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1.
Med Sci Monit ; 27: e929913, 2021 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-33556045

RESUMO

BACKGROUND Two diagnostic models of prostate cancer (PCa) and clinically significant prostate cancer (CS-PCa) were established using clinical data of among patients whose prostate-specific antigen (PSA) levels are in the gray area (4.0-10.0 ng/ml). MATERIAL AND METHODS Data from 181 patients whose PSA levels were in the gray area were retrospectively analyzed, and the following data were collected: age, digital rectal examination, total PSA, PSA density (PSAD), free/total PSA (f/t PSA), transrectal ultrasound, multiparametric magnetic resonance imaging (mpMRI), and pathological reports. Patients were diagnosed with benign prostatic hyperplasia (BPH) and PCa by pathology reports, and PCa patients were separated into non-clinically significant PCa (NCS-PCa) and CS-PCa by Gleason score. Afterward, predictor models constructed by above parameters were researched to diagnose PCa and CS-PCa, respectively. RESULTS According to the analysis of included clinical data, there were 109 patients with BPH, 44 patients with NCS-PCa, and 28 patients with CS-PCa. Regression analysis showed PCa was correlated with f/t PSA, PSAD, and mpMRI (P<0.01), and CS-PCa was correlated with PSAD and mpMRI (P<0.01). The area under the receiver operating characteristic curves of 2 models for PCa (sensitivity=73.64%, specificity=64.23%) and for CS-PCa (sensitivity=71.41%, specificity=81.82%) were 0.79 and 0.87, respectively. CONCLUSIONS The prediction models had satisfactory diagnostic value for PCa and CS-PCa among patients with PSA in the gray area, and use of these models may help reduce overdiagnosis.


Assuntos
Calicreínas/sangue , Modelos Estatísticos , Antígeno Prostático Específico/sangue , Hiperplasia Prostática/diagnóstico , Neoplasias da Próstata/diagnóstico , Fatores Etários , Idoso , Biópsia/estatística & dados numéricos , Diagnóstico Diferencial , Exame Retal Digital/estatística & dados numéricos , Humanos , Masculino , Sobremedicalização/prevenção & controle , Imageamento por Ressonância Magnética Multiparamétrica/estatística & dados numéricos , Gradação de Tumores , Próstata/diagnóstico por imagem , Próstata/patologia , Hiperplasia Prostática/sangue , Hiperplasia Prostática/patologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Curva ROC , Valores de Referência , Estudos Retrospectivos , Medição de Risco/métodos , Ultrassonografia/estatística & dados numéricos
2.
Toxicol Appl Pharmacol ; 411: 115384, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33359661

RESUMO

Benign prostatic hyperplasia (BPH) is an age-related disease in men. Mesenchymal /stromal and epithelial cells interactions are essential to prostate functions. In this study, human nonmalignant prostate epithelial RWPE-1 cells were cocultured with testosterone (TE) -exposed prostate stromal fibroblasts WPMY-1 cells (TE-WPMY-1). The survival rate, epithelial-mesenchymal transition (EMT) and collagen deposition of RWPE-1 were observed. The expression profiles of circRNAs, lncRNAs and mRNAs in WPMY-1-derived exosome-like vesicles (WPMY-1-exo) were explored by high-throughput RNA sequencing. Firstly, both TE-WPMY-1 and TE-WPMY-1-exo significantly promoted RWPE-1 cells proliferation. Secondly, 41 circRNAs, 132 lncRNAs and 1057 mRNAs were differentially expressed (DE) between TE-WPMY-1-exo and the control. Functional enrichment analyses, co-expression analyses and quantitative real-time PCR verification showed that the DE RNAs played important roles in cell proliferation, structure, phenotype and fibrosis. Lastly, blocking WPMY-1-exo biogenesis/release by GW4869 can attenuate TE-WPMY-1-stimulated RWPE-1 cells EMT and collagen deposition. Taken together, our results indicated that WPMY-1-exo modulated the phenotypes changes and collagen deposition of prostate epithelial cells. It provided a novel basis for understanding the underlying mechanisms of RWPE-1 cells EMT and fibrosis induced by WPMY-1 in BPH.


Assuntos
Proliferação de Células , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal , Exossomos/metabolismo , Comunicação Parácrina , Próstata/metabolismo , Hiperplasia Prostática/metabolismo , Células Estromais/metabolismo , Linhagem Celular , Técnicas de Cocultura , Colágeno/metabolismo , Células Epiteliais/patologia , Exossomos/efeitos dos fármacos , Exossomos/genética , Exossomos/patologia , Fibrose , Redes Reguladoras de Genes , Humanos , Masculino , Fenótipo , Próstata/efeitos dos fármacos , Próstata/patologia , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , RNA Circular/genética , RNA Circular/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Estromais/efeitos dos fármacos , Células Estromais/patologia , Testosterona/farmacologia , Transcriptoma
4.
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
5.
Life Sci ; 266: 118924, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33352172

