RESUMEN
BACKGROUND: Direct evidence for the relationship between a large prostate (≥80 ml) and androgen receptor/PSA signal remains lacking in benign prostatic hyperplasia (BPH). Our aim is to identify whether the cause of a large prostate is related to progesterone receptor (PGR) androgen receptor (AR), oestrogen receptor α, ß (ERα,ß) and prostate-specific antigen (PSA). MATERIALS AND METHODS: Surgical specimens of BPH in plasmakinetic resection of the prostate (PKRP) with three groups of different prostate-sizes with mean volumes of 25.97 ml, 63.80 ml, and 122.37 ml were collected for immunohistochemical analysis of the tissue microarray with PGR, AR, PSA and ERs. Rats were castrated and treated with testosterone replacement to explore androgen and PGR, AR and ERs expression levels in the prostate. Quantitative real-time reverse transcription polymerase chain reaction (Rt-PCR) for mRNA detection of above genes was conducted. RESULTS: Immunoblotting, Rt-PCR and immunohistochemistry assays showed that PGR, PSA, AR, ERα expression levels were positively correlated with prostate size and that ERß expression levels were negatively correlated with prostate volume. Animal experiments have shown that prostate volume is decreased in castrated rats with decreased PGR, AR, ERα and increased ERß expression levels. CONCLUSION: PGR, AR, ERs signals can be regarded as important factors for large-sized prostates in BPH patients (≥100 ml).
Asunto(s)
Modelos Animales de Enfermedad , Receptor alfa de Estrógeno , Antígeno Prostático Específico , Próstata , Hiperplasia Prostática , Receptores Androgénicos , Receptores de Progesterona , Masculino , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patología , Animales , Receptores Androgénicos/metabolismo , Receptores de Progesterona/metabolismo , Receptores de Progesterona/análisis , Ratas , Humanos , Antígeno Prostático Específico/sangre , Anciano , Receptor alfa de Estrógeno/metabolismo , Receptor alfa de Estrógeno/análisis , Próstata/metabolismo , Próstata/patología , Ratas Sprague-Dawley , Persona de Mediana Edad , Receptores de Estrógenos/metabolismo , Receptores de Estrógenos/análisis , Receptor beta de Estrógeno/metabolismo , Receptor beta de Estrógeno/análisis , Tamaño de los ÓrganosRESUMEN
Myofibroblast buildup and prostatic fibrosis play a crucial role in the development of benign prostatic hyperplasia (BPH). Treatments specifically targeting myofibroblasts could be a promising approach for treating BPH. Tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor, holds the potential to intervene in this biological process. This study employs prostatic stromal fibroblasts to induce myofibroblast differentiation through TGFß1 stimulation. As a result, tadalafil significantly inhibited prostatic stromal fibroblast proliferation and fibrosis process, compared to the control group. Furthermore, our transcriptome sequencing results revealed that tadalafil inhibited FGF9 secretion and simultaneously improved miR-3126-3p expression via TGFß1 suppression. Overall, TGFß1 can trigger pro-fibrotic signaling through miR-3126-3p in the prostatic stroma, and the use of tadalafil can inhibit this process.
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Factor 9 de Crecimiento de Fibroblastos , Fibrosis , MicroARNs , Inhibidores de Fosfodiesterasa 5 , Hiperplasia Prostática , Tadalafilo , Masculino , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/tratamiento farmacológico , Hiperplasia Prostática/genética , MicroARNs/genética , MicroARNs/metabolismo , Tadalafilo/farmacología , Inhibidores de Fosfodiesterasa 5/farmacología , Humanos , Factor 9 de Crecimiento de Fibroblastos/metabolismo , Factor 9 de Crecimiento de Fibroblastos/genética , Próstata/efectos de los fármacos , Próstata/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/efectos de los fármacos , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Proliferación Celular/efectos de los fármacosRESUMEN
The kallikrein-related peptidase KLK2 has restricted expression in the prostate luminal epithelium, and its protein target is unknown. The present work reports the hydrolytic activities of KLK2 on libraries of fluorescence resonance energy-transfer peptides from which the sequence SYRIF was the most susceptible substrate for KLK2. The sequence SYRIF is present at the extracellular N-terminal segment (58SYRIF63Q) of IL-10R2. KLK2 was fully active at pH 8.0-8.2, found only in prostate inflammatory conditions, and strongly activated by sodium citrate and glycosaminoglycans, the quantities and structures controlled by prostate cells. Bone-marrow-derived macrophages (BMDM) have IL-10R2 expressed on the cell surface, which is significantly reduced after KLK2 treatment, as determined by flow cytometry (FACS analysis). The IL-10 inhibition of the inflammatory response to LPS/IFN-γ in BMDM cells due to decreased nitric oxide, TNF-α, and IL-12 p40 levels is significantly reduced upon treatment of these cells with KLK2. Similar experiments with KLK3 did not show these effects. These observations indicate that KLK2 proteolytic activity plays a role in prostate inflammation and makes KLK2 a promising target for prostatitis treatment.
