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The Journal of Clinical Investigation Dec 2023Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA...
Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA utilization in the prostate gland correlated with tumor aggressiveness at early disease stages, and 3βHSD1 inhibitors were promising for early intervention. [3H]-labeled DHEA consumption was traced in fresh prostatic biopsies ex vivo. Active DHEA utilization was more frequently found in patients with metastatic disease or therapy-resistant disease. Genetic and transcriptomic features associated with the potency of prostatic DHEA utilization were analyzed to generate clinically accessible approaches for patient stratification. UBE3D, by regulating 3βHSD1 homeostasis, was discovered to be a regulator of patient metabolic heterogeneity. Equilin suppressed DHEA utilization and inhibited tumor growth as a potent 3βHSD1 antagonist, providing a promising strategy for the early treatment of aggressive prostate cancer. Overall, our findings indicate that patients with active prostatic DHEA utilization might benefit from 3βHSD1 inhibitors as early intervention.
Topics: Male; Humans; Prostate; Dehydroepiandrosterone; Prostatic Neoplasms
PubMed: 38099500
DOI: 10.1172/JCI171199 -
Phytotherapy Research : PTR Jan 2024Ursolic acid (UA) is a naturally occurring pentacyclic triterpenoid widely found in fruits and vegetables. It has been reported that UA has anti-inflammatory effects....
Ursolic acid (UA) is a naturally occurring pentacyclic triterpenoid widely found in fruits and vegetables. It has been reported that UA has anti-inflammatory effects. However, its efficacy and mechanism of action in the treatment of chronic prostatitis (CP) remain unclear. This study aimed to investigate the efficacy of UA treatment in CP and further explore the underlying mechanism. CP rat and pyroptosis cell models were established in vivo and in vitro, respectively. The efficacy of UA in inhibiting CP was evaluated via haematoxylin-eosin (HE) staining and measurement of inflammatory cytokines. RNA sequencing and molecular docking were used to predict the therapeutic targets of UA in CP. The expression of pyroptosis-related proteins was examined using various techniques, including immunohistochemistry, immunofluorescence, and flow cytometry. UA significantly ameliorated pathological damage and reduced the levels of proinflammatory cytokines in the CP model rats. RNA sequencing analysis and molecular docking suggested that NLRP3, Caspase-1, and GSDMD may be key targets. We also found that UA decreased ROS levels, alleviated oxidative stress, and inhibited p-NF-κB protein expression both in vivo and in vitro. UA improved pyroptosis morphology as indicated by electron microscope and inhibited the expression of the pyroptosis-related proteins NLRP3, Caspase-1, ASC, and GSDMD, reversed the levels of IL-1β, IL-18, and lactate dehydrogenase in vivo and in vitro. UA can mitigate CP by regulating the NLRP3 inflammasome-mediated Caspase-1/GSDMD pathway. Therefore, UA may be a potential for the treatment of CP.
Topics: Humans; Male; Rats; Animals; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Ursolic Acid; Pyroptosis; Caspase 1; Prostatitis; Molecular Docking Simulation; Gasdermins; Phosphate-Binding Proteins
PubMed: 37807970
DOI: 10.1002/ptr.8034 -
Scientific Reports Oct 2023Prostate cancer is the most common cancer in men and a major cause of cancer related deaths worldwide. Nearly all affected men develop resistance to current therapies...
Prostate cancer is the most common cancer in men and a major cause of cancer related deaths worldwide. Nearly all affected men develop resistance to current therapies and there is an urgent need to develop new treatments for advanced disease. Aberrant glycosylation is a common feature of cancer cells implicated in all of the hallmarks of cancer. A major driver of aberrant glycosylation in cancer is the altered expression of glycosylation enzymes. Here, we show that GCNT1, an enzyme that plays an essential role in the formation of core 2 branched O-glycans and is crucial to the final definition of O-glycan structure, is upregulated in aggressive prostate cancer. Using in vitro and in vivo models, we show GCNT1 promotes the growth of prostate tumours and can modify the glycome of prostate cancer cells, including upregulation of core 2 O-glycans and modifying the O-glycosylation of secreted glycoproteins. Furthermore, using RNA sequencing, we find upregulation of GCNT1 in prostate cancer cells can alter oncogenic gene expression pathways important in tumour growth and metastasis. Our study highlights the important role of aberrant O-glycosylation in prostate cancer progression and provides novel insights regarding the mechanisms involved.