RESUMO

AIMS: We investigated the therapeutic effects of losartan, an angiotensin II type 1 receptor blocker, on prostatic hyperplasia in spontaneously hypertensive rats (SHRs). MAIN METHODS: Male SHRs (age, 36 weeks) were perorally treated with losartan (3 or 10 mg·kg-1) or vehicle once daily for 18 weeks. Age-matched Wistar Kyoto rats (WKYs) were used as vehicle-treated controls (n = 8). The effects of losartan were evaluated by analyzing prostate weight, blood pressure, and prostatic blood flow. The tissue malondialdehyde (MDA), interleukin-6 (IL-6), and basic fibroblast growth factor (bFGF) levels were measured. Histological analysis for the ventral prostate involved hematoxylin and eosin staining and TdT-mediated dUTP nick-end labeling (TUNEL) assay. KEY FINDINGS: Compared to the vehicle-treated WKYs, the vehicle-treated SHRs had significantly higher prostate weight, prostate weight/body weight ratio (PBR), blood pressure, glandular epithelial area, and tissue MDA, IL-6, and bFGF levels in the ventral prostate and lower prostatic blood flow. Treatment with losartan caused significant recovery of blood flow and decreased PBR and glandular epithelial area as well as tissue MDA, IL-6, and bFGF levels in the SHR ventral prostate without affecting blood pressure. High-dose losartan significantly decreased blood pressure and increased TUNEL-positive cells in the ventral prostate in SHRs. SIGNIFICANCE: Chronic losartan treatment could ameliorate prostatic hyperplasia via recovery of reduced prostatic blood flow and induction of apoptosis in the ventral prostate in SHRs. Losartan might have therapeutic effects on not only hypertension but also prostatic hyperplasia in humans.


Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão/complicações , Losartan/farmacologia , Hiperplasia Prostática/tratamento farmacológico , Animais , Pressão Sanguínea , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo , Hiperplasia Prostática/etiologia , Hiperplasia Prostática/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
6.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33334082

RESUMO

Cornus officinalis, widely used in traditional Chinese medicine, exhibits pharmacological effects against erectile dysfunction and pollakisuria, which are pathological symptoms of benign prostatic hyperplasia (BPH). Although traditional usage and a study on BPH have been reported, to our knowledge, no study has investigated the exact molecular mechanism(s) underlying the anti-proliferative effects of standardized C. officinalis on prostatic cells. We standardized C. officinalis 30% ethanol extract (COFE) and demonstrated the therapeutic effects of COFE on human BPH epithelial cells and testosterone-induced BPH in rats. In vitro studies using BPH-1 cells demonstrated an upregulation of BPH-related and E2F Transcription Factor 1(E2F1)-dependent cell cycle markers, whereas treatment with COFE clearly inhibited the proliferation of BPH epithelial cells and reduced the overexpression of G1 and S checkpoint genes. Additionally, COFE administration alleviated the androgen-dependent prostatic enlargement in a testosterone-induced BPH animal model. COFE exerted these anti-BPH effects by the inhibition of anti-apoptotic markers, suppression of PCNA expression, and regulation of E2F1/pRB-dependent cell cycle markers in rats with BPH. These results suggest that COFE exerts anti-proliferative effect by regulating PCNA/E2F1-dependent cell cycle signaling pathway both in vivo and in vitro. These findings reveal the therapeutic potential of COFE, which could be used as a substitute for BPH treatment.


Assuntos
Cornus/química , Fator de Transcrição E2F1/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Extratos Vegetais/farmacologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Próstata/metabolismo , Androgênios/metabolismo , Animais , Biomarcadores , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Humanos , Masculino , Extratos Vegetais/química , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/etiologia , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Testosterona/metabolismo , Testosterona/farmacologia
7.
Life Sci ; 260: 118414, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32926929

RESUMO

AIM: To investigate the possible modulatory effect of febuxostat in testosterone-induced benign prostatic hyperplasia (BPH) in rats with emphasis on xanthine oxidase (XO)/Janus Kinases (JAK)/signal transducer and activator of transcription (STAT) axis. MAIN METHODS: Male Wistar rats were treated with testosterone with/out febuxostat. Effect of febuxostat on BPH was assessed at the structural level by histopathology and determination of prostate weight/index. Cyclin D1 protein expression was assessed immunohistochemically and the ratio of Bax/Bcl-2 mRNA expression was determined by real time polymerase chain reaction analysis (RT-PCR). Besides, uric acid serum level was determined colorimetrically. Prostatic XO activity, as well as oxidative stress and inflammatory markers were evaluated. Additionally, western blot analysis was performed for determination of JAK-1 and phosphorylated form of STAT-3 expression in tissues. KEY FINDINGS: Results revealed that febuxostat inhibited the increase in prostatic weight and index compared to testosterone-treated group. Additionally, febuxostat ameliorated testosterone-induced histopathological changes, prevented the rise in cyclin D1 expression and enhanced Bax/Bcl2 ratio. Febuxostat suppressed testosterone induced- increase in XO activity in prostates and serum level of uric acid. Moreover, it regulated oxidative stress markers including; malondialdehyde (MDA), superoxide dismutase (SOD) activity and glutathione (GSH) content. Also, it inhibited the increase in prostate contents of interleukin-6 (IL-6), interleukin-1ß (IL-1 ß), tumor necrosis factor (TNF-α) and nuclear factor (NF-κB). Interestingly, febuxostat markedly reduced JAK-1 and subsequent phosphorylation of STAT-3 protein expression. SIGNIFICANCE: Febuxostat ameliorates testosterone-induced BPH via suppressing XO/JAK/STAT axis. This may help to re-purpose the use of XO inhibitors.