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Calicreínas , Humanos , Masculino , Calicreínas/metabolismo , Calicreínas/química , Arginina/metabolismo , Arginina/química , Próstata/metabolismo , Próstata/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Animales , Ratones , Péptidos/química , Péptidos/farmacología , Péptidos/metabolismo , Dominios Proteicos , Interleucina-10/metabolismo , Especificidad por SustratoRESUMEN
Paradoxical sleep deprivation (PSD) presents different effects on metabolism and neurological functions. In addition, over long duration, sleep restriction (SR) can promote permanent changes. The prostate is an endocrine-dependent organ with homeostatic regulation directly related to hormone levels. Our study proposed to demonstrate the experimental prostatic effects of PSD (96 h), PSD with recovery (PSR - 96/96 h), and sleep restriction (SR - 30 PSD cycles/recovery). PSD and SR promoted decrease in serum testosterone and significant increase in serum and intraprostatic corticosterone. In agreement, androgen receptors (AR) were less expressed and glucocorticoid receptors (GR) were enhanced in PSR and SR. Thus, the prostate, especially under SR, demonstrates a castration-like effect due to loss of responsiveness and sensitization by androgens. SR triggered an important inflammatory response through enhancement of serum and intraprostatic pro- (IL-1α, IL-6, TNF-α) and anti-inflammatory (IL-10) cytokines. Furthermore, the respective receptors of anti-inflammatory cytokines (IL-1RI and TNF-R) were highly expressed in the prostatic epithelium and stroma. PSR can partially restore prostate homeostasis, as it restores testosterone and the prostate proliferation index, in addition to promoting balance in the inflammatory response that is considered protective. PSD and SR are key factors in the endocrine axis that coordinate prostatic homeostasis, and significant changes in these factors have consequences on prostate functionality.
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Gerbillinae , Próstata , Receptores Androgénicos , Privación de Sueño , Testosterona , Animales , Masculino , Privación de Sueño/metabolismo , Privación de Sueño/patología , Próstata/metabolismo , Próstata/patología , Testosterona/sangre , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Corticosterona/sangre , Citocinas/metabolismo , Inflamación/metabolismo , Inflamación/patología , Castración , Andrógenos/metabolismoRESUMEN
Benign prostatic hyperplasia (BPH) may decrease patient quality of life and often leads to acute urinary retention and surgical intervention. While effective treatments are available, many BPH patients do not respond or develop resistance to treatment. To understand molecular determinants of clinical symptom persistence after initiating BPH treatment, we investigated gene expression profiles before and after treatments in the prostate transitional zone of 108 participants in the Medical Therapy of Prostatic Symptoms (MTOPS) Trial. Unsupervised clustering revealed molecular subgroups characterized by expression changes in a large set of genes associated with resistance to finasteride, a 5α-reductase inhibitor. Pathway analyses within this gene cluster found finasteride administration induced changes in fatty acid metabolism, amino acid metabolism, immune response, steroid hormone metabolism, and kinase activity within the transitional zone. We found that patients without this transcriptional response were highly likely to develop clinical progression, which is expected in 13.2% of finasteride-treated patients. Importantly, a patient's transcriptional response to finasteride was associated with their pre-treatment kinase expression. Further, we identified novel expression signatures of finasteride resistance among the transcriptionally responded patients. These patients showed different gene expression profiles at baseline and increased prostate transitional zone volume compared to the patients who responded to the treatment. Our work suggests molecular mechanisms of clinical resistance to finasteride treatment that could be potentially helpful for personalized BPH treatment as well as new drug development to increase patient drug response.
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Doxazosina , Finasterida , Próstata , Enfermedades de la Próstata , Próstata/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Finasterida/farmacología , Finasterida/uso terapéutico , Doxazosina/farmacología , Doxazosina/uso terapéutico , Agentes Urológicos/farmacología , Agentes Urológicos/uso terapéutico , Resistencia a Medicamentos , Enfermedades de la Próstata/tratamiento farmacológico , HumanosRESUMEN
Chronic prostatitis is one of the most common urologic diseases that troubles young men, with unclear etiology and ineffective treatment approach. Pyroptosis is a novel model of cell death, and its roles in chronic prostatitis are unknown. In this study, P2X7R, NEK7, and GSDMD-NT expression levels were detected in prostate tissues from benign prostate hyperplasia (BPH) patients and experiment autoimmune prostatitis (EAP) mice. P2X7R agonist, antagonist, NLRP3 inhibitor, and disulfiram were used to explore the roles of the P2X7R-NEK7-NLRP3 axis in prostate epithelial cell pyroptosis and chronic prostatitis development. We found that P2X7R, NEK7, and GSDMD-NT were highly expressed in the prostate epithelial cells of BPH patients with prostatic inflammation and EAP mice. Activation of P2X7R exacerbated prostatic inflammation and increased NLRP3 inflammasome component expressions and T helper 17 (Th17) cell proportion. Moreover, P2X7R-mediated potassium efflux promoted NEK7-NLRP3 interaction, and NLRP3 assembly and activation, which caused GSDMD-NT-mediated prostate epithelial cell pyroptosis to exacerbate EAP development. Disulfiram could effectively improve EAP by inhibiting GSDMD-NT-mediated prostate epithelial cell pyroptosis. In conclusion, the P2X7R-NEK7-NLRP3 axis could promote GSDMD-NT-mediated prostate epithelial cell pyroptosis and chronic prostatitis development, and disulfiram may be an effective drug to treat chronic prostatitis.
