Progression Of Benign Prostatic Hyperplasia Research Articles

PD16-11 TRANS-ETHNIC GENOME-WIDE ASSOCIATION STUDY REVEALS NEW THERAPEUTIC TARGETS FOR BENIGN PROSTATIC HYPERPLASIA

You have accessJournal of UrologyCME1 May 2022PD16-11 TRANS-ETHNIC GENOME-WIDE ASSOCIATION STUDY REVEALS NEW THERAPEUTIC TARGETS FOR BENIGN PROSTATIC HYPERPLASIA Michael Ng, Koichi Matsuda, Chizu Tanikawa, Chikashi Terao, Yoichiro Kamatani, Wei Wang, Adam Auton, 23andme Research Team, Benjamin Turney, Richard Bryant, and Dominic Furniss Michael NgMichael Ng More articles by this author , Koichi MatsudaKoichi Matsuda More articles by this author , Chizu TanikawaChizu Tanikawa More articles by this author , Chikashi TeraoChikashi Terao More articles by this author , Yoichiro KamataniYoichiro Kamatani More articles by this author , Wei WangWei Wang More articles by this author , Adam AutonAdam Auton More articles by this author , 23andme Research Team More articles by this author , Benjamin TurneyBenjamin Turney More articles by this author , Richard BryantRichard Bryant More articles by this author , and Dominic FurnissDominic Furniss More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002548.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Benign prostatic hyperplasia (BPH) is a common condition affecting men in and beyond middle age, causing significant morbidity. Medical treatments comprise a small number of pharmacological agents, and patients often progress to require surgery. There is an unmet clinical need to identify genomic drivers of BPH progression requiring surgery, and to identify novel targets for pharmacological intervention. METHODS: We performed a large genome-wide association study of BPH in 126,082 subjects from UK Biobank, with replication in 44,093 subjects from the RIKEN Japanese biobank, and 756,878 subjects from 23andMe (total 110,916 BPH cases and 816,137 controls). We investigated candidate genes using differential expression between single cell subtypes in samples from BPH versus normal prostate. A genetic risk score for BPH was constructed to assess its use for prognostication. Therapeutic targets were identified from the Open Targets platform. RESULTS: We identified 17 BPH-associated loci. Two loci were only associated with this condition in men of Western European or Japanese origin, and represent ethnicity-specific risk alleles. We demonstrated differential expression of associated genes in cells derived from BPH compared to normal prostate. For example, we provide evidence that the homeobox gene NKX3.1 specifically plays a role in BPH in basal epithelial cells. Patients with BPH managed with surgery had a higher genetic risk score than those managed conservatively or with non-surgical treatment. Several genes implicated in our genetic analysis are tractable to therapeutic targeting or drug repurposing, and represent attractive targets for new therapeutic development. CONCLUSIONS: These results point to important genes driving the pathophysiology of BPH, and reveal promising candidates for future therapeutic development. Our proof-of-principle that the genetic risk score correlates with the severity of BPH, and the need for surgery, provides a first step towards personalised medicine in the management of this common condition. Source of Funding: This work was co-funded by co-funded by the John Black Foundation and the Rosetrees Trust, with funding administered by The Urology Foundation. The BioBank Japan project was supported by the Ministry of Education, Culture, Sports, Sciences and Technology Japan and the Japan Agency for Medical Research and Development. The funders had no role in the design of the study, the collection, analysis or interpretation of data, the writing of the manuscript, or the decision to publish the results. We would like to thank the research participants and employees of 23andMe for making this work possible © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e272 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michael Ng More articles by this author Koichi Matsuda More articles by this author Chizu Tanikawa More articles by this author Chikashi Terao More articles by this author Yoichiro Kamatani More articles by this author Wei Wang More articles by this author Adam Auton More articles by this author 23andme Research Team More articles by this author Benjamin Turney More articles by this author Richard Bryant More articles by this author Dominic Furniss More articles by this author Expand All Advertisement PDF DownloadLoading ...

Prostate diseases and microbiome in the prostate, gut, and urine.