Assuntos
Febuxostat/farmacologia , Regulação Neoplásica da Expressão Gênica/genética , Supressores da Gota/farmacologia , Janus Quinase 1/metabolismo , Hiperplasia Prostática/tratamento farmacológico , Fator de Transcrição STAT3/metabolismo , Testosterona/toxicidade , Androgênios/toxicidade , Animais , Janus Quinase 1/genética , Masculino , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Ratos , Ratos Wistar , Fator de Transcrição STAT3/genética
8.
Life Sci ; 259: 118380, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32898524

RESUMO

AIMS: Benign prostatic hyperplasia (BPH) is a progressive disease, which severely affects men's health. Here, we sought to analyze the functions and mechanism of action of the tripartite motif protein 52 (TRIM52), a novel prostate basal cell biomarker in BPH. MATERIALS AND METHODS: Immunohistochemistry assay was performed in sectioned human BPH tissues, BPH-1 cells, and prostate RWPE-1 cells, to detect the expressions of TRIM52 and NF-κB. Western blotting and qRT-PCR analyses were conducted to measure the relative protein and mRNA expression levels, respectively. Further, lentiviral transfection was performed in BPH-1 and RWPE-1 cells to study the overexpression and siRNA knockdown of TRIM52. Dual-luciferase reporter assay was applied to evaluate the relationship between NF-κB and TRIM52. Furthermore, CCK-8 assay and flow cytometry were employed to analyze cell proliferation and apoptosis. KEY FINDINGS: TRIM52 and NF-κB levels were elevated in BPH tissues, and TRIM52 expression positively correlated with NF-κB expression. TRIM52 silencing suppressed the growth of BPH-1 cells and decreased the promoter activity of NF-κB. Moreover, the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), suppressed TRIM52-induced proliferation of RWPE-1 cells and inhibited NF-κB promoter activity in oeTRIM52 transfected RWPE-1 cells. Silencing TRIM52 also inhibited TRAF2 ubiquitination in BPH-1 cells. Further, NF-κB promoter activity in siNC transfected cells was enhanced by the recombinant protein TNF-α and inhibited by siTRIM52. SIGNIFICANCE: TRIM52 accelerated the growth of BPH-1 cells by upregulating NF-κB, and TRIM52 could promote TRAF2 ubiquitination. These findings might contribute to the understanding of the biological functions and action mechanisms of TRIM52 in BPH.


Assuntos
NF-kappa B/metabolismo , Hiperplasia Prostática/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Western Blotting , Progressão da Doença , Citometria de Fluxo , Humanos , Masculino , Hiperplasia Prostática/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ubiquitinação
9.
Niger J Clin Pract ; 23(9): 1215-1220, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32913159

RESUMO

Background: Benign Prostatic Hypertrophy [BPH] is associated with voiding dysfunctions. Urodynamic study is the gold standard for diagnosis of voiding dysfunctions but is invasive. Bladder wall thickness (BWT), post-void urine residue (PVR), and bladder emptying efficiency (BEE) are noninvasive predictors of voiding dysfunction. Objective: To study the relationship among BWT, PVR, and BEE in BPH. Subjects and Methods: A hospital-based cross-sectional prospective study of new BPH patients at Nnamdi Azikiwe University Teaching Hospital, Nnewi. The participants had abdominal ultrasonography measurement of anterior BWT (at bladder volume ≥200 mls), prostate volume (PV), and PVR using Prosound SSD3500 (Aloka Co Ltd, Tokyo, Japan) with an abdominal probe frequency of 3.5 MHz. Then the BEE was calculated. The anterior BWT was divided into two groups: <5 mm and ≥5 mm. The data were analyzed using SPSS version 20. Pearson's correlation was used to assess correlation and the differences between the means of the two groups of BWT were compared by Mann-Whitney test. A P- Value <0.05 was considered significant. Results: Seventy seven men with a mean age of 66.66 ± 10.74 years were included in the study. Sixty one percent had symptoms lasting >12 months. The average anterior BWT, PBV, PVR, BEE, PV, and PSA were 4.55 ± 1.02 mm, 260.98 ± 57.44 mls, 58.36 ± 52.94 mls, 77.98 ± 17.37%, 66.31 ± 46.38 mls, and 8.04 ± 5.97 ng/ml, respectively. There was a significant positive correlation between BWT and duration of symptoms (P = 0.044) and a significant negative correlation between BWT and BEE (P = 0.005). An insignificant positive correlation was found between BWT and PVR (P = 0.255). Fifty four (70.1%) had BWT <5 mm and 29.9% had BWT ≥5 mm. The mean IPSS (P = 0.000), PV (P = 0.032) and PVR (P = 0.020) were significantly higher in the ≥5 mm group. The ≥5 mm group also had a significantly lower BEE (P = 0.002). Conclusion: Voiding dysfunction was more severe in patients with BWT of 5 mm or more. There was a positive, but insignificant, correlation between anterior BWT and PVR and a significant negative correlation between BWT and BEE.