Topics: Humans; Male; Glycosylation; Polysaccharides; Prostate; Prostatic Neoplasms
PubMed: 37813880
DOI: 10.1038/s41598-023-43019-8 -
Annual Review of Medicine Jan 2024Prostate-specific membrane antigen (PSMA) as a transmembrane protein is overexpressed by prostate cancer (PC) cells and is accessible for binding antibodies or... (Review)
Review
Prostate-specific membrane antigen (PSMA) as a transmembrane protein is overexpressed by prostate cancer (PC) cells and is accessible for binding antibodies or low-molecular-weight radioligands due to its extracellular portion. Successful targeting of PSMA began with the development of humanized J591 antibody. Due to their faster clearance compared to antibodies, small-molecule radioligands for targeted imaging and therapy of PC have been favored in recent development efforts. PSMA positron emission tomography (PET) imaging has higher diagnostic performance than conventional imaging for initial staging of high-risk PC and biochemical recurrence detection/localization. However, it remains to be demonstrated how to integrate PSMA PET imaging for therapy response assessment and as an outcome endpoint measure in clinical trials. With the recent approval of Lu-PSMA-617 by the US Food and Drug Administration for metastatic castration-resistant PC progressing after chemotherapy, the high value of PSMA-targeted therapy was confirmed. Compared to standard of care, PSMA-based radioligand therapy led to a better outcome and a higher quality of life. This review, focusing on the advanced PC setting, provides an overview of different approved and nonapproved PSMA-targeted imaging and therapeutic modalities and discusses the future of PSMA-targeted theranostics, also with an outlook on non-radiopharmaceutical-based PSMA-targeted therapies.
Topics: United States; Male; Humans; Quality of Life; Prostate; Prostatic Neoplasms; Positron-Emission Tomography; Precision Medicine
PubMed: 38285513
DOI: 10.1146/annurev-med-081522-031439 -
PET Clinics Jan 2024This article summarizes the evolution of dedicated prostate PET instrumentation. It starts by introducing prostate cancer, as well as the most common diagnostic and... (Review)
Review
This article summarizes the evolution of dedicated prostate PET instrumentation. It starts by introducing prostate cancer, as well as the most common diagnostic and staging methods that are used in the clinics. Then, it describes the key aspects of PET detectors and their assembly in full PET scanners highlighting the most suitable geometries for prostate examination, and a review on the existing prostate dedicated PET. Finally, the next steps for extending the use of PET in the daily diagnose, staging, and image-guided biopsy of patients with prostate cancer are discussed.
Topics: Male; Humans; Prostate; Positron Emission Tomography Computed Tomography; Prostatic Neoplasms; Prostate-Specific Antigen; Gallium Radioisotopes
PubMed: 37778967
DOI: 10.1016/j.cpet.2023.06.001 -
Advanced Science (Weinheim,... Mar 2024The extracellular matrix (ECM) undergoes substantial changes during prostate cancer (PCa) progression, thereby regulating PCa growth and invasion. Herein, a... (Meta-Analysis)
Meta-Analysis
The extracellular matrix (ECM) undergoes substantial changes during prostate cancer (PCa) progression, thereby regulating PCa growth and invasion. Herein, a meta-analysis of multiple PCa cohorts is performed which revealed that downregulation or genomic loss of ITGA1 and ITGA2 integrin genes is associated with tumor progression and worse prognosis. Genomic deletion of both ITGA1 and ITGA2 activated epithelial-to-mesenchymal transition (EMT) in benign prostate epithelial cells, thereby enhancing their invasive potential in vitro and converting them into tumorigenic cells in vivo. Mechanistically, EMT is induced by enhanced secretion and autocrine activation of TGFβ1 and nuclear targeting of YAP1. An unbiased genome-wide co-expression analysis of large PCa cohort datasets identified the transcription factor TEAD1 as a key regulator of ITGA1 and ITGA2 expression in PCa cells while TEAD1 loss phenocopied the dual loss of α1- and α2-integrins in vitro and in vivo. Remarkably, clinical data analysis revealed that TEAD1 downregulation or genomic loss is associated with aggressive PCa and together with low ITGA1 and ITGA2 expression synergistically impacted PCa prognosis and progression. This study thus demonstrated that loss of α1- and α2-integrins, either via deletion/inactivation of the ITGA1/ITGA2 locus or via loss of TEAD1, contributes to PCa progression by inducing TGFβ1-driven EMT.