Asunto(s)
Células Epiteliales , Quinasas Relacionadas con NIMA , Proteína con Dominio Pirina 3 de la Familia NLR , Proteínas de Unión a Fosfato , Próstata , Prostatitis , Piroptosis , Animales , Humanos , Masculino , Ratones , Enfermedades Autoinmunes/metabolismo , Células Epiteliales/metabolismo , Gasderminas , Ratones Endogámicos C57BL , Quinasas Relacionadas con NIMA/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas de Unión a Fosfato/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Próstata/metabolismo , Prostatitis/metabolismo , Piroptosis/efectos de los fármacos , Receptores Purinérgicos P2X7/metabolismoRESUMEN
BACKGROUND: From the first steps of prostate cancer (PCa) initiation, tumours are in contact with the most-proximal adipose tissue called periprostatic adipose tissue (PPAT). Extracellular vesicles are important carriers of non-coding RNA such as miRNAs that are crucial for cellular communication. The secretion of extracellular vesicles by PPAT may play a key role in the interactions between adipocytes and tumour. Analysing the PPAT exovesicles (EVs) derived-miRNA content can be of great relevance for understanding tumour progression and aggressiveness. METHODS: A total of 24 samples of human PPAT and 17 samples of perivesical adipose tissue (PVAT) were used. EVs were characterized by western blot and transmission electron microscopy (TEM), and uptake by PCa cells was verified by confocal microscopy. PPAT and PVAT explants were cultured overnight, EVs were isolated, and miRNA content expression profile was analysed. Pathway and functional enrichment analyses were performed seeking potential miRNA targets. In vitro functional studies were evaluated using PCa cells lines, miRNA inhibitors and target gene silencers. RESULTS: Western blot and TEM revealed the characteristics of EVs derived from PPAT (PPAT-EVs) samples. The EVs were up taken and found in the cytoplasm of PCa cells. Nine miRNAs were differentially expressed between PPAT and PVAT samples. The RORA gene (RAR Related Orphan Receptor A) was identified as a common target of 9 miRNA-regulated pathways. In vitro functional analysis revealed that the RORA gene was regulated by PPAT-EVs-derived miRNAs and was found to be implicated in cell proliferation and inflammation. CONCLUSION: Tumour periprostatic adipose tissue is linked to PCa tumour aggressiveness and could be envisaged for new therapeutic strategies.
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Tejido Adiposo , Proliferación Celular , Vesículas Extracelulares , Regulación Neoplásica de la Expresión Génica , Inflamación , MicroARNs , Neoplasias de la Próstata , Humanos , Masculino , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Línea Celular Tumoral , Vesículas Extracelulares/metabolismo , Inflamación/patología , Inflamación/genética , MicroARNs/metabolismo , MicroARNs/genética , Próstata/patología , Próstata/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismoRESUMEN
OBJECTIVE: To determine the therapeutic effects of the Zhuangyao Jianshen pill (, ZYJSP) against benign prostatic hyperplasia (BPH) and investigate the underlying mechanism. METHODS: Forty-eight male Sprague-Dawley rats were randomly divided into six groups: Control group, BPH model group, finasteride-treated group, ZYJSP low, medium and high dose groups. Except for the control group, 40 rats were castrated and injected with testosterone propionate (TP) for 28 consecutive day to induce BPH. Meanwhile, the corresponding drugs were administered by gavage. The prostate wet weight, prostate index (PI), and the histopathological changes in the prostate were measured as the basis for examining the efficacy of ZYJSP against BPH. Levels of the serum sex hormones, oxidative stress markers, inflammatory markers, renal function markers, growth factors, and Cyclin D1 expression in prostate were measured to characterize the therapeutic mechanism of ZYJSP against BPH. RESULTS: ZYJSP administration significantly reduced prostate wet weight and PI and ameliorated histological changes of the prostate in TP-treated castrated rats. TP markedly increased the levels of creatinine, blood urea nitrogen and growth factors in the serum as well as the expression of the Cyclin D1 in the prostate. Most of these markers were significantly decreased by ZYJSP. ZYJSP significantly restored the dysregulation of testosterone, estradiol, and dihydrotestosterone caused by TP. Furthermore, ZYJSP relieved TP-induced prostate injury and exhibited both anti-inflammatory and anti-oxidant activity by decreasing interleukin-6, interleukin-8, and malondialdehyde levels and increasing the activity of superoxide dismutase in the serum. CONCLUSION: These findings indicate that ZYJSP can effectively ameliorate BPH induced by TP in castrated rats, and the underlying mechanism might be related to regulating sex hormone balance, reducing oxidative stress, and inhibiting the inflammatory response.