Assuntos
Hiperplasia Prostática/patologia , Ultrassonografia/métodos , Bexiga Urinária/diagnóstico por imagem , Retenção Urinária , Transtornos Urinários/patologia , Idoso , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso/anatomia & histologia , Músculo Liso/diagnóstico por imagem , Músculo Liso/patologia , Nigéria , Estudos Prospectivos , Hiperplasia Prostática/complicações , Bexiga Urinária/anatomia & histologia , Bexiga Urinária/fisiopatologia , Transtornos Urinários/diagnóstico por imagem , Transtornos Urinários/etiologia , Urodinâmica
10.
Niger Postgrad Med J ; 27(3): 242-247, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32687126

RESUMO

Giant prostatic enlargement often referred to as giant prostatic hyperplasia (GPH) is a rare condition described as a massive prostatic enlargement >500 g. Up until now, the total number of GPH reported worldwide in medical literature is < 30. To the best of our knowledge, only one case of a giant prostate has been reported in Nigeria. We report a case of a giant prostatic enlargement treated by open simple retropubic prostatectomy in a 73-year-old man who was suffering from lower urinary tract symptoms and persistent visible (gross) haematuria necessitating repeated blood transfusions. Transrectal ultrasound (TRUS) scan revealed a markedly enlarged prostate measuring 565 ml with a suspicious nodule and prostate-specific antigen level of 48.5 ng/ml. He had a 20-core TRUS-guided prostatic biopsy which showed benign prostatic hyperplasia. We performed a retropubic open simple prostatectomy for complete enucleation of the adenoma. Specimen weighed 512.5 g with dimensions of 17 cm × 16 cm and a volume of 528 ml. Histological examination showed prostatic fibromuscular hyperplasia with a focus of adenocarcinoma. The patient had an uneventful post-operative recovery and was discharged within a week post-surgery. Urethral catheter was removed after 2 weeks with satisfactory outcome.


Assuntos
Hematúria/etiologia , Prostatectomia , Hiperplasia Prostática/diagnóstico por imagem , Hiperplasia Prostática/cirurgia , Retenção Urinária/etiologia , Adenoma , Idoso , Humanos , Masculino , Nigéria , Próstata/patologia , Hiperplasia Prostática/patologia , Resultado do Tratamento , Ultrassonografia Doppler em Cores
11.
PLoS One ; 15(6): e0234714, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32584842

RESUMO

As a consequence of a hormonal imbalance, Prostatic Hyperplasia (PH) is characterized by increased prostate volume, along with higher local angiogenesis and vascularization. Orchiectomy is the common treatment for dogs, however it is not an option for breeding animals. Thus, finasteride arises as the drug of choice for stud dogs. Therefore, the aim of this study was to evaluate the effects of orchiectomy or finasteride therapies on hormonal and vascular dynamics of PH dogs. Fifteen dogs, aged 6-13 years were assigned to: Untreated Group (dogs diagnosed with PH-n = 5), Finasteride treated group (PH dogs treated with finasteride-n = 5) and Orchiectomy treated group (PH dogs submitted to orchiectomy-n = 5). Evaluations were performed in a monthly interval (first day of treatment; after 30 and 60 days). Doppler ultrasonography was performed to measure prostatic volume, vascularization and hemodynamic profile of prostatic artery. Dihydrotestosterone, estrogen and testosterone concentrations were measured. At day 60, prostatic biopsy was performed for histological, immunohistochemical and qPCR analysis for VEGF-A expression. At day 60, vascularization score was higher in untreated compared to treated groups (finasteride and orchiectomy). Furthermore, VEGF-A expression was lower in the Orchiectomy Treated Group, but VEGF-A was immunohistochemically lower in both treated groups (finasteride and orchiectomy) compared to the Untreated Group. The efficiency of finasteride treatment in reducing clinical signs, prostate volume and vascularization appears to be similar to orchiectomy. In conclusion, both PH medical and surgical therapy lead to reduction in prostate dimension and VEGF-A expression and, consequently, lower local vascularization. However, orchiectomy promotes marked hormonal changes, which ultimately lead to prostate atrophy.


Assuntos
Doenças do Cão/fisiopatologia , Finasterida/farmacologia , Hemodinâmica/efeitos dos fármacos , Hormônios/sangue , Neovascularização Patológica , Orquiectomia , Hiperplasia Prostática/veterinária , Animais , Doenças do Cão/tratamento farmacológico , Doenças do Cão/patologia , Doenças do Cão/cirurgia , Cães , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Hiperplasia Prostática/patologia , Hiperplasia Prostática/fisiopatologia , Hiperplasia Prostática/terapia , Ultrassonografia Doppler , Fator A de Crescimento do Endotélio Vascular/metabolismo
12.
Prostate ; 80(12): 938-949, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32542667