The microbiome in various organs involves a vast network that plays a key role in the health and wellness of the human body. With recent advances in biological technologies such as high-throughput sequencing, transcriptomics, and metabolomics, it appears that the microbial signature varies dynamically among individuals, creating various roles in metabolism, local and systemic inflammation, and host immunity. Urinary and genital organs, including the prostate, seminal vesicles, and urinary bladder, are reservoirs of several bacterial, viral, and fungal communities. Accumulating evidence has suggested profound roles for the gut, urinary, and intraprostate microbiomes in genitourinary benign and malignant diseases. This review article addresses microbiome-related evidence for three major diseases involved in prostate cancer: chronic prostatitis (CP), benign prostatic hyperplasia (BPH), and prostate cancer (PCa). Symptomatic CP is known as CP/chronic pelvic pain syndrome. CP is one of the most common prostate diseases in young men, accounting for 8% of all men visiting a urologic clinic. Although oral medication is the gold standard therapy for patients with BPH, approximately 13% of men present with clinical progression within 4 years after the initiation of treatment, with 5% requiring surgical intervention. The identification of proinflammatory cytokines and pathogens responsible for the clinical progression of BPH is still underway. Several topics regarding the association between PCa and the microbiome are discussed in this review as follows: i) intraprostatic microbiome and the risk of PCa, ii) gut microbiome and PCa, iii) gut microbiome and the risk of radiation-induced side effects, iv) isoflavone intake and equol-producing intestinal flora on PCa, and v) the inhibitory effect of daidzein and equol on tumor growth and progression of PCa. Further studies are required for a comprehensive understanding between the urogenital microbiome and prostate pathogenesis to facilitate the development of preventive and therapeutic approaches for prostate diseases.

Immune Cell Proinflammatory Microenvironment and Androgen-Related Metabolic Regulation During Benign Prostatic Hyperplasia in Aging.

To review the role of inflammation in the occurrence and development of benign prostatic hyperplasia (BPH), we searched PubMed for the latest published articles up to February 2021 using the following key words: “benign prostatic hyperplasia”, “inflammation”, “pathogenesis” and “disease development”. Articles were obtained and reviewed to provide a systematic review of the current progress of the role of inflammation in the pathogenesis and progression of BPH. Inflammation contributes to the initiation and maintenance of unregulated cell proliferation and is closely related to the occurrence and development of BPH. Its action pathways include tissue damage and subsequent chronic healing, autoimmunity, and coaction with androgens. During the progression of inflammation, macrophages, interleukin-8 (IL-8), interleukin-1 (IL-1) and other inflammatory-related substances aggregate locally and cause BPH through various biochemical pathways. At the same time, BPH can also counteract inflammation to expand its scope and aggravate the situation. Inflammation can independently affect the development of BPH in a variety of ways, and it can also interact with androgens. In the course of treatment, early intervention in the occurrence and development of inflammation in prostate tissue can slow down the progression of BPH. The combination of standard therapies and anti-inflammatory measures may provide valuable new ideas for the treatment of BPH.

The association between histological prostatitis and benign prostatic hyperplasia: a single-center retrospective study

Objective To investigate the relationship between histological prostatitis (HP) and clinical parameters related to benign prostatic hyperplasia (BPH) in male. Method The clinical data of 196 BPH patients who underwent transurethral resection of the prostate were collected. According to the results of hematoxylin-eosin (H&E) staining of prostate tissue, patients were divided into two groups: BPH with HP group and BPH without HP group. Differences in acute urinary retention (AUR), prostate volume (PV), serum sex hormones, lower urinary tract symptoms (LUTS) related parameters, and systemic inflammation indicators were compared between the two groups. SPSS software v.25 was used for statistical analysis. Results Compared with the BPH without HP group, the BPH with HP group had greater AUR rate, PV, total IPSS, and IPSS-storage in BPH with HP group (p < 0.05). However, there were no significant differences in IPSS-voiding, post-void residual volume, maximum urinary flow rate, serum sex hormones, and systemic inflammation indicators between the two groups (p > 0.05). Conclusions This study suggests that patients with HP have larger PV, more severe LUTS, and a higher risk of AUR. HP is closely related to BPH and may be a key factor in the occurrence and clinical progress of BPH.

Association between predictors of progression of benign prostatic hyperplasia and moderate-to-severe prostatitis-like symptoms: Apropensity score-matched analysis.

