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1.
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
2.
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
3.
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
4.
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
5.
Prostate ; 80(6): 481-490, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32104919

RESUMO

OBJECTIVE: To investigate the potential mechanism of the effect of metabolic syndrome (MetS) on prostate volume (PV) and the risk of benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) and the relationships of MetS and the major pathogenic factors of MetS with the clinical progression of BPH/LUTS in older Chinese men. SUBJECTS AND METHODS: We analyzed clinical data obtained from 506 ostensibly healthy men who underwent routine health check-ups and recruited 415 subjects from a group of previously studied men after 4 years. We evaluated the associations of major pathological factors of MetS, including insulin resistance, subclinical inflammatory state, and sex hormone changes, with PV, the risk of BPH and the clinical progression of BPH/LUTS by using multiple linear regression and logistic regression. RESULTS: After adjustment for age, insulin, HOMA (homeostatic model assessment) index, leptin, resistin, adiponectin, C-reactive protein, tumor necrosis factor-α (TNF-α), sex hormone-binding globulin, and testosterone levels were significantly associated with PV (all P < .05), and in the age-adjusted logistic regression model, positive associations of resistin and TNF-α with BPH/LUTS were found (OR, 1.662, P = .007 and OR, 1.044, P < .001, respectively). Predictors of BPH/LUTS clinical progression were significantly correlated with MetS and TNF-α. The group with higher TNF-α levels had a higher rate of newly diagnosed BPH (9.5% vs 19.1%, P = .006) and a greater increase in PV levels (0.61 ± 0.08 vs 1.09 ± 0.35 cm3 , P <.001) after 4 years. CONCLUSIONS: MetS and its pathological factors were associated with an increased PV and an increased risk of BPH/LUTS that is more prone to clinical progression. TNF-α may serve as an early biological indicator to identify which patients with BPH/LUTS are at higher risk of unfavorable outcomes.


Assuntos
Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Idoso , Pressão Sanguínea/fisiologia , Humanos , Modelos Logísticos , Masculino , Próstata/metabolismo , Próstata/patologia , Circunferência da Cintura/fisiologia
6.
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
7.
Food Funct ; 11(2): 1585-1598, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32003376

RESUMO

Benign prostatic hyperplasia (BPH) is a common chronic disease in aging men. The present study aimed to identify the active fraction of a purple rice extract and determine its anti-prostatic hyperplasia effect in a testosterone implanted rat model. The hexane insoluble fraction (HIF) which mainly contains hydrophilic phytochemicals from the purple rice crude ethanolic extract was defined as the active fraction, due to a potent effect on the downregulation of androgen receptor (AR) expression in malignant prostate cells, in addition to low toxicity for normal fibroblast cells. To induce BPH, subcutaneous implanting of a testosterone containing tube was performed in the castrated rats. Oral administration of HIF of at least 0.1 g kg-1 retarded prostate enlargement and improved histological changes induced by testosterone, without any effects on the serum testosterone levels. A lower proliferating cell nuclear antigen (PCNA) labelling index and the downregulated expression of AR, cyclinD1, and fatty acid synthase were clearly observed in the prostates of HIF-fed rats. Additionally, the mRNA levels of inflammation-related cytokines and enzymes in the prostate tissues significantly decreased after HIF treatment. Taken together, these findings demonstrate molecular mechanisms underlying the potential protective effects of the purple rice active fraction against testosterone-induced BPH in rats.


Assuntos
Oryza/química , Extratos Vegetais/farmacologia , Próstata , Hiperplasia Prostática/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Interações Hidrofóbicas e Hidrofílicas , Masculino , Camundongos , Células NIH 3T3 , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Ratos , Ratos Wistar , Testosterona
8.
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
9.
Sci Rep ; 10(1): 322, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941927

RESUMO

Prostatic hyperplasia, characterized by progressive hyperplasia of glandular and stromal tissues, is the most common proliferative abnormality of the prostate in aging men. A high-fat diet (HFD) usually is a major factor inducing oxidative stress, inflammation, and an abnormal state of the prostate. Mangosteen pericarp powder (MPP) has abundant xanthones which can be antioxidant, anti-inflammatory, and antiproliferative agents. Therefore, the purpose of this study was to research whether MPP supplementation can affect the progression of prostatic hyperplasia. Twenty-four male F344 rats were randomly divided into four groups, including a control group (C), prostatic hyperplasia-induced group (P), prostatic hyperplasia-induced with low-dose MPP group (PL), and induced with high-dose MPP group (PH). The P, PL, and PH groups were given weekly intraperitoneal injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) at 25 mg/kg body weight for 10 weeks, and simultaneously fed an HFD for 24 weeks. Our findings first demonstrated that MPP consumption significantly decreased the prostate weight, serum testosterone and dihydrotestosterone concentrations, protein expression of proliferating cell nuclear antigen, and malondialdehyde levels and ameliorated mitochondrial function in prostatic tissues. These results suggest that MPP supplementation could be used to attenuate the progression of prostatic hyperplasia.


