen deprivation. METHODS: Male mice were fed a control diet (4 mg FA/kg feed) or a folic acid supplemented diet (24 mg FA/kg feed) beginning at conception and continuing through early adulthood, when mice were castrated. RESULTS: We made the surprising observation that dietary FA supplementation confers partial resistance to castration-mediated prostate involution. At 3, 10, and 14 days post-castration, FA enriched diet fed mice had larger prostates as assessed by wet weight, taller prostatic luminal epithelial cells, and more abundant RNAs encoding prostate secretory proteins than castrated control diet fed mice. Diet did not significantly affect prostate weights of intact mice or serum testosterone concentrations of castrated mice. RNA-Seq analysis revealed that the FA enriched diet was associated with a unique prostate gene expression signature, affecting several signaling and metabolic pathways. CONCLUSIONS: Continuous exposure to a FA enriched diet slows prostate involution in response to androgen deprivation. Prostates from FA diet mice have increased secretory gene expression and increased luminal cell heights. The influence of dietary FA supplementation on the prostate response to androgen deprivation raises a future need to consider how dietary folic acid supplementation affects efficacy of androgen-reducing therapies for treating prostate disease.


Assuntos
Androgênios/deficiência , Ácido Fólico/administração & dosagem , Próstata/efeitos dos fármacos , Androgênios/sangue , Animais , Castração , Suplementos Nutricionais , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Próstata/anatomia & histologia , Próstata/fisiologia , Receptores Androgênicos/biossíntese , Testosterona/sangue
19.
J Cell Physiol ; 234(5): 6886-6897, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30362535

RESUMO

Androgens induce rat prostate induction from the urogenital sinus epithelium at embryonic day 17.5. Subsequent morphogenesis, including epithelial cord growth, branching, and canalization, results from concerted paracrine interactions with the stroma. A significant number of paracrine factors bind heparan sulfate (HS). We hypothesized that interfering with overall sulfation could disrupt the signaling mediated by HS-binding factors and that the undersulfated environment would allow investigation of individual exogenous morphogens. First, we investigated whether acinar morphogenesis involved HS-proteoglycan expression and found that syndecans 1 and 3 were upregulated in RWPE1 cells in the transition from two- to three-dimensional (3D) Matrigel, capable of promoting spheroid formation. We then investigated whether sodium chlorate, a general sulfation inhibitor, interfered with spheroid formation by RWPE1 cells and acinar morphogenesis in ex vivo ventral prostate (VP) organ culture. As expected, treatment with sodium chlorate inhibited spheroid formation by RWPE1 cells in 3D culture. Chlorate also inhibited ex vivo VP epithelial branching and canalization, resulting in long branchless epithelial structures. We then investigated whether the HS-binding factors, FGF10, TGFß1, and SDF1, could reverse the effect of sodium chlorate. Although no effect was seen in the FGF10- and TGFß1-treated samples, SDF1 promoted epithelial canalization in the low sulfated environment, highlighting its specific role in lumen formation. Altogether, the results show that sodium chlorate perturbed prostate morphogenesis and allowed investigation of factors involved in branching and/or canalization, implicating SDF1 signaling in epithelial canalization.


Assuntos
Quimiocina CXCL12/metabolismo , Células Epiteliais/metabolismo , Morfogênese/fisiologia , Próstata/metabolismo , Próstata/fisiologia , Animais , Linhagem Celular , Colágeno/metabolismo , Combinação de Medicamentos , Células Epiteliais/fisiologia , Epitélio/metabolismo , Epitélio/fisiologia , Fator 10 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteoglicanas de Heparan Sulfato/metabolismo , Heparitina Sulfato/metabolismo , Humanos , Laminina/metabolismo , Masculino , Técnicas de Cultura de Órgãos/métodos , Organogênese/fisiologia , Proteoglicanas/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta1/metabolismo
20.
Clin Sci (Lond) ; 132(20): 2189-2205, 2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-30279228

RESUMO

To investigate the effect of blebbistatin (BLEB, a selective myosin inhibitor) on regulating contractility and growth of prostate cells and to provide insight into possible mechanisms associated with these actions. BLEB was incubated with cell lines of BPH-1 and WPMY-1, and intraprostatically injected into rats. Cell growth was determined by flow cytometry, and in vitro organ bath studies were performed to explore muscle contractility. Smooth muscle (SM) myosin isoform (SM1/2, SM-A/B, and LC17a/b) expression was determined via competitive reverse transcriptase PCR. SM myosin heavy chain (MHC), non-muscle (NM) MHC isoforms (NMMHC-A and NMMHC-B), and proteins related to cell apoptosis were further analyzed via Western blotting. Masson's trichrome staining was applied to tissue sections. BLEB could dose-dependently trigger apoptosis and retard the growth of BPH-1 and WPMY-1. Consistent with in vitro effect, administration of BLEB to the prostate could decrease rat prostatic epithelial and SM cells via increased apoptosis. Western blotting confirmed the effects of BLEB on inducing apoptosis through a mechanism involving MLC20 dephosphorylation with down-regulation of Bcl-2 and up-regulation of BAX and cleaved caspase 3. Meanwhile, NMMHC-A and NMMHC-B, the downstream proteins of MLC20, were found significantly attenuated in BPH-1 and WPMY-1 cells, as well as rat prostate tissues. Additionally, BLEB decreased SM cell number and SM MHC expression, along with attenuated phenylephrine-induced contraction and altered prostate SMM isoform composition with up-regulation of SM-B and down-regulation of LC17a, favoring a faster contraction. Our novel data demonstrate BLEB regulated myosin expression and functional activity. The mechanism involved MLC20 dephosphorylation and altered SMM isoform composition.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Miosina Tipo II/metabolismo , Próstata/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Músculo Liso/fisiologia , Miosina Tipo II/genética , Próstata/citologia , Próstata/fisiologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética
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