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Medicamentos Herbarios Chinos , Hiperplasia Prostática , Ratas Sprague-Dawley , Testosterona , Animales , Masculino , Hiperplasia Prostática/tratamiento farmacológico , Hiperplasia Prostática/inducido químicamente , Medicamentos Herbarios Chinos/administración & dosificación , Ratas , Testosterona/sangre , Humanos , Estrés Oxidativo/efectos de los fármacos , Próstata/efectos de los fármacos , Próstata/metabolismo , Próstata/patologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Anemarrhena asphodeloides Bunge (Ane) and Phellodendron chinense C. K. Schneid (Phe) is classical herb pair in traditional Chinese medicine, commonly used to ameliorate the symptoms of Benign Prostatic Hyperplasia (BPH). However, the mechanisms underlying this effect are remained indistinct. AIM OF THE STUDY: This study aimed to clarify potential therapeutic mechanisms of herb pair on BPH from a metabolic perspective. MATERIALS AND METHODS: Testosterone propionate-induced BPH rat model was established, prostatic parameters, histopathology and the levels of serum dihydrotestosterone (DHT) and testosterone (T) were used to evaluate the pharmacological effect of the herb pair on BPH. Subsequently, untargeted metabolomics of prostate tissues samples was performed by UHPLC-Q-Exactive-Orbitrap-MS, followed by multivariate statistical analysis. Targeted metabolomics by UHPLC-QQQ-MS was further utilized to verify and supplement the results of lipids and amino acids found by untargeted metabolomics, clarifying the relationship between disease, herbal pair and metabolism pathway. RESULTS: The study found that Ane-Phe could relieve the progression of BPH and regulate metabolic imbalances. The levels of 13 metabolites decreased and 11 increased in prostatic tissues including glycerolphospholipid, arachidonic acid, citric acid and so on, these altered metabolites were primarily associated with TCA cycle, arachidonic acid metabolism, lipid metabolism and amino acid metabolism. Furthermore, targeted metabolomics was fulfilled to further analyze the lipid metabolism disorders, the levels of 5 lipids in serum and 21 in prostatic tissues were changed in the herb pair group compared to the model group, which closely related to glycerophospholipid, sphingolipid and glycerolipid metabolism. Besides, amino acid metabolism may be regulated by activating arginine metabolism pathway. CONCLUSIONS: In this study, the combination of untargeted metabolomics and targeted metabolomics was applied to explore therapeutic mechanisms of Ane-Phe on BPH. In summary, Ane-Phe could improve the levels of endogenous metabolites by regulating multiple metabolic pathways and plays a role in energy supply, anti-inflammation and oxidative stress in BPH treatment.
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Anemarrhena , Metabolómica , Phellodendron , Hiperplasia Prostática , Ratas Sprague-Dawley , Masculino , Hiperplasia Prostática/tratamiento farmacológico , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patología , Animales , Phellodendron/química , Anemarrhena/química , Ratas , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Próstata/efectos de los fármacos , Próstata/metabolismo , Próstata/patología , Modelos Animales de Enfermedad , Cromatografía Líquida de Alta PresiónRESUMEN
Benign Prostatic Hyperplasia (BPH) is a complex condition leading to Lower Urinary Tract Symptoms in aging men, characterized by cellular proliferation, smooth muscle dysfunction, inflammation, and fibrosis. While BPH is known to involve heightened macrophage infiltration, the specific contribution of infiltrating monocytes/macrophages to the disease mechanism remains uncertain. This research explores the impact of reducing circulating monocytes and subsequently limiting their tissue infiltration by using Ccr2 knockout (Ccr2-KO) mice. Ccr2-KO and wild type mice were implanted with testosterone and estradiol (T + E2, 25 mg + 2.5 mg) pellets. Urinary function was assessed via weekly void spot assays over 12 weeks, and prostatic macrophage levels were visualized and quantified in tissue sections using an F4/80 antibody. Additionally, Ki-67 staining was used to evaluate cell proliferation, and picrosirius red staining to assess collagen accumulation. Increased voiding frequency which developed in T + E2 mice, was significantly ameliorated in Ccr2-KO mice, however, both Ccr2-KO and wild type (WT) mice showed increased bladder weights after three month, representing a hypertrophic response to bladder outlet obstruction. T + E2 substantially increased the density of macrophages in WT but not Ccr2-KO mouse prostate. Proliferation rate, as indicated by Ki-67 positivity, was elevated in the vental and anterior prostate lobes but was only marginally reduced in Ccr2-KO mice. Most importantly, a significant prostatic collagen accumulation was observed in WT mice that was markedly reduced by Ccr2 deficiency post T + E2 treatment. The absence of Ccr2 mitigates urinary dysfunction and alters prostatic macrophage levels and collagen accumulation in steroid hormone imbalance. These findings suggest a crucial role for monocyte infiltration, giving rise to macrophages or other cell derivatives, to drive fibrosis.