BackgroundWe investigated the association between moderate-to-severe prostatitis-like symptoms and the predictors of benign prostatic hyperplasia (BPH) progression.MethodsMen who underwent health checkups were analyzed. We classified symptoms as “moderate to severe” if the pain score according to the National Institutes of Health-Chronic Prostatitis Symptoms Index was ≥8 and predictors of the progression of BPH were defined as having a prostate-specific antigen (PSA) ≥1.6 ng/mL, total prostate volume (TPV) ≥31 mL, international prostate symptom score (IPSS) ≥20, and maximal flow rate (Qmax) <10.6 mL/s. A total of 8368 patients formed the cohort for propensity score matching, including 445 men with moderate-to-severe prostatitis-like symptoms and 5390 men with no symptoms; ultimately, however, the propensity score of these groups matched at a 1:2 ratio.ResultsAfter propensity matching, the two groups were evenly distributed with respect to age, International Index of Erectile Function-5 score, metabolic syndrome, and testosterone. The percentage of participants with ≥1 predictor for the progression of BPH, a TPV of ≥31 cm3, PSA levels of ≥1.6 ng/mL, Qmax <10.6 mL/s, and IPSS ≥20 were all greater in men with moderate-to-severe prostatitis-like symptoms. There were significant differences in the percentage of participants with ≥1 predictor for the progression of BPH (30.6% vs. 58.0%; p < 0.001), Qmax <10.6 mL/s (3.9% vs. 7.0%, p = 0.023), and IPSS ≥20 (9.6% vs. 44.7%, p < 0.001).ConclusionModerate-to-severe prostatitis-like symptoms are significantly and independently associated with predictors of BPH progression.

A Cross-Sectional Study for Association between Periodontitis and Benign Prostatic Hyperplasia Using the Korean Genome and Epidemiology Study Data

Recently, several studies have suggested the relationship between periodontitis and prostatic disease. However, epidemiological studies on the association between periodontitis and benign prostatic hyperplasia (BPH) are scarce. Hence, we aimed to identify the association between the two diseases using data from the Korean Genome and Epidemiology Study. Among the 173,209 participants, 3297 men with periodontitis and 35,292 controls (without periodontitis) were selected. The history of BPH in participants with periodontitis and the controls were also investigated. Two-tailed analyses, independent t-tests, and chi-square tests were used for statistical analysis. The adjusted odds ratio (OR) for BPH was 1.50 (95% confidence interval, 1.35–1.68; p &lt; 0.001) after adjusting for past medical histories. The adjusted OR for BPH was 1.57 (95% confidence interval, 1.41–1.76; p &lt; 0.001) after adjusting for anthropometric and laboratory data. Collectively, this study provides evidence that periodontitis is associated with BPH. This finding supports the use of regular dental checkups and periodontal treatments to reduce the prevalence and progression of BPH.

Thyroid hormone and androgen signals mutually interplay and enhance inflammation and tumorigenic activation of tumor microenvironment in prostate cancer

Prostate Cancer (PCa) is the most commonly diagnosed non-cutaneous cancer in males and the fifth leading cause of death worldwide. The majority of PCas are androgen-sensitive, with a significant up-regulation of Androgen Receptor (AR) that causes a stimulatory effect on growth and progression of cancer cells. For this reason, the first-line therapy for PCa is androgen ablation, even if it ultimately fails due to the onset of hormone-refractory state, in which the malignant cells do not sense the androgen signal anymore. Besides androgens, a growing number of evidence suggests that Thyroid Hormones (THs) mediate tumor-promoting effects in a variety of human cancers, as Epithelial-to-Mesenchymal Transition (EMT), invasion and metastasis and also stimulation of angiogenesis and tumor metabolism. Moreover, epidemiological studies demonstrated an increased risk for PCa in patients with lower levels of Thyreotropin (TSH). Here, we investigated if intracellular TH metabolism affects Benign Prostatic Hyperplasia (BPH) and PCa formation and progression.We found that the intracellular TH metabolism is a crucial determinant of PCa behavior. We observed that a dynamic stage-specific expression of the THs modulating enzymes, the deiodinases, is required for the progression of BPH to PCa malignancy. By acting simultaneously on epithelial cancer cells and fibroblasts, THs exert a proliferative and pro-inflammatory effect cooperating with androgens.These findings suggest that androgens and THs may interplay and mediate a coordinate effect on human PCa formation and progression. In light of our results, future perspective could be to explore the potential benefits of THs intracellular modulators aimed to counteract PCa progression.