RESUMO

BACKGROUND: The clinical manifestation of benign prostatic hyperplasia (BPH) is causally linked to the inflammatory microenvironment and proliferation of epithelial and stromal cells in the prostate transitional zone. The CXC-chemokine interleukin-8 (IL-8) contributes to inflammation. We evaluated the expression of inflammatory cytokines in clinical specimens, primary cultures, and prostatic lineage cell lines. We investigated whether IL-8 via its receptor system (IL-8 axis) promotes BPH. METHODS: The messenger RNA and protein expression of chemokines, including components of the IL-8 axis, were measured in normal prostate (NP; n = 7) and BPH (n = 21), urine (n = 24) specimens, primary cultures, prostatic lineage epithelial cell lines (NHPrE1, BHPrE1, BPH-1), and normal prostate cells (RWPE-1). The functional role of the IL-8 axis in prostate epithelial cell growth was evaluated by CRISPR/Cas9 gene editing. The effect of a combination with two natural compounds, oleanolic acid (OA) and ursolic acid (UA), was evaluated on the expression of the IL-8 axis and epithelial cell growth. RESULTS: Among the 19 inflammatory chemokines and chemokine receptors we analyzed, levels of IL-8 and its receptors (CXCR1, CXCR2), as well as, of CXCR7, a receptor for CXCL12, were 5- to 25-fold elevated in BPH tissues when compared to NP tissues (P ≤ .001). Urinary IL-8 levels were threefold to sixfold elevated in BPH patients, but not in asymptomatic males and females with lower urinary tract symptoms (P ≤ .004). The expression of the IL-8 axis components was confined to the prostate luminal epithelial cells in both normal and BPH tissues. However, these components were elevated in BPH-1 and primary explant cultures as compared to RWPE-1, NHPrE1, and BHPrE1 cells. Knockout of CXCR7 reduced IL-8, and CXCR1 expression by 4- to 10-fold and caused greater than or equal to 50% growth inhibition in BPH-1 cells. Low-dose OA + UA combination synergistically inhibited the growth of BPH-1 and BPH primary cultures. In the combination, the drug reduction indices for UA and OA were 16.4 and 7852, respectively, demonstrating that the combination was effective in inhibiting BPH-1 growth at significantly reduced doses of UA or OA alone. CONCLUSION: The IL-8 axis is a promotor of BPH pathogenesis. Low-dose OA + UA combination inhibits BPH cell growth by inducing autophagy and reducing IL-8 axis expression in BPH-epithelial cells.


Assuntos
Interleucina-8/metabolismo , Próstata/metabolismo , Próstata/patologia , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Receptores CXCR/metabolismo , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Epitélio/patologia , Humanos , Interleucina-8/biossíntese , Interleucina-8/genética , Masculino , Ácido Oleanólico/farmacologia , Próstata/efeitos dos fármacos , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CXCR/biossíntese , Receptores CXCR/genética , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia
13.
Prostate ; 80(10): 731-741, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32356572

RESUMO

BACKGROUND: Male lower urinary tract symptoms (LUTS) occur in more than half of men above 50 years of age. LUTS were traditionally attributed to benign prostatic hyperplasia (BPH) and therefore the clinical terminology often uses LUTS and BPH interchangeably. More recently, LUTS were also linked to fibrogenic and inflammatory processes. We tested whether osteopontin (OPN), a proinflammatory and profibrotic molecule, is increased in symptomatic BPH. We also tested whether prostate epithelial and stromal cells secrete OPN in response to proinflammatory stimuli and identified downstream targets of OPN in prostate stromal cells. METHODS: Immunohistochemistry was performed on prostate sections obtained from the transition zone of patients who underwent surgery (Holmium laser enucleation of the prostate) to relieve LUTS (surgical BPH, S-BPH) or patients who underwent radical prostatectomy to remove low-grade prostate cancer (incidental BPH, I-BPH). Images of stained tissue sections were captured with a Nuance Multispectral Imaging System and histoscore, as a measure of OPN staining intensity, was determined with inForm software. OPN protein abundance was determined by Western blot analysis. The ability of prostate cells to secrete osteopontin in response to IL-1ß and TGF-ß1 was determined in stromal (BHPrS-1) and epithelial (NHPrE-1 and BHPrE-1) cells by enzyme-linked immunosorbent assay. Quantitative polymerase chain reaction was used to measure gene expression changes in these cells in response to OPN. RESULTS: OPN immunostaining and protein levels were more abundant in S-BPH than I-BPH. Staining was distributed across all cell types with the highest levels in epithelial cells. Multiple OPN protein variants were identified in immortalized prostate stromal and epithelial cells. TGF-ß1 stimulated OPN secretion by NHPrE-1 cells and both IL-1ß and TGF-ß1 stimulated OPN secretion by BHPrS-1 cells. Interestingly, recombinant OPN increased the mRNA expression of CXCL1, CXCL2, CXCL8, PTGS2, and IL6 in BHPrS-1, but not in epithelial cell lines. CONCLUSIONS: OPN is more abundant in prostates of men with S-BPH compared to men with I-BPH. OPN secretion is stimulated by proinflammatory cytokines, and OPN acts directly on stromal cells to drive the synthesis of proinflammatory mRNAs. Pharmacological manipulation of prostatic OPN may have the potential to reduce LUTS by inhibiting both inflammatory and fibrotic pathways.