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Estradiol , Fibrosis , Macrófagos , Ratones Noqueados , Monocitos , Próstata , Receptores CCR2 , Testosterona , Animales , Masculino , Receptores CCR2/metabolismo , Macrófagos/metabolismo , Ratones , Monocitos/metabolismo , Próstata/metabolismo , Próstata/patología , Testosterona/metabolismo , Estradiol/metabolismo , Estradiol/farmacología , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patología , Proliferación Celular , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Benign prostatic hyperplasia (BPH) is a condition generally associated with advanced age in men that can be accompanied by bothersome lower urinary tract symptoms (LUTS) including intermittency, weak stream, straining, urgency, frequency, and incomplete bladder voiding. Pharmacotherapies for LUTS/BPH include alpha-blockers, which relax prostatic and urethral smooth muscle and 5É-reductase inhibitors such as finasteride, which can block conversion of testosterone to dihydrotestosterone thereby reducing prostate volume. Celecoxib is a cyclooxygenase-2 inhibitor that reduces inflammation and has shown some promise in reducing prostatic inflammation and alleviating LUTS for some men with histological BPH. However, finasteride and celecoxib can reduce mitochondrial function in some contexts, potentially impacting their efficacy for alleviating BPH-associated LUTS. METHODS: To determine the impact of these pharmacotherapies on mitochondrial function in prostate tissues, we performed immunostaining of mitochondrial Complex I (CI) protein NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) and inflammatory cells on BPH specimens from patients naïve to treatment, or who were treated with celecoxib and/or finasteride for 28 days, as well as prostate tissues from male mice treated with celecoxib or vehicle control for 28 days. Quantification and statistical correlation analyses of immunostaining were performed. RESULTS: NDUFS3 immunostaining was decreased in BPH compared to normal adjacent prostate. Patients treated with celecoxib and/or finasteride had significantly decreased NDUFS3 in both BPH and normal tissues, and no change in inflammatory cell infiltration compared to untreated patients. Mice treated with celecoxib also displayed a significant decrease in NDUFS3 immunostaining and no change in inflammatory cell infiltration. CONCLUSIONS: These findings suggest that celecoxib and/or finasteride are associated with an overall decrease in NDUFS3 levels in prostate tissues but do not impact the presence of inflammatory cells, suggesting a decline in mitochondrial CI function in the absence of enhanced inflammation. Given that BPH has recently been associated with increased prostatic mitochondrial dysfunction, celecoxib and/or finasteride may exacerbate existing mitochondrial dysfunction in some BPH patients thereby potentially limiting their overall efficacy in providing metabolic stability and symptom relief.
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Celecoxib , Finasterida , Hiperplasia Prostática , Masculino , Hiperplasia Prostática/tratamiento farmacológico , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patología , Finasterida/farmacología , Finasterida/uso terapéutico , Humanos , Animales , Celecoxib/farmacología , Celecoxib/uso terapéutico , Ratones , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Anciano , Próstata/efectos de los fármacos , Próstata/patología , Próstata/metabolismo , Inhibidores de 5-alfa-Reductasa/farmacología , Inhibidores de 5-alfa-Reductasa/uso terapéutico , Transporte de Electrón/efectos de los fármacos , Persona de Mediana Edad , Proteínas Mitocondriales/metabolismo , Síntomas del Sistema Urinario Inferior/tratamiento farmacológico , Síntomas del Sistema Urinario Inferior/metabolismo , Síntomas del Sistema Urinario Inferior/patología , Complejo I de Transporte de Electrón/metabolismoRESUMEN
The prevailing biomarker employed for prostate cancer (PCa) screening and diagnosis is the prostate-specific antigen (PSA). Despite excellent sensitivity, PSA lacks specificity, leading to false positives, unnecessary biopsies and overdiagnosis. Consequently, PSA is increasingly less used by clinicians, thus underscoring the imperative for the identification of new biomarkers. An emerging biomarker in this context is citrate, a molecule secreted by the normal prostate, which has been shown to be inversely correlated with PCa. Here, we discuss about PSA and its usage for PCa diagnosis, its lack of specificity, and the various conditions that can affect its levels. We then provide our vision about what we think would be a valuable addition to our PCa diagnosis toolkit, citrate. We describe the unique citrate metabolic program in the prostate and how this profile is reprogrammed during carcinogenesis. Finally, we summarize the evidence that supports the usage of citrate as a biomarker for PCa diagnosis, as it can be measured in various patient samples and be analyzed by several methods. The unique relationship between citrate and PCa, combined with the stability of citrate levels in other prostate-related conditions and the simplicity of its detection, further accentuates its potential as a biomarker.