Assuntos
Garcinia mangostana/química , Mitocôndrias/efeitos dos fármacos , Extratos Vegetais/farmacologia , Hiperplasia Prostática/patologia , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Suplementos Nutricionais , Di-Hidrotestosterona/sangue , Modelos Animais de Doenças , Progressão da Doença , Garcinia mangostana/metabolismo , Masculino , Malondialdeído/metabolismo , Mitocôndrias/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Antígeno Nuclear de Célula em Proliferação/metabolismo , Próstata/metabolismo , Próstata/patologia , Hiperplasia Prostática/metabolismo , Ratos , Ratos Endogâmicos F344 , Testosterona/sangue
10.
Biochem Biophys Res Commun ; 524(1): 16-21, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-31964530

RESUMO

Activating Transcription Factor 2 (ATF2) is a member of the ATF/CREB bZIP family of transcription factors and an oncogene in prostate cancer. ATF2 has been reported to be a critical substrate of the CUL3-SPOP-RBX1 E3 ubiquitin ligase complex and the recurrent somatic mutation of SPOP has been believed to be a key feature of prostate cancer. However, the deubiquitinating enzyme required for ATF2 stabilization is still unknown. Here, we show that ATF2 is associated with ubiquitin-specific protease 14 (USP14), which increased the protein abundance and transcriptional activity of ATF2. Pharmacologic inhibition or siRNA-mediated depletion of USP14 resulted in the decline and inactivation of ATF2. USP14 deubiquitinates and activates ATF2, resulting in enhanced prostate cancer cells proliferation both in vitro and in vivo. Importantly, silencing of ATF2 largely attuned USP14-mediated prostate cancer cells proliferation. Thus, our data revealed a critical role of USP1-ATF2 axis in the progress of prostate cancer and the inhibition of USP14 might be a promising strategy against prostate cancer.


Assuntos
Fator 2 Ativador da Transcrição/metabolismo , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Animais , Proteína de Ligação a CREB/metabolismo , Linhagem Celular , Progressão da Doença , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Mutação , Ligação Proteica , RNA Interferente Pequeno/metabolismo , Proteases Específicas de Ubiquitina/genética , Ubiquitinação
11.
Sci Rep ; 9(1): 19233, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848441

RESUMO

Environmental and nutritional factors, including fatty acids (FA), are associated with prostatitis, benign prostate hyperplasia and prostate cancer. We hypothesized that different FA in normolipidic diets (7%) affect prostate physiology, increasing the susceptibility to prostate disorders. Thus, we fed male C57/BL6 mice with normolipidic diets based on linseed oil, soybean oil or lard (varying saturated and unsaturated FA contents and ω-3/ω-6 ratios) for 12 or 32 weeks after weaning and examined structural and functional parameters of the ventral prostate (VP) in the systemic metabolic context. Mongolian gerbils were included because they present a metabolic detour for low water consumption (i.e., oxidize FA to produce metabolic water). A linseed oil-based diet (LO, 67.4% PUFAs, ω-3/ω-6 = 3.70) resulted in a thermogenic profile, while a soybean oil-based diet (SO, 52.7% PUFAs, ω-3/ω-6 = 0.11) increased body growth and adiposity. Mice fed lard (PF, 13.1% PUFA, ω-3/ω-6 = 0.07) depicted a biphasic growth, resulting in decreased adiposity in adulthood. SO and PF resulted in hepatic steatosis and steatohepatitis, respectively. PF and SO increased prostate epithelial volume, and lard resulted in epithelial hyperplasia. Animals in the LO group had smaller prostates with predominant atrophic epithelia and inflammatory loci. Inflammatory cells were frequent in the VP of PF mice (predominantly stromal) and LO mice (predominantly luminal). RNAseq after 12 weeks revealed good predictors of a later-onset inflammation. The transcriptome unveiled ontologies related to ER stress after 32 weeks on PF diets. In conclusion, different FA qualities result in different metabolic phenotypes and differentially impact prostate size, epithelial volume, inflammation and gene expression.