Topics: Male; Humans; Prostate; Cell Line, Tumor; Prostatic Neoplasms; Signal Transduction; Integrin alpha2; TEA Domain Transcription Factors
PubMed: 38169150
DOI: 10.1002/advs.202305547 -
Journal of the Science of Food and... Dec 2023Rapeseed bee pollen has been recognized as a critical treatment for chronic non-bacterial prostatitis (CNP) and it also can modulate gut microbiota and improve gut...
BACKGROUND
Rapeseed bee pollen has been recognized as a critical treatment for chronic non-bacterial prostatitis (CNP) and it also can modulate gut microbiota and improve gut health. This study aimed to explore the anti-prostatitis effects of rapeseed bee pollen with or without wall-disruption, and to investigate the connection between this treatment and gut microbiota.
RESULTS
The results reveal that rapeseed bee pollen can effectively alleviate chronic non-bacteria prostatitis by selectively regulating gut microbiota, with higher doses and wall-disrupted pollen showing greater efficacy. Treatment with a high dose of wall-disrupted rapeseed bee pollen (WDH, 1.26 g kg body weight) reduced prostate wet weight and prostate index by approximately 32% and 36%, respectively, nearly the levels observed in the control group. Wall-disrupted rapeseed bee pollen treatment also reduced significantly (p < 0.05) the expression of proinflammatory cytokines (IL-6, IL-8, IL-1β, and TNF-α), as confirmed by immunofluorescence with laser scanning confocal microscope. Our results show that rapeseed bee pollen can inhibit pathogenic bacteria and enhance probiotics, particularly in the Firmicutes-to-Bacteroidetes (F/B) ratio and the abundance of Prevotella (genus).
CONCLUSION
This is the first study to investigate the alleviation of CNP with rapeseed bee pollen through gut microbiota. These results seem to provide better understanding for the development of rapeseed bee pollen as a complementary medicine. © 2023 Society of Chemical Industry.
Topics: Humans; Male; Bees; Animals; Prostatitis; Gastrointestinal Microbiome; Brassica napus; Pollen; Bacteria; Brassica rapa
PubMed: 37486857
DOI: 10.1002/jsfa.12878 -
Prostate Cancer and Prostatic Diseases Sep 2023We performed this systematic review and meta-analysis to investigate the efficacy and safety of Li-ESWT combined with or without medications for patients with Chronic... (Meta-Analysis)
Meta-Analysis Review
The efficacy and safety of low-intensity extracorporeal shock wave treatment combined with or without medications in Chronic prostatitis/chronic pelvic pain syndrome: a systematic review and meta-analysis.
BACKGROUND
We performed this systematic review and meta-analysis to investigate the efficacy and safety of Li-ESWT combined with or without medications for patients with Chronic prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS).
METHODS
A comprehensive search was conducted of PUBMED, Cochrane Library, and Web of Science databases from inception to February 2022 for randomized controlled trials (RCTs) assessing the efficacy and safety of Li-ESWT with or without the combination of medications compared with the control group. The National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), Visual Analogue Scale/Score (VAS), International Index of Erectile Function (IIEF), and International prostate symptom score (IPSS) were used to assess the improvements of symptoms in CP/CPPS patients.
RESULTS
651 patients from 12 randomized controlled studies were included in this study. The total NIH-CPSI scores, pain domain scores, and quality of life (QOL) scores were significantly lower in the Li-ESWT group than those in the control group at the termination of treatment, and 1, 4, 12, and 24 weeks after treatment. And these scores were significantly reduced in the Li-ESWT group than in baselines. In the subgroup analysis, reductions of these scores lasted longer and were greater in Li-ESWT combined with medications than in Li-ESWT alone. In the Li-ESWT group, the VAS score; IIEF score; and IPSS score were significant improvements than those in control group at the termination of treatment, and 1, 4, and 12 weeks after treatment; 4, 12, and 24 weeks after treatment; and 1, 4, and 12 weeks after treatment, respectively.