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Biomarcadores de Tumor , Ácido Cítrico , Antígeno Prostático Específico , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/metabolismo , Antígeno Prostático Específico/sangre , Biomarcadores de Tumor/sangre , Ácido Cítrico/metabolismo , Próstata/patología , Próstata/metabolismoRESUMEN
To detect and analyze the changes of microorganisms in expressed prostatic secretion (EPS) of patients with IIIB prostatitis before and after low-intensity pulsed ultrasound (LIPUS) treatment, and to explore the mechanism of LIPUS in the treatment of chronic prostatitis (CP). 25 patients (study power was estimated using a Dirichlet-multinomial approach and reached 96.5% at α = 0.05 using a sample size of 25) with IIIB prostatitis who were effective in LIPUS treatment were divided into two groups before and after LIPUS treatment. High throughput second-generation sequencing technique was used to detect and analyze the relative abundance of bacterial 16 s ribosomal variable regions in EPS before and after treatment. The data were analyzed by bioinformatics software and database, and differences with P < 0.05 were considered statistically significant. Beta diversity analysis showed that there was a significant difference between groups (P = 0.046). LEfSe detected four kinds of characteristic microorganisms in the EPS of patients with IIIB prostatitis before and after LIPUS treatment. After multiple comparisons among groups by DESeq2 method, six different microorganisms were found. LIPUS may improve patients' clinical symptoms by changing the flora structure of EPS, stabilizing and affecting resident bacteria or opportunistic pathogens.
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Próstata , Prostatitis , Ondas Ultrasónicas , Humanos , Masculino , Prostatitis/terapia , Prostatitis/microbiología , Prostatitis/metabolismo , Próstata/microbiología , Próstata/metabolismo , Próstata/patología , Adulto , Bacterias/metabolismo , Bacterias/genética , Persona de Mediana Edad , Terapia por Ultrasonido/métodos , Microbiota , ARN Ribosómico 16S/genéticaRESUMEN
Dysregulation of zinc and zinc transporters families has been associated with the genesis and progression of prostate cancer. The prostate epithelium utilizes two types of zinc transporters, the ZIP (Zrt-, Irt-related Protein) and the ZnTs (Zinc Transporter), to transport zinc from the blood plasma to the gland lumen. ZIP transporters uptake zinc from extracellular space and organelle lumen, while ZnT transporters release zinc outside the cells or to organelle lumen. In prostate cancer, a commonly observed low zinc concentration in prostate tissue has been correlated with downregulations of certain ZIPs (e.g., ZIP1, ZIP2, ZIP3, ZIP14) and upregulations of specific ZnTs (e.g., ZnT1, ZnT9, ZnT10). These alterations may enable cancer cells to adapt to toxic high zinc levels. While zinc supplementation has been suggested as a potential therapy for this type of cancer, studies have yielded inconsistent results because some trials have indicated that zinc supplementation could exacerbate cancer risk. The reason for this discrepancy remains unclear, but given the high molecular and genetic variability present in prostate tumors, it is plausible that some zinc transporters-comprising 14 ZIP and 10 ZnT members-could be dysregulated in others patterns that promote cancer. From this perspective, this review highlights novel dysregulation, such as ZIP-Up/ZnT-Down, observed in prostate cancer cell lines for ZIP4, ZIP8, ZnT2, ZnT4, ZnT5, etc. Additionally, an in silico analysis of an available microarray from mouse models of prostate cancer (Nkx3.1;Pten) predicts similar dysregulation pattern for ZIP4, ZIP8, and ZnT2, which appear in early stages of prostate cancer progression. Furthermore, similar dysregulation patterns are supported by an in silico analysis of RNA-seq data from human cancer tumors available in cBioPortal. We discuss how these dysregulations of zinc transporters could impact zinc supplementation trials, particularly focusing on how the ZIP-Up/ZnT-Down dysregulation through various mechanisms might promote prostate cancer progression.