Assuntos
Osteopontina/biossíntese , Hiperplasia Prostática/metabolismo , Quimiocinas CXC/biossíntese , Quimiocinas CXC/genética , Ciclo-Oxigenase 2/biossíntese , Ciclo-Oxigenase 2/genética , Humanos , Imuno-Histoquímica , Interleucina-6/biossíntese , Interleucina-6/genética , Masculino , Osteopontina/genética , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Células Estromais/metabolismo , Células Estromais/patologia
14.
J Vasc Interv Radiol ; 31(5): 820-830, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32305243

RESUMO

PURPOSE: To prospectively assess safety and efficacy of prostatic artery embolization (PAE) with bleomycin-eluting microspheres for benign prostatic hyperplasia (BPH) in a canine model. MATERIALS AND METHODS: Twelve adult male beagles (mean age, 1.6 y ± 0.2; range, 1.2-2.0 y) were randomly assigned to group A (n = 6; PAE with bleomycin-eluting 30-60-µm HepaSphere microspheres) and group B (n = 6; PAE with bland 30-60-µm HepaSphere microspheres) between April 2017 and November 2018. Plasma bleomycin concentration in group A was measured within 7 days. Prostate volume (PV) and ischemic volume after PAE were measured by magnetic resonance imaging. Prostates and adjacent organs were harvested after the last magnetic resonance study and histopathologically examined. RESULTS: Plasma bleomycin concentration peaked at 10 minutes at 2,055.0 ng/mL ± 606.1 and lasted for 1,440 min at low levels after PAE. PV reduction percentage was greater in group A than in group B at 1 month (74.1% ± 4.3 vs 63.7% ± 3.5; P = .006) and 3 months (61.5% ± 6.7 vs 46.1% ± 3.8; P = .001) after PAE. Proportion of prostate ischemic volume was greater in group A than in group B (75.3% ± 3.0 vs 62.0% ± 7.1; P = .006) at 1 month after PAE. Proportion of prostate ischemic volume at 1 month positively correlated with PV percentage reduction at 3 months in group A (r = 0.840, P = .036) and group B (r = 0.844, P = .035). There were no complications or nontarget embolization to surrounding organs after the procedures. CONCLUSIONS: In a canine model, PAE with bleomycin-eluting microspheres was feasible and well tolerated and caused ischemic necrosis and reduction in PV.


Assuntos
Artérias , Bleomicina/administração & dosagem , Embolização Terapêutica , Próstata/irrigação sanguínea , Hiperplasia Prostática/terapia , Angiografia Digital , Animais , Artérias/diagnóstico por imagem , Modelos Animais de Doenças , Cães , Imagem por Ressonância Magnética , Masculino , Microesferas , Necrose , Próstata/diagnóstico por imagem , Próstata/patologia , Hiperplasia Prostática/diagnóstico por imagem , Hiperplasia Prostática/patologia , Fatores de Tempo
15.
Nat Commun ; 11(1): 1987, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332823

RESUMO

Benign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, is among the most common diseases affecting aging men, but the underlying molecular features remain poorly understood, and therapeutic options are limited. Here we employ a comprehensive molecular investigation of BPH, including genomic, transcriptomic and epigenetic profiling. We find no evidence of neoplastic features in BPH: no evidence of driver genomic alterations, including low coding mutation rates, mutational signatures consistent with aging tissues, minimal copy number alterations, and no genomic rearrangements. At the epigenetic level, global hypermethylation is the dominant process. Integrating transcriptional and methylation signatures identifies two BPH subgroups with distinct clinical features and signaling pathways, validated in two independent cohorts. Finally, mTOR inhibitors emerge as a potential subtype-specific therapeutic option, and men exposed to mTOR inhibitors show a significant decrease in prostate size. We conclude that BPH consists of distinct molecular subgroups, with potential for subtype-specific precision therapy.


Assuntos
Próstata/patologia , Hiperplasia Prostática/genética , Serina-Treonina Quinases TOR/antagonistas & inibidores , Agentes Urológicos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Biomarcadores/análise , Metilação de DNA , Epigênese Genética , Epigenômica , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Mutação , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/genética , Medicina de Precisão/métodos , Estudos Prospectivos , Próstata/diagnóstico por imagem , Próstata/efeitos dos fármacos , Hiperplasia Prostática/diagnóstico por imagem , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/patologia , RNA-Seq , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Agentes Urológicos/farmacologia , Sequenciamento Completo do Genoma
16.
Medicine (Baltimore) ; 99(15): e19678, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282720

