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1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
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
8.
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
9.
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
10.
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
11.
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
12.
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
13.
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
14.
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
16.
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
17.
Gene ; 675: 191-196, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30180965

RESUMO

The prostate gland is one of the last internal organs to deteriorate during human decomposition; however, this phenomenon is still mysterious. Gene expression in antemortem cases has been widely studied and a majority of the analyses concentrate on discovering basic physiological processes. The question of "What happens to gene expression after a human dies?" is a novel and emerging topic. Thanatotranscriptome (thanatos-, Greek for death) involves research on mRNA transcript abundances and gene expression in human tissues after death. Our previous studies have shown that RNA is a suitable and stable molecule in postmortem liver samples up to two days. Consequently, we hypothesized that there are also measurable and significant differences in mRNA transcript abundances in prostate tissues from human remains. In the current study, the goal was to identify apoptotic molecular markers (i.e., pro- and/or anti-apoptosis genes) that provide accurate gene expression profiles regarding the time of death. Tissue samples were removed by a medical examiner from the prostate of five cadavers during autopsy. After RNA extraction, cDNA was synthesized and the concentration was determined. The cDNA was reacted in apoptosis-related gene expression profiling by human PCR Array. The PCR Array results showed that at 38 h after death, a majority of the genes for apoptosis induction and positive regulation (i.e., caspases) were over-expressed more than at five days. The expression of anti-apoptotic genes such as BAG1, BCL2, and negative regulator of apoptosis, XIAP, was significantly elevated in a time-dependent manner. However, pro-apoptotic gene expression such as TP53 and TNFSF10 was not significantly upregulated. Therefore, postmortem prostate cells counteract programmed cell death with its anti-apoptotic machinery; yet as time progresses, pro-apoptotic mechanisms dominate. In conclusion, our study implies that over-expression of genes in male reproductive organs still occurs during decomposition, which may play substantial roles in forensic research and clinical application. These findings demonstrate that there is still active postmortem gene expression; however, our future research question will be, "When does gene expression terminate after death?"


Assuntos
Mudanças Depois da Morte , Próstata/fisiologia , Transcriptoma/genética , Adulto , Idoso , Apoptose/genética , Caspase 2/genética , Cisteína Endopeptidases/genética , Proteínas de Ligação a DNA/genética , Humanos , Masculino , Reação em Cadeia da Polimerase/métodos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ligante Indutor de Apoptose Relacionado a TNF/genética , Fatores de Tempo , Fatores de Transcrição/genética , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
18.
Reprod Domest Anim ; 53 Suppl 2: 70-73, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30238660

RESUMO

Local vessels ultrasonography evaluates prostatic physio-pathologic states. Testosterone promotes tissue and vascular growth. Knowing variables on prostatic vasculature is crucial to correctly apply Pulsed-Wave exam. The study aims to assess how ejaculation and blood testosterone affect Pulsed-Wave indexes. Serial blood testosterone dosages and Pulsed-Wave exams were performed in 20 dogs, immediately before (T0) and after (T1) ejaculation and 6 hr later (T2). Arteria prostatica cranialis, Arteriola capsularis, Arteriola trabecularis and Arteriola parenchimalis were evaluated and mean Pulsatility and Resistivity Index, Systolic-Peak, End-Diastolic and Mean Velocity calculated. Data were grouped by time and vessel (ANOVA, p ≤ 0.05). At T1, Resistivity Index significantly lowered in A. prostatica cranialis, A. trabecularis and A. parenchimalis but grew in A. capsularis; Pulsatility Index had the same pattern, but not significant in A. parenchimalis; Systolic Peak Velocity, End-Diastolic Velocity, Mean Velocity significantly rose in A. capsularis and A. trabecularis. No indexes differed at T0 and T2. Testosterone did not differ at T0 (10.93 ± 7.05 ng/ml), T1 (12.71 ± 7.29) and T2 (10.54 ± 6.63). Results stated the risen prostatic vascular flow postejaculation, affecting Pulsed-Wave. Due to semi-rigid capsule, impairing vasodilation of other vessels, only A. capsularis indexes increased. Intimal cushions of A. prostatica cranialis kept velocities fixed; A. capsularis and A. trabecularis lack of intimal cushions, thus velocities grew. In A. parenchimalis, precapillary sphincters opening allows increased flow redistribution in vasodilated parenchymal bed, keeping velocities fixed. As testosterone, not affected by ejaculation, did not peak, vascular changes are not due to testosterone itself. These physiological effects of ejaculation suggest proper sexual rest before Pulsed-Wave exam planned to explore suspected prostatic neovascularization.