Statička i dinamska komponenta opstrukcije kod benigne hiperplazije prostate

Introduction / Goal: Benign prostatic hyperplasia (BPH) is the most common benign neoplasm that occures in male population with an incidence of 45 to 90% between 50 and 80 years of age. BPH can cause an increase in output resistance, or an increase in resistance to urine flow, with its static and dynamic components. In clinical practice, the most common pharmacological treatment of lower urinary tract symptoms (LUTS) in patients with BPH is based on monotherapy with alpha-blockers, 5-alpha-reductase inhibitors or combination therapy. The aim of this review is to determine the main therapeutic and side effects of the most common pharmacological therapy and the recommended approaches of the European Association of Urology (EAU) and the American Urological Association (AUA) in the diagnosis of benign prostate obstruction (BPO). Method: Selective literature search with additional examination of EAU and AUA guidelines and meta-analysis. Results: The treatment of patients with BPH is complex. The factors on the basis of which treatment decisions are made are based on the patient's subjective perception of symptoms and quality of life due to LUTS and in relation to the presence of subvesical obstruction. Urodynamic pressureflow studies are the basis for the definition of BPO due to BPH or other etiology. Non-invasive uroflowmetry, determination of residual urine after urination (PVR) and non-invasive ultrasound tests are of great use in the diagnosis of BPO. Treatment with alpha1 receptor inhibitors (alpha-blockers), or 5-alpha-reductase inhibitors may be considered in patients with predominantly urinary dysfunction. Conclusion: Standard pharmacological medical treatment for BPH / LUTS is still based on alphablockers, 5-alpha-reductase inhibitors or a combination thereof. In the future, BPH / LUTS treatment is expected to become individualized, according to the type of symptoms, the presence of sexual dysfunction and the risk of BPH progression.

Combined treatment with dihydrotestosterone and lipopolysaccharide modulates prostate homeostasis by upregulating TNF-α from M1 macrophages and promotes proliferation of prostate stromal cells

Androgens and chronic inflammation, which play essential roles in the development of benign prostatic hyperplasia (BPH), are considered to be important factors in disorders of prostate homeostasis. These two factors may lead to pathological hyperplasia in the prostate transition zone of patients with BPH. However, few studies have examined the mechanism of how dihydrotestosterone (DHT) affects chronic inflammation in prostate tissue during the progression of BPH. This study examined the performance of DHT in lipopolysaccharide-treated M1 macrophages and the subsequent effects on the proliferation of prostate stromal and epithelial cells. We found that DHT increased secretion of the pro-inflammatory factor tumor necrosis factor (TNF)-α from M1 macrophages differentiated from THP-1 cells. The supernatant of M1 macrophages promoted the proliferation of WPMY-1 prostate stromal cells by upregulating B-cell lymphoma-extra large (Bcl-xL) and cellular Myc (c-Myc) levels by activating TNF-α-mediated nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Moreover, this supernatant increased the expression of androgen receptor in WPMY-1 cells, which was TNF-α-independent. Additionally, TNF-α protein expression was significantly higher in patients with BPH and a large prostate volume than that in those with a small prostate volume. Further analysis showed that higher serum testosterone combined with prostate-specific androgen concentrations was related to TNF-α expression. This study suggests that DHT modulates the inflammatory environment of BPH by increasing TNF-α expression from lipopolysaccharide-treated M1 macrophages and promotes the proliferation of prostate stromal cells. Targeting TNF-α, but not DHT, may be a promising strategy for patients with BPH.

Association of Frailty Index with Clinical BPH Progression and Serious Adverse Events: the MTOPS Trial

Lower urinary tract symptoms due to suspected benign prostatic hyperplasia (BPH) are increasingly treated with medications targeting obstruction among older men, but frailty may represent a novel risk factor for this condition. Our objective was to assess the associations between frailty and clinical BPH progression or serious adverse events (SAE) among 3047 men, age 50-89 years, enrolled in the Medical Therapy of Prostatic Symptoms Study, a placebo-controlled RCT of doxazosin, finasteride, or combination therapy on clinical BPH progression. We created a frailty index using 69 items collected at baseline and categorized men as fit (0-0.1), less fit (0.1-<0.25), or frail (0.25-1.0). The primary outcomes were time to 1) first composite event of clinical BPH progression, and 2) SAE requiring hospitalization. Cox proportional hazards models were adjusted for demographics, intervention, BPH surrogates, and comorbidities. At baseline, 28% men were fit, 58% were less fit, and 14% were frail. During follow-up (mean 4.5 years), the incidence rate of clinical BPH progression was 2.2/100p-y among fit, 3.0/100p-y among less fit (HR =1.28, 95% CI 0.98, 1.67), and 4.1/100p-y among frail men (HR=1.60, 95% CI 1.13, 2.26). Among men randomized to combination therapy, the SAE incidence rate was 3.4/100p-y for fit men versus 12.7/100p-y for frail men (HR=5.98, 95% CI 3.76, 9.52). In conclusion, frailty is independently associated with greater risk of both clinical BPH progression and SAE. The decision to initiate medical therapy for BPH among frail men should therefore include a discussion of both benefits and risks via shared decision making.