RESUMO

BACKGROUND: Benign prostatic hyperplasia (BPH) is a medical condition that affects the quality of life by causing lower urinary tract symptoms (LUTS) in 40% to 70% of men aged ≥60 years. Medication treatment is primarily recommended for patients with BPH if their symptom score based on the International Prostate Symptom score (IPSS) is above the moderate level. However, electroacupuncture (EA) and electronic moxibustion (EM), one of the most recent complementary and alternative treatments, are suggested as adjuvant treatments in the improvement of LUTS caused by BPH with respect to the limitations of medication treatments, such as side effects or no improvement in LUTS despite treatment. Therefore, this study aimed to evaluate the effectiveness and safety of EA and its cotreatment with EM for the improvement of LUTS in patients diagnosed with BPH using an alpha blocker but with moderate symptoms on the basis of IPSS. METHODS/DESIGN: This protocol is a 2-arm parallel-design, randomized, controlled assessor-blinded clinical trial. Seventy-eight patients diagnosed with BPH are randomized to one of the following groups: [EA and its cotreatment with EM + alpha blocker group] and [alpha blocker group]. [EA and its cotreatment with EM + alpha blocker group] continues to use the previously prescribed alpha blocker and visits the study institution 3 times a week for 6 weeks to receive the cotreatment of EA and EM. [Alpha blocker group] continues to use the previously prescribed alpha blocker for 6 weeks. To evaluate the effectiveness of the EA and its cotreatment with EM, the followings are measured: total score of the IPSS, IPSS quality of life assessment, EuroQol-Five dimension, maximum and average urinary flow rate (Qmax and Qave), and prostate size at the baseline, 3rd, 6th, and 12th weeks. The primary effectiveness endpoint measures the average change in the total score of the IPSS at the 6th week. Side effects are recorded at each visit. DISCUSSION: The results of this study are expected to provide useful information on the effectiveness and safety of the EA and its cotreatment with EM for patients with BPH with regard to the improvements in LUTS. TRIAL REGISTRATION: Clinical Research Information Service of Republic of Korea (CRIS-KCT0004411), October 31, 2019.


Assuntos
Eletroacupuntura/métodos , Sintomas do Trato Urinário Inferior/psicologia , Moxibustão/métodos , Hiperplasia Prostática/terapia , Antagonistas Adrenérgicos alfa/uso terapêutico , Idoso , Algoritmos , Terapia Combinada , Eletroacupuntura/efeitos adversos , Humanos , Sintomas do Trato Urinário Inferior/etiologia , Masculino , Pessoa de Meia-Idade , Moxibustão/efeitos adversos , Hiperplasia Prostática/complicações , Hiperplasia Prostática/diagnóstico , Hiperplasia Prostática/patologia , Qualidade de Vida , República da Coreia/epidemiologia , Segurança , Resultado do Tratamento
17.
Sci Rep ; 10(1): 5308, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32210252

RESUMO

We investigated the efficacy of and risk from holmium laser enucleation of the prostate (HoLEP) due to discontinuation of antithrombotics in patients with benign prostatic hyperplasia (BPH). Patients in the prospective SNUH-BPH Database Registry who underwent HoLEP between December 2010 and December 2017 were enrolled. Preoperative evaluation included symptom score questionnaires, laboratory tests, urine tests, prostate-specific antigens, urodynamic study, and transrectal ultrasonography. Postoperative evaluation was performed at 2 weeks, 3 months, and 6 months. Information regarding the types of antithrombotics and their use, underlying disease, and antithrombotic management during surgery was collected. The study included 55 patients. The mean age and preoperative prostate volume were 68.7 ± 6.4 years and 70.3 ± 32.2 mL, respectively. The mean preoperative hemoglobin level was 13.5 ± 2.6 g/dL in the patients receiving antithrombotics. Of the patients, 71% were taking aspirin. Seventy-five (66.5%) and 70 patients (28.2%) discontinued the antithrombotic therapy 5-7 days and <1 week preoperatively, respectively. Three patients (1.21%) were switched to low-molecular-weight heparin therapy, and 10 (4.03%) continued antithrombotic therapy. No significant differences were found in the incidence rates of postoperative transfusion (p = 0.894) or complications from antithrombotic use, thrombosis (p = 0.946), haemorrhage requiring bladder irrigation (p = 0.959), transurethral coagulation (p = 0.894), cardiovascular events (p = 0.845), and cerebrovascular events (p = 0.848). Efficacy and complications related to the short-term antithrombotic withdrawal before and after HoLEP also showed no significant differences. HoLEP may be a beneficial surgical technique for patients with BPH who are receiving antithrombotics.


Assuntos
Fibrinolíticos/uso terapêutico , Hólmio/química , Terapia a Laser/métodos , Lasers de Estado Sólido/uso terapêutico , Hiperplasia Prostática/cirurgia , Qualidade de Vida , Idoso , Terapia Combinada , Humanos , Masculino , Estudos Prospectivos , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/patologia , Resultado do Tratamento , Urodinâmica
18.
Neurourol Urodyn ; 39(3): 926-934, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32049380

RESUMO

AIM: To characterize purinergic signaling in overactive bladder (OAB). METHODS: Mucosal biopsies were taken by flexible cystoscopy from patients with storage symptoms referred to Urology Departments of collaborating hospitals. Immunohistochemistry (n = 12) and Western blot analysis (n = 28) were used to establish the qualitative and quantitative expression profile of P2Y6 in human mucosa. Participants from the general population provided a mid-stream urine sample. Bioluminescent assays were used to quantify adenosine triphosphate (ATP; n = 66) and adenosine diphosphate (ADP; n = 60) concentrations, which were normalized to creatinine (Cr) concentration. All participants completed a questionnaire (International Consultation on Incontinence Questionnaire - Overactive Bladder) to score urinary symptoms of OAB. RESULTS: P2Y6 immunoreactivity, more prominent in the urothelium (colocalized with the uroepithelial marker pan-cytokeratin), was more greatly expressed in OAB compared to age- and sex-matched controls (benign prostatic hyperplasia) without OAB symptoms. Mucosal P2Y6 was positively correlated only with incontinence (P = .009). Both urinary ATP and its hydrolysis product, ADP, an agonist to P2Y6, were positively correlated with total OAB symptom score (P = .010 and P = .042, respectively). CONCLUSIONS: The positive correlation of P2Y6 only with incontinence may indicate a different phenotype in OAB wet and warrants further investigation. Positive correlations of ATP and ADP with total OAB symptom score demonstrate upregulation in purinergic signaling in OAB; shown previously only in animal models. Further research is required to validate whether purinoceptors are indeed new therapeutic targets for this highly prevalent symptom complex.