Assuntos
Cães/fisiologia , Ejaculação/fisiologia , Próstata/diagnóstico por imagem , Próstata/fisiologia , Testosterona/sangue , Animais , Velocidade do Fluxo Sanguíneo , Diástole , Masculino , Sístole , Ultrassonografia Doppler/veterinária
19.
J Therm Biol ; 76: 58-67, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30143298

RESUMO

Cryosurgery is a promising novel minimally invasive surgical technique to eradicate carcinoma and non-carcinoma tissues by freezing. In this research, we applied a transient 3D two-phase refrigerant flow model inside the LN2 boiling chamber as well as a bioheat transfer model inside the tissues to evaluate the optimized ablation outcome during prostatic cryosurgery. For the evaluation of the scenarios, a defect function was used that considers non-ablated target tissue (prostate/cancer tissue) as well as ablated healthy tissue, in which the ablated tissue was evaluated using a temperature threshold. Three different configurations using three LN2 cryoprobes were analyzed during the modeling study, and the best configuration with the three LN2 cryoprobes positioned isoscelesly was found. For this configuration, temperature distributions and temperature profiles at specific points within the tissue were investigated numerically. Owing to its low computational cost, the 3D coupled model has an advantage in accurate modeling cryosurgery for curing numerous diseases.


Assuntos
Criocirurgia/instrumentação , Criocirurgia/métodos , Neoplasias da Próstata/terapia , Temperatura Corporal , Humanos , Masculino , Modelos Biológicos , Próstata/fisiologia , Próstata/fisiopatologia , Neoplasias da Próstata/fisiopatologia , Termografia
20.
Int Arch Allergy Immunol ; 177(4): 334-341, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30130757

RESUMO

OBJECTIVES: We explored the association between asthma severity and lower urinary tract symptoms (LUTS) using the International Prostate Symptom Score in a population-based study of males (aged ≥19 years) and evaluated voiding and urine storage symptoms. METHODS: This was a cross-sectional study of 101,848 males, 2,544 of whom had asthma, who participated in the 2011 Korean Community Health Survey. All subjects were assessed in terms of sociodemographic data, pre-existing conditions, and the presence of LUTS. Logistic regression was used to identify risk factors for LUTS in asthmatics. RESULTS: Urine storage symptoms (frequency, urgency, and nocturia) and voiding symptoms (straining, a weak stream, intermittency, and incomplete emptying) were significantly higher in the asthma group than in the non-asthma group (all p < 0.001). Moderate and severe LUTS were significantly more common in the asthma group (moderate, 24.3%; severe, 22.5%) than in the nonasthma group (moderate, 9.5%; severe, 2.9%). Compared to the mild LUTS group, the odds ratio (OR) for asthma was 2.21 (95% confidence interval [CI] 1.99-2.46) in the moderate LUTS group, and 3.04 (95% CI 2.64-3.51) in the severe LUTS group. In a model evaluating multiple variables, the OR for asthma in the moderate LUTS group was 1.95 (95% CI 1.74-2.16) and that in the severe LUTS group was 2.17 (95% CI 1.87-2.53). Asthma was associated with both voiding and storage symptoms. CONCLUSIONS: Male asthma was associated with moderate-to-severe LUTS. More aggressive urological diagnosis and treatment are needed for patients with asthma.


Assuntos
Asma/epidemiologia , Sintomas do Trato Urinário Inferior/epidemiologia , Grupos Populacionais , Próstata/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Humanos , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Projetos de Pesquisa , Risco , Índice de Gravidade de Doença , Adulto Jovem
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