Assuntos
Gorduras na Dieta/efeitos adversos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácidos Graxos/efeitos adversos , Lesões Pré-Cancerosas/metabolismo , Hiperplasia Prostática/metabolismo , Prostatite/metabolismo , Transcriptoma/efeitos dos fármacos , Animais , Gorduras na Dieta/farmacologia , Ácidos Graxos/farmacologia , Masculino , Camundongos , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/patologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/patologia , Prostatite/induzido quimicamente , Prostatite/patologia
12.
Life Sci ; 239: 117048, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730867

RESUMO

Benign prostatic hyperplasia (BPH) is an aging-related and progressive disease linked to an up-regulation of α1-adrenoceptors. The participation of EGF receptors (EGFR) in the GPCRs' signalosome has been described but so far data about the contribution of these receptors to prostatic stromal hyperplasia are scanty. We isolated and cultured vimentin-positive prostate stromal cells obtained from BPH patients. According to intracellular Ca2+ measurements, cell proliferation and Western blotting assays, these cultured hyperplastic stromal cells express functional α1-adrenoceptors and EGFR, and proliferate in response to the α1-adrenoceptor agonist phenylephrine. Interestingly, in these cells the inhibition of EGFR signaling with GM6001, CRM197, AG1478 or PD98059 was associated with full blockage of α1-adrenoceptor-mediated cell proliferation, while cell treatment with each inhibitor alone did not alter basal cell growth. Moreover, the co-incubation of AG1478 (EGFR inhibitor) with α1A/α1D-adrenoceptor antagonists showed no additive inhibitory effect. These findings highlight a putative role of EGFR signaling to α1-adrenoceptor-mediated human prostate hyperplasia, suggesting that the inhibition of this transactivation cascade could be useful to reduce BPH progression.


Assuntos
Receptores ErbB/metabolismo , Hiperplasia Prostática/metabolismo , Receptores Adrenérgicos alfa 1/fisiologia , Antagonistas de Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Humanos , Hiperplasia/metabolismo , Masculino , Piperazinas/farmacologia , Cultura Primária de Células , Próstata/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Estromais
13.
Eur J Pharmacol ; 865: 172729, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31605676

RESUMO

Benign prostatic hyperplasia (BPH) is the most widespread urological disorder among elderly men. It is influenced by several factors, among which is the prostatic renin angiotensin system (RAS). Prostatic RAS activates several signaling pathways as proliferation, inflammation and angiogenesis that contribute to BPH development and progression. Captopril is a potent inhibitor of the angiotensin converting enzyme. Therefore, this study was performed to explore the potential protective effect of captopril against testosterone-induced BPH in rats. Male Sprague-Dawley rats were treated with either testosterone (3 mg/kg, s. c.) and/or captopril (100 mg/kg, orally) for four weeks. After treatments, prostatic serum markers and histopathology were assessed. Mechanistically, apoptotic, inflammatory and angiogenic pathways were examined. Testosterone significantly increased prostate weight, prostatic index, prostatic acid phosphatase and prostate specific antigen. These effects were almost prevented by captopril (100 mg/kg). Moreover, testosterone significantly elevated proliferating cell nuclear antigen and reduced Bax/Bcl-2 ratio, p53 and caspase-3 activity. Furthermore, it significantly elevated nuclear factor kappa-B, cyclooxygenase-II, tumor necrosis factor-α and interleukin-8. Besides, it caused a significant rise in vascular endothelial growth factor, basic fibroblast growth factor and matrix metalloproteinase-9. On the contrary, captopril effectively neutralised the proliferative, inflammatory and angiogenic effects of testosterone. Finally, the angiotensin-1 receptor expression in the BPH group was markedly decreased while captopril restored the receptor expression. Collectively, these findings indicate that captopril possesses a potent protective effect against testosterone-induced BPH via inducing apoptotic and suppressing inflammatory and angiogenic signaling pathways.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/farmacologia , Hiperplasia Prostática/induzido quimicamente , Hiperplasia Prostática/tratamento farmacológico , Testosterona/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Captopril/uso terapêutico , Fator 2 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-8/metabolismo , Masculino , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/genética , Sistema Renina-Angiotensina/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
BMC Complement Altern Med ; 19(1): 233, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31464618