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Proteínas de Transporte de Catión , Neoplasias de la Próstata , Zinc , Humanos , Masculino , Neoplasias de la Próstata/metabolismo , Zinc/metabolismo , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/genética , Animales , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , Regulación Neoplásica de la Expresión Génica , Suplementos Dietéticos , Próstata/metabolismoRESUMEN
Glyphosate, the active ingredient of several broad-spectrum herbicides, is widely used throughout the world, although many adverse effects are known. Among these, it has been recognized as an endocrine disruptor. This work aimed to test the effects and potential endocrine disrupting action of glyphosate on PNT1A human prostate cells, an immortalized non-tumor epithelial cell line, possessing both ERα and ERß estrogen receptors. The results showed that glyphosate induces cytotoxicity, mitochondrial dysfunction, and rapid activation of ERα and ERß via nuclear translocation. Molecular analysis indicated a possible involvement of apoptosis in glyphosate-induced cytotoxicology. The apoptotic process could be attributed to alterations in mitochondrial metabolism; therefore, the main parameters of mitochondrial functionality were investigated using the Seahorse analyzer. Impaired mitochondrial function was observed in glyphosate-treated cells, with reductions in ATP production, spare respiratory capacity, and proton leakage, along with increased efficiency of mitochondrial coupling. Finally, the results of immunofluorescence analysis demonstrated that glyphosate acts as an estrogen disruptor determining the nuclear translocation of both ERs. Nuclear translocation occurred independent of dose, faster than the specific hormone, and persisted throughout treatment. In conclusion, the results collected show that in non-tumor prostate cells glyphosate can cause cell death and acts as a xenoestrogen, activating estrogen receptors. The consequent alteration of hormonal functions can have negative effects on the reproductive health of exposed animals, compromising their fertility.
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Apoptosis , Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Glicina , Glifosato , Mitocondrias , Próstata , Glicina/análogos & derivados , Glicina/farmacología , Glicina/toxicidad , Humanos , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Receptor beta de Estrógeno/metabolismo , Receptor alfa de Estrógeno/metabolismo , Próstata/efectos de los fármacos , Próstata/metabolismo , Próstata/patología , Apoptosis/efectos de los fármacos , Línea Celular , Herbicidas/toxicidad , Disruptores Endocrinos/toxicidad , Disruptores Endocrinos/farmacología , Supervivencia Celular/efectos de los fármacosRESUMEN
Hyperpolarised magnetic resonance imaging (HP-13C-MRI) has shown promise as a clinical tool for detecting and characterising prostate cancer. Here we use a range of spatially resolved histological techniques to identify the biological mechanisms underpinning differential [1-13C]lactate labelling between benign and malignant prostate, as well as in tumours containing cribriform and non-cribriform Gleason pattern 4 disease. Here we show that elevated hyperpolarised [1-13C]lactate signal in prostate cancer compared to the benign prostate is primarily driven by increased tumour epithelial cell density and vascularity, rather than differences in epithelial lactate concentration between tumour and normal. We also demonstrate that some tumours of the cribriform subtype may lack [1-13C]lactate labelling, which is explained by lower epithelial lactate dehydrogenase expression, higher mitochondrial pyruvate carrier density, and increased lipid abundance compared to lactate-rich non-cribriform lesions. These findings highlight the potential of combining spatial metabolic imaging tools across scales to identify clinically significant metabolic phenotypes in prostate cancer.
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Ácido Láctico , Imagen por Resonancia Magnética , Fenotipo , Neoplasias de la Próstata , Masculino , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Humanos , Ácido Láctico/metabolismo , Imagen por Resonancia Magnética/métodos , Próstata/diagnóstico por imagen , Próstata/metabolismo , Próstata/patología , Isótopos de Carbono , Clasificación del Tumor , Mitocondrias/metabolismo , L-Lactato Deshidrogenasa/metabolismoRESUMEN
Urine is a complex biofluid that reflects both overall physiologic state and the state of the genitourinary tissues through which it passes. It contains both secreted proteins and proteins encapsulated in tissue-derived extracellular vesicles (EVs). To understand the population variability and clinical utility of urine, we quantified the secreted and EV proteomes from 190 men, including a subset with prostate cancer. We demonstrate that a simple protocol enriches prostatic proteins in urine. Secreted and EV proteins arise from different subcellular compartments. Urinary EVs are faithful surrogates of tissue proteomes, but secreted proteins in urine or cell line EVs are not. The urinary proteome is longitudinally stable over several years. It can accurately and non-invasively distinguish malignant from benign prostatic lesions and can risk-stratify prostate tumors. This resource quantifies the complexity of the urinary proteome and reveals the synergistic value of secreted and EV proteomes for translational and biomarker studies.
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Vesículas Extracelulares , Neoplasias de la Próstata , Proteoma , Humanos , Neoplasias de la Próstata/orina , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Masculino , Vesículas Extracelulares/metabolismo , Proteoma/metabolismo , Anciano , Biomarcadores de Tumor/orina , Biomarcadores de Tumor/metabolismo , Proteómica/métodos , Persona de Mediana Edad , Próstata/metabolismo , Próstata/patología , Línea Celular TumoralRESUMEN
BACKGROUND: Chronic infection and inflammation have been linked to the development of prostate cancer. Dysbiosis of the oral and gut microbiomes and subsequent microbial translocation can lead to pathogenic prostate infections. Microbial-produced metabolites have also been associated with signaling pathways that promote prostate cancer development. A comprehensive discussion on the mechanisms of microbiome infection and the prostate microenvironment is essential to understand prostate carcinogenesis. METHODS: Published studies were used from the National Center for Biotechnology Information (NCBI) database to conduct a narrative review. No restrictions were applied in the selection of articles. RESULTS: Microbiome-derived short-chain fatty acids (SCFAs) have been found to upregulate multiple signaling pathways, including MAPK and PI3K, through IGF-1 signaling and M2 macrophage polarization. SCFAs can also upregulate Toll-like receptors, leading to chronic inflammation and the creation of a pro-prostate cancer environment. Dysbiosis of oral microbiota has been correlated with prostate infection and inflammation. Additionally, pathogenic microbiomes associated with urinary tract infections have shown a link to prostate cancer, with vesicoureteral reflux potentially contributing to prostate infection. CONCLUSIONS: This review offers a comprehensive understanding of the impact of microbial infections linked to intraprostatic inflammation as a causative factor for prostate cancer. Further studies involving the manipulation of the microbiome and its produced metabolites may provide a more complete understanding of the microenvironmental mechanisms that promote prostate carcinogenesis.