Assuntos
Difosfato de Adenosina/urina , Trifosfato de Adenosina/urina , Membrana Mucosa/metabolismo , Receptores Purinérgicos P2/metabolismo , Bexiga Urinária Hiperativa/metabolismo , Bexiga Urinária/metabolismo , Incontinência Urinária/metabolismo , Urotélio/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Creatinina/urina , Cistoscopia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Hiperplasia Prostática/fisiopatologia , Inquéritos e Questionários , Bexiga Urinária/patologia , Bexiga Urinária/fisiopatologia , Bexiga Urinária Hiperativa/patologia , Bexiga Urinária Hiperativa/fisiopatologia , Incontinência Urinária/patologia , Incontinência Urinária/fisiopatologia
19.
Aktuelle Urol ; 51(1): 59-64, 2020 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-32018335

RESUMO

BACKGROUND: Transurethral resection of the prostate (TUR-P) is considered the gold standard in the surgical treatment of symptomatic benign prostatic hyperplasia. Besides the conventional TUR-P, there are numerous technological modifications of the procedure. An increasing use of the 180 W Greenlight-XPS™ laser vaporisation of the prostate (GLL) has been observed recently. OBJECTIVE: TUR-P and GLL have already been studied for safety, efficacy and economy. The aim of the present study was to analyse patient-related postsurgical aspects such as patient comfort and pain. METHODS: A total of 250 consecutive patients (100 TUR-P and 150 GLL) were analysed by examining anonymised medical records. Information on resection weight (TUR-P), applied energy (GLL), prostate volume, antiplatelet/anticoagulant therapy, catheter size, length of catheterisation, length of bladder irrigation, length of hospital stay and postoperative pain score was gathered. RESULTS: The prostate volume was comparable between the two procedures (p = 0.434). The proportion of patients with ongoing antiplatelet and anticoagulant therapy was significantly higher with GLL (p < 0.0001). The catheter size was comparable with no statistical difference (p = 0.102). Length of catheterisation and duration of bladder irrigation were significantly shorter with GLL (p = 0.016 and p = 0.01). While the length of hospital stay was not statistically different (p = 0.233), a tendency to shorter hospital stays was seen with GLL. A similar postoperative pain score was observed with a low pain level in general and the highest scores being recorded shortly after the procedure. CONCLUSIONS: The results demonstrate that GLL - a procedure preferably used for patients with ongoing antiplatelet and anticoagulant therapy - provides a high experience of postoperative comfort and offers potential for savings in terms of nursing resources (duration and intensity of bladder irrigation).


Assuntos
Terapia a Laser , Próstata/cirurgia , Hiperplasia Prostática/cirurgia , Ressecção Transuretral da Próstata , Humanos , Masculino , Dor Pós-Operatória , Próstata/patologia , Hiperplasia Prostática/patologia , Estudos Retrospectivos
20.
Int J Mol Sci ; 21(4)2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093293

RESUMO

We investigated the metabolite changes of Morus roots (MRs) according to different cultivar families (Simheung, Daesim, Cheong-il, Sangchon, Daeseong, Suhong, Suwon, and Igsu) using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) to understand the relationship between different cultivars and metabolite changes. Data were analyzed by partial least squares discriminant analysis (PLS-DA), and samples were successfully separated in PLS-DA scores. Eight metabolites in the electrospray ionization (ESI)-positive mode and 16 metabolites in the ESI-negative mode contributed to the separation in PLS-DA. Our data suggest that comparative analysis of MR metabolites according to different cultivars is useful to better understand the relationship between the different cultivars and metabolite changes. Furthermore, we analyzed the MRs for their ability to improve benign prostatic hyperplasia (BPH). LNCaP cells were used to evaluate the prostate-specific antigen (PSA) inhibitory activity of MRs, and, amongst them, the extract with the highest activity was selected. Igsu demonstrated the highest inhibition effect of prostate-specific antigen (PSA) expression among the MR cultivars. Igsu was also evaluated by administration in a testosterone-induced benign prostatic hyperplasia model in Sprague-Dawley rats. Igsu was shown to ameliorate BPH as evidenced by the prostate index, expression of androgen receptor (AR) signaling-related protein, growth factors, cell proliferation-related proteins, apoptosis-related proteins, mitogen-activated protein kinase (MAPK) signaling proteins, and histological analysis. Hence, this study strongly suggests that Igsu may have a beneficial effect of on BPH.


Assuntos
Morus/química , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Próstata/metabolismo , Hiperplasia Prostática , Testosterona/efeitos adversos , Animais , Masculino , Extratos Vegetais/química , Próstata/patologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Ratos , Ratos Sprague-Dawley , Testosterona/farmacologia
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