RESUMO

BACKGROUND: Resveratrol is reported to inhibit the growth of prostate, which is characteristic of benign prostatic hyperplasia (BPH) condition. However, the mechanism remains unclear. This study aimed to identify the effects and probable mechanism of resveratrol on BPH. METHODS: We used the BPH epithelial cell line BPH-1 to investigate the effect of resveratrol. Cells were treated with various concentrations of resveratrol, and its effects on cells viability, apoptosis, ROS accumulation, and cell cycle were assessed. Western blot was used to examine activation of p38 MAPK and protein levels of FOXO3a, Bcl2, Bcl-XL, and caspase3. Cells were also co-treated with the p38 MAPK inhibitor SB203580 or ROS scavenger N-Acetyl-L-cysteine (NAC) to further investigate the mechanism. RESULTS: Resveratrol treatment inhibited the growth of BPH-1 and increased apoptosis of cells. In addition, levels of phosphorylated p38 MAPK level was elevated and FOXO3a repression was observed. Concomitantly, ROS was accumulated. All of these resveratrol-mediated effects were suppressed by additional treatment with SB203580 or NAC. Resveratrol was also found to induce cell cycle arrest at S phase. CONCLUSIONS: Resveratrol can activate p38 MAPK and repress FOXO3a, thereby causing repression of SOD2, catalase, and increase of ROS accumulation, leading to apoptosis in BPH-1 cells.


Assuntos
Apoptose/efeitos dos fármacos , Proteína Forkhead Box O3/metabolismo , Hiperplasia Prostática/metabolismo , Resveratrol/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Espécies Reativas de Oxigênio/metabolismo
15.
Anal Chim Acta ; 1081: 93-102, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31446969

RESUMO

Metabolomics analysis of biofluids is a feasible tool for disease characterization and monitoring due to its minimally invasive nature. To reduce unwanted variation in biobanks and clinical studies, it is important to determine the effect of external factors on metabolic profiles of biofluids. In this study we examined the effect of sample collection and sample processing procedures on NMR measured serum lipoproteins and small-molecule metabolites in serum and urine, using a cohort of men diagnosed with either prostate cancer or benign prostatic hyperplasia. We determined day-to-day reliability of metabolites by systematic sample collection at two different days, in both fasting and non-fasting conditions. Study participants received prostate massage the first day to assess the differences between urine with and without prostate secretions. Further, metabolic differences between first-void and mid-stream urine samples, and the effect of centrifugation of urine samples before storage were assessed. Our results show that day-to-day reliability is highly variable between metabolites in both serum and urine, while lipoprotein subfractions possess high reliability. Further, fasting status clearly influenced the metabolite concentrations, demonstrating the importance of keeping this condition constant within a study cohort. Day-to-day reliabilities were however comparable in fasting and non-fasting samples. Urine sampling procedures such as sampling of first-void or mid-stream urine, and centrifugation or not before sample storage, were shown to only have minimal effect on the overall metabolic profile, and is thus unlikely to constitute a confounder in clinical studies utilizing NMR derived metabolomics.


Assuntos
Metabolômica/métodos , Próstata/metabolismo , Urina/química , Idoso , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/metabolismo , Manejo de Espécimes
16.
Anticancer Res ; 39(8): 4171-4177, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366502

RESUMO

BACKGROUND/AIM: Identification of prostatic stem cells in primary prostate tissue sections, organ cultures of prostate and cell lines requires a range of techniques that allows characterization of stem cells for their potential use in the treatment of patients. Isolated cells usually round-up and develop changes in shape, size and cellular characteristics. The aim of this study was to provide a range of methods for identifying prostatic stem cells and characterizing them with regard to ultrastructure, nuclear morphology, cytoplasmic organelles, and/or expression stem cell marker CD133. MATERIALS AND METHODS: Prostate biopsy and prostatectomy specimens were used for studying prostatic stem cells and their known marker CD133 in tissue sections by light and/or electron microscopy. Inverted capsule embedding was used to study archival metastatic prostate in pelvic nodes and Du145 cell line in a monolayer culture. RESULTS: Staining for CD133 positively identified stem cells that were found in benign prostatic hyperplasia, benign prostate, and prostate cancer cells. Paraffin embedded sections showed a single type of stem cells, whereas methylene blue-stained Epon sections showed both light and dark stem cells. Electron microscopy showed that both basal and stem cells were closely associated with the basement membrane (basal lamina). Stem cells had smooth plasma and nuclear membranes, a prominent nucleolus, small mitochondria, and few ribosomes. Du145 cells were separated by intercellular spaces in monolayer culture. CONCLUSION: The inverted capsule embedding method allowed the study of metastasized prostate cancer in pelvic lymph nodes. Our approach enabled the assessment of stem cells in tissue sections by light and electron microscopy.