A Review of Prostate Organogenesis and a Role for iPSC-Derived Prostate Organoids to Study Prostate Development and Disease.

The prostate is vulnerable to two major age-associated diseases, cancer and benign enlargement, which account for significant morbidity and mortality for men across the globe. Prostate cancer is the most common cancer reported in men, with over 1.2 million new cases diagnosed and 350,000 deaths recorded annually worldwide. Benign prostatic hyperplasia (BPH), characterised by the continuous enlargement of the adult prostate, symptomatically afflicts around 50% of men worldwide. A better understanding of the biological processes underpinning these diseases is needed to generate new treatment approaches. Developmental studies of the prostate have shed some light on the processes essential for prostate organogenesis, with many of these up- or downregulated genes expressions also observed in prostate cancer and/or BPH progression. These insights into human disease have been inferred through comparative biological studies relying primarily on rodent models. However, directly observing mechanisms of human prostate development has been more challenging due to limitations in accessing human foetal material. Induced pluripotent stem cells (iPSCs) could provide a suitable alternative as they can mimic embryonic cells, and iPSC-derived prostate organoids present a significant opportunity to study early human prostate developmental processes. In this review, we discuss the current understanding of prostate development and its relevance to prostate-associated diseases. Additionally, we detail the potential of iPSC-derived prostate organoids for studying human prostate development and disease.

Assessment of Frailty and Association With Progression of Benign Prostatic Hyperplasia Symptoms and Serious Adverse Events Among Men Using Drug Therapy

Benign prostatic hyperplasia (BPH) in older men can cause lower urinary tract symptoms (LUTS), which are increasingly managed with medications. Frailty may contribute to both symptom progression and serious adverse events (SAEs), shifting the balance of benefits and harms of drug therapy. To assess the association between a deficit accumulation frailty index and clinical BPH progression or SAE. This cohort study used data from the Medical Therapy of Prostatic Symptoms trial, which compared placebo, doxazosin, finasteride, and combination therapy in men with moderate-to-severe LUTS, reduced urinary flow rate, and no prior BPH interventions, hypotension, or elevated prostate-specific antigen. Enrollment was from 1995 to 1998, and follow-up was through 2001. Data were assessed in February 2021. A frailty index (score range, 0-1) using 68 potential deficits collected at baseline was used to categorized men as robust (score ≤0.1), prefrail (score 0.1 to <0.25), or frail (score ≥0.25). Primary outcomes were time to clinical BPH progression and time to SAE, as defined in the parent trial. Adjusted hazard ratios (AHRs) were estimated using Cox proportional hazards regressions adjusted for demographic variables, treatment group, measures of obstruction, and comorbidities. Among 3047 men (mean [SD] age, 62.6 [7.3] years; range, 50-89 years) in this analysis, 745 (24%) were robust, 1824 (60%) were prefrail, and 478 (16%) were frail at baseline. Compared with robust men, frail men were older (age ≥75 years, 12 men [2%] vs 62 men [13%]), less likely to be White (646 men [87%] vs 344 men [72%]), less likely to be married (599 men [80%] vs 342 men [72%]), and less likely to have 16 years or more of education (471 men [63%] vs 150 men [31%]). During mean (SD) follow-up of 4.0 (1.5) years, the incidence rate of clinical BPH progression was 2.2 events per 100 person-years among robust men, 2.9 events per 100 person-years among prefrail men (AHR, 1.36; 95% CI, 1.02-1.83), and 4.0 events per 100 person-years among frail men (AHR, 1.82; 95% CI, 1.24-2.67; linear P = .005). Larger point estimates were seen among men who received doxazosin or combination therapy, although the test for interaction between frailty index and treatment group did not reach statistical significance (P for interaction = .06). Risk of SAE was higher among prefrail and frail men (prefrail vs robust AHR, 1.81; 95% CI, 1.48-2.23; frail vs robust AHR, 2.86; 95% CI, 2.21-3.69; linear P < .001); this association was similar across treatment groups (P for interaction = .76). These findings suggest that frailty is independently associated with greater risk of both clinical BPH progression and SAEs. Older frail men with BPH considering initiation of drug therapy should be counseled regarding their higher risk of progression despite combination therapy and their likelihood of experiencing SAEs regardless of treatment choice.

SNPs of Metabolic Syndrome are Associated with Benign Prostatic Hyperplasia Development and Progression in Chinese Population

Objective: Benign Prostatic Hyperplasia (BPH) is a common disease prevalent in elderly men, but the genetic determinants of BPH still remain unclear. Since metabolic syndrome, especially diabetes, may influence the progression of benign prostatic hyperplasia, we investigated whether susceptibility loci for diabetes would increase the risk of BPH development and progression in elderly Chinese men. Material and Methods: Fifteen SNPs associated with the diabetes risk in a Chinese population were genotyped in 377 BPH cases (152 aggressive and 225 non-aggressive BPH cases) and 1,008 controls. The association between the SNPs and the risk of BPH development was evaluated through logistic regression. Additionally, the effects of the 15 SNPs on BPH related clinical parameters, including Body Mass Index (BMI) International Prostate Symptom Score (IPSS), Quality of Life (QoL) and Prostate Volume (PV) were also evaluated. Results: SNP rs9864104 in IGF2BP2 at 3q27 (OR=1.24, P =0.0148) was significantly associated with BPH development. In addition, SNP rs9863780, rs9864104, rs10229583 and rs17727841 were significantly associated with baseline clinical parameters in BPH patients. Moreover, the risk allele of rs6763887 (C) and rs17727841 (C) was significantly associated with the change of storage score and voiding score after treatment. No SNPs were associated with the risk of BPH progression. Conclusions: This is a systematic investigation of the contributions of diabetes susceptibility loci to the risk of BPH development and progression. Our findings advance the understanding of the genetic basis of BPH and provide new insights into the genetic determinants shared between BPH and metabolic syndrome.

The bioactive alkaloids identified from Cortex Phellodendri ameliorate benign prostatic hyperplasia via LOX-5/COX-2 pathways

BackgroundThe bioactive alkaloids identified from Cortex Phellodendri (CP) were highly effective in treating rats with benign prostatic hyperplasia (BPH). Specifically, lipoxygenase-5 (LOX-5) and cyclooxygenase-2 (COX-2) were identified as two primary targets for alleviating inflammation in BPH rats. However, it remains unknown whether the alkaloid components in CP can interact with the two target proteins. PurposeTo further identify bioactive alkaloids targeting LOX/COX pathways. MethodsAn affinity-ultrafiltration mass spectrometry approach was employed to screen dual-target LOX-5/COX-2 ligands from alkaloid extract. The structures of bioactive alkaloids were characterized by high-resolution Fourier transform ion cyclotron resonance mass spectrometry. To understand the molecular mechanisms underlying the effects of bioactive alkaloids, the expression levels of LOX-5 and COX-2 in BPH model rats were investigated at both protein and mRNA levels. The LOX-5/COX-2 enzymes activity experiments and molecular docking analysis were performed to fully evaluate the interactions between bioactive alkaloids and LOX-5/COX-2. ResultsAfter comprehensive analysis, the results showed that bioactive alkaloids could suppress the expression of LOX-5 and COX-2 simultaneously to exert an anti-inflammatory effect on the progression of BPH. In addition, the screened protoberberine, demethyleneberberine was found to exhibit prominent inhibitory activities against both LOX-5 and COX-2 enzymes, palmatine and berberine with moderate inhibitory activities. Molecular docking analysis confirmed that demethyleneberberine could interact well with LOX-5/COX-2. ConclusionThis study is the first to explore the inhibitory effects of bioactive alkaloids from CP on LOX-5 and COX-2 activities in BPH rats. Our findings demonstrate that the bioactive alkaloids from CP can ameliorate BPH via dual LOX-5/COX-2 pathways, which serves as an efficient approach for the discovery of novel drug leads from natural products with reduced side effects.

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PD11-10 PROSTATE-SPECIFIC DELETION OF Cdh1 IN MICE MIMICS PROSTATIC PERFUSION OF BENIGN PROSTATIC HYPERPLASIA (BPH) PATIENTS

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