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Microbiota , Neoplasias de la Próstata , Neoplasias de la Próstata/microbiología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Humanos , Masculino , Microbiota/fisiología , Prostatitis/microbiología , Prostatitis/metabolismo , Prostatitis/patología , Prostatitis/inmunología , Inflamación/microbiología , Inflamación/metabolismo , Disbiosis/microbiología , Próstata/microbiología , Próstata/patología , Próstata/metabolismo , Animales , Microambiente TumoralRESUMEN
The prostate gland is one of the main sites of hyperplasia and cancer in elderly men. Numerous factors have been demonstrated to disrupt prostate homeostasis, including exposure to environmental pollutants. Arsenic is a metalloid found ubiquitously in soil, air, and water, which favors human poisoning through the involuntary intake of contaminated drinking water and food and has harmful effects by increasing the oxidative stress response. This study aimed to investigate the effects of prolonged exposure to arsenic at environmentally relevant concentrations on the prostate biology of adult Wistar rats. Thirty 80-day-old male rats were divided into three experimental groups. Rats from the control group received filtered water, whereas animals from the arsenic groups ingested 1â¯mgâ¯L-1 and 10â¯mgâ¯L-1 of arsenic, in the form of sodium arsenite, daily. The arsenic solutions were provided ad libitum in the drinking water for eight weeks. Our results showed that 1â¯mgâ¯L-1 and 10â¯mgâ¯L-1 of arsenic made the prostate susceptible to evolving benign and premalignant histopathological changes. While the ingestion of 1â¯mgâ¯L-1 of arsenic reduced SOD activity only, 10â¯mgâ¯L-1 diminished SOD and CAT activity in the prostate tissue, culminating in high MDA production. These doses, however, did not affect the intraprostatic levels of DHT and estradiol. In conclusion, exposure to arsenic at environmentally relevant concentrations through drinking water induces histological and oxidative stress-related changes in the prostate of adult rats, strengthening the between arsenic exposure and prostate disorders.
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Estrés Oxidativo , Próstata , Ratas Wistar , Animales , Masculino , Estrés Oxidativo/efectos de los fármacos , Próstata/efectos de los fármacos , Próstata/patología , Próstata/metabolismo , Superóxido Dismutasa/metabolismo , Arsénico/toxicidad , Contaminantes Ambientales/toxicidad , Arsenitos/toxicidad , Catalasa/metabolismo , Compuestos de Sodio/toxicidad , Ratas , Malondialdehído/metabolismo , Estradiol/sangreRESUMEN
Bisphenol F (BPF) has gained prominence as an alternative to bisphenol A (BPA) in various manufacturing applications, yet being detected in diverse environments and posed potential public health risk. This research aims to elucidate the putative toxic targets and underlying molecular mechanisms of prostate injury induced by exposure to BPF through multi-level bioinformatics data, integrating network toxicology and molecular docking. Systematically leveraging multilevel databases, we determined 276 targets related to BPF and prostate injury. Subsequent screenings through STRING and Cytoscape tool highlighted 27 key targets, including BCL2, HSP90AA1, MAPK3, ESR1, and CASP3. GO and KEGG enrichment analyses demonstrated enrichment of targets involved in apoptosis, abnormal hormonal activities, as well as cancer-related signal transduction cascades, ligand-receptor interaction networks, and endocrine system signaling pathways. Molecular docking simulations conducted via Autodock corroborated high-affinity binding interaction between BPF and key targets. The results indicate that BPF exposure can contribute to the initiation and progression of prostate cancer and prostatic hyperplastic by modulating apoptosis and proliferation, altering nerve function in blood vessel endothelial cells, and disrupting androgen metabolism. This study offers theoretical underpinnings for comprehending the molecular mechanisms implicated in BPF-elicited prostatic toxicity, while concomitantly establishing foundational framework for the development of prophylactic and therapeutic strategies for prostatic injuries related to polycarbonate and epoxy resin plastics incorporated with BPF, as well as environments afflicted by elevated levels of these compounds.