Assuntos
Antígeno AC133/genética , Membrana Basal/ultraestrutura , Hiperplasia Prostática/genética , Neoplasias da Próstata/genética , Membrana Basal/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Microscopia Eletrônica , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/ultraestrutura , Próstata/metabolismo , Próstata/patologia , Próstata/ultraestrutura , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/ultraestrutura
17.
Mediators Inflamm ; 2019: 7894017, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31360119

RESUMO

Investigations on prostate inflammation-related disorders, including acute and chronic prostatitis, chronic pelvic pain syndrome, benign prostate hyperplasia (BPH), and prostate cancer (PCa), are still ongoing to find new, accurate, and noninvasive biomarkers for a differential diagnosis of those pathological conditions sharing some common macroscopic features. Moreover, an ideal biomarker should be useful for risk assessment of prostate inflammation progression to more severe disorders, like BPH or PCa, as well as for monitoring of treatment response and prognosis establishment in carcinoma cases. Recent literature evidence highlighted that changes in the expression of transglutaminases, enzymes that catalyze transamidation reactions leading to posttranslational modifications of soluble proteins, occur in prostate inflammation-related disorders. This review focuses on the role specifically played by transglutaminases 4 (TG4) and 2 (TG2) and suggests that both isoenzymes hold a potential to be included in the list of candidates as novel diagnostic biomarkers for the above-cited prostate pathological conditions.


Assuntos
Biomarcadores Tumorais/metabolismo , Isoenzimas/metabolismo , Transglutaminases/metabolismo , Biomarcadores Tumorais/genética , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Humanos , Isoenzimas/genética , Masculino , Hiperplasia Prostática/genética , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Processamento de Proteína Pós-Traducional , Transglutaminases/genética
18.
Life Sci ; 232: 116626, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276688

RESUMO

PURPOSE: The aim of this study was to investigate the role of the suppressor of activator protein-1 regulated by interferon (SARI), in the development and progression of prostate cancer. METHODS: Sixty-seven prostate cancer tissue specimens and 20 benign prostatic hyperplasia specimens were used to investigate the correlation between SARI expression and clinicopathologic parameters. Immunohistochemistry was used to detect the SARI and E-cadherin protein expression in the prostate cancer and benign prostatic hyperplasia specimens, and their correlation was established. Quantitative PCR (qPCR) was used to determine the SARI mRNA expression in a normal prostate cell line (RWPE-1) and prostate cancer cell lines (LNCaP and PC3). Western blotting was used to detect the SARI protein expression in the RWPE-1, LNCaP, and PC3 cell lines. RESULTS: SARI protein expression did not correlate with the prostate cancer patients' age or serum Prostate-Specific Antigen value but did show a correlation with the tumor stage of prostate cancer and Gleason score. SARI and E-cadherin expression in the prostate cancer tissue was significantly lower than in the benign prostatic hyperplasia specimens, suggesting a positive correlation between the SARI and E-cadherin expression. SARI mRNA and protein were highly expressed in RWPE-1, the normal prostate cell line, but SARI mRNA and protein expression were reduced in the prostate cancer cell lines, LNCaP and PC3. Significant differences in the expression were found between the prostate cancer cell lines and the normal prostate cell line. CONCLUSION: In this study, high SARI expression was found to be negatively correlated with the development and progression of prostate cancer.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Neoplasias da Próstata/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Idoso , Western Blotting , Caderinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Imuno-Histoquímica , Interferons/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Fosfatidilinositol 3-Quinases/metabolismo , Próstata/citologia , Próstata/patologia , Hiperplasia Prostática/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , Fator de Transcrição AP-1/metabolismo , beta Catenina/metabolismo
19.
Prostate ; 79(11): 1199-1210, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31251827