CONCLUSIONS
Li-ESWT is a safe, non-invasive, and effective option for patients with CP/CPPS, whether combined with medications or not, should be recommended for widespread use in clinical practice.
Topics: Male; Humans; Prostatitis; Prostatic Neoplasms; Chronic Disease; Pelvic Pain; Databases, Factual; Chronic Pain
PubMed: 35798855
DOI: 10.1038/s41391-022-00571-0 -
International Urology and Nephrology Dec 2023Prostatitis is known as the inflammation of the prostate. The treatments of prostatitis are either pharmacological or non-pharmacological treatment. However, some of the... (Review)
Review
BACKGROUND
Prostatitis is known as the inflammation of the prostate. The treatments of prostatitis are either pharmacological or non-pharmacological treatment. However, some of the treatments are not effective and very invasive which can lead to side effects. Thus, low-intensity extracorporeal shockwave therapy (LI-ESWT) is used as an alternative treatment for prostatitis due to its convenient and non-invasive procedure. However, a definite protocol for this treatment is not available due to the variability of the treatment protocols and the lack of research comparing the efficacy of these protocols.
OBJECTIVE
To review and compare the efficacy of different LI-ESWT protocols in treating prostatitis.
METHODS
The study was performed by comparing the intensity, duration, frequency and combination with different types of pharmacotherapy drugs of the different LI-ESWT protocols from various studies. The finding from various studies which consist of disease improvement and quality of life (QoL) were also presented in this review.
RESULT
From the findings, the protocol can be categorized into three different intensities which are at 3000 pulses, < 3000 pulses and > 3000 pulses. Most studies reported that each protocol is very effective and safe to use and can improve CP symptoms, urinary symptoms, erectile function and QoL. It is also found that no complications or adverse effects occur to the patient.
CONCLUSION
Most of the LI-ESWT protocols described are safe and effective in treating CP through the absence of treatment-related adverse effects and maintenance of clinical effects.
Topics: Male; Humans; Quality of Life; Prostatitis; Extracorporeal Shockwave Therapy; Penile Erection
PubMed: 37145375
DOI: 10.1007/s11255-023-03616-y -
The Journal of Pathology Sep 2023Club cells are a type of bronchiolar epithelial cell that serve a protective role in the lung and regenerate damaged lung epithelium. Single-cell RNA sequencing...
Club cells are a type of bronchiolar epithelial cell that serve a protective role in the lung and regenerate damaged lung epithelium. Single-cell RNA sequencing (scRNA-seq) of young adult human prostate and urethra identified cell populations in the prostatic urethra and collecting ducts similar in morphology and transcriptomic profile to lung club cells. We further identified club cell-like epithelial cells by scRNA-seq of prostate peripheral zone tissues. Here, we aimed to identify and spatially localize club cells in situ in the prostate, including in the peripheral zone. We performed chromogenic RNA in situ hybridization for five club cell markers (CP, LTF, MMP7, PIGR, SCGB1A1) in a series of (1) nondiseased organ donor prostate and (2) radical prostatectomy specimens from individuals with prostate cancer. We report that expression of club cell genes in the peripheral zone is associated with inflammation and limited to luminal epithelial cells classified as intermediate cells in proliferative inflammatory atrophy (PIA). Club-like cells were enriched in radical prostatectomy specimens compared to nondiseased prostates and associated with high-grade prostate cancer. We previously reported that luminal epithelial cells in PIA can rarely harbor oncogenic TMPRSS2:ERG (ERG+) gene fusions, and we now demonstrate that club cells are present in association with ERG+ PIA that is transitioning to early adenocarcinoma. Finally, prostate epithelial organoids derived from prostatectomy specimens demonstrate that club-like epithelial cells can be established in organoids and are sensitive to anti-androgen-directed treatment in vitro in terms of decreased androgen signaling gene expression signatures compared to basal or hillock cells. Overall, our study identifies a population of club-like cells in PIA and proposes that these cells play an analogous role to that of club cells in bronchiolar epithelium. Our results further suggest that inflammation drives lineage plasticity in the human prostate and that club cells in PIA may be prone to oncogenic transformation. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Topics: Male; Young Adult; Humans; Prostate; Prostatic Neoplasms; Epithelial Cells; Inflammation; Atrophy
PubMed: 37550827
DOI: 10.1002/path.6149