RESUMO

BACKGROUND: With the popularity of serum prostate-specific antigen (PSA) screening, the number of newly diagnosed prostate cancer (PCa) patients is increasing. However, indolent or invasive PCa cannot be distinguished by PSA levels. Here, we mainly explored the role of heterogeneous nuclear ribonucleoprotein M (hnRNPM) in the invasiveness of PCa. METHODS: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis was used to detect the expressions of hnRNPM in PCa and benign prostate hyperplasia (BPH) tissues as well as in PCa cell lines. Immunohistochemistry was applied to detect the hnRNPM or Yin Yang 1 (YY1) expression in BPH, prostate adenocarcinoma (ADENO) and neuroendocrine prostate cancer (NEPC) tissues. After aberrant, the expression of hnRNPM in C4-2 and PC3 cells, the changes of cell migration and invasion were observed through wound-healing and transwell assays. We also predicted the transcription factor of hnRNPM through databases, then verified the association of hnRNPM and YY1 using chromatin immunoprecipitation (ChIP) and luciferase assays. RESULTS: The expression level of hnRNPM is gradually reduced in BPH, ADENO, and NEPC tissues and it is less expressed in more aggressive PCa cell lines. Overexpression of hnRNPM can significantly reduce Twist1 expression, which inhibits the migration and invasion of PCa cells in vitro. In PCa cells, overexpression of YY1 can promote epithelial-mesenchymal transition by reducing hnRNPM expression. Furthermore, this effect caused by overexpression of YY1 can be partially attenuated by simultaneous overexpression of hnRNPM. CONCLUSIONS: Our study demonstrates that hnRNPM negatively regulated PCa cell migration and invasion, and its expression can be transcriptionally inhibited by YY1. We speculated that hnRNPM may be a biomarker to assist in judging the aggressiveness of PCa.


Assuntos
Adenocarcinoma/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/metabolismo , Invasividade Neoplásica/genética , Neoplasias da Próstata/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/genética , Humanos , Masculino , Invasividade Neoplásica/patologia , Hiperplasia Prostática/genética , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Fator de Transcrição YY1/genética , Fator de Transcrição YY1/metabolismo
20.
J Biol Chem ; 294(32): 12231-12249, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31243101

RESUMO

Voiding symptoms in benign prostatic hyperplasia (BPH) are driven by prostate smooth muscle contraction and prostate growth. Smooth muscle contraction in the prostate and other organs critically depends on activation of the small monomeric GTPase RhoA and probably Rac1. A role of another GTPase, ADP-ribosylation factor 6 (ARF6), for smooth muscle contraction has been recently suggested by indirect evidence but remains to be proven for any organ. Here, we report effects of NAV2729, an inhibitor with assumed specificity for ARF6, in human prostate tissues and cultured prostate stromal cells (WPMY-1). NAV2729 (5 µm) inhibited neurogenic and α1-adrenergic contractions of human prostate tissues. Contractions induced by endothelin-1, by the thromboxane A2 agonist U46619, or by high molar KCl were not inhibited. Correlation analyses suggested up-regulation of prostatic ARF6 expression with increasing degree of BPH, as ARF6 expression increased with the content of prostate-specific antigen (PSA) of prostate tissues. NAV2729 inhibited ARF6 activity but not other GTPases (ARF1, RhoA, Rac1) in prostate tissues and in WPMY-1 cells. Proliferation of WPMY-1 cells was inhibited concentration-dependently by NAV2726, as reflected by decreased viability, 5-ethynyl-2'-deoxyuridine (EdU) assay, colony formation assay, and expression of Ki-67. Silencing of ARF6 expression mimicked effects of NAV2729 on viability and in the EdU assay. Effects of NAV2729 on viability and proliferation were attenuated in cells with silenced ARF6 expression. Our findings suggest that a NAV2729-sensitive mechanism promotes adrenergic contraction and stromal cell growth in the human prostate, which is probably ARF6-mediated. Similar actions in other organs and urodynamic effects of NAV2729 appear possible.


Assuntos
Proliferação de Células/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Nitrocompostos/farmacologia , Pirazóis/farmacologia , Pirimidinonas/farmacologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Fatores de Ribosilação do ADP/antagonistas & inibidores , Fatores de Ribosilação do ADP/genética , Fatores de Ribosilação do ADP/metabolismo , Citoesqueleto de Actina/efeitos dos fármacos , Humanos , Masculino , Músculo Liso/fisiologia , Nitrocompostos/química , Norepinefrina/farmacologia , Próstata/citologia , Próstata/efeitos dos fármacos , Próstata/metabolismo , Antígeno Prostático Específico/metabolismo , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Pirazóis/química , Pirimidinonas/química , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Células Estromais/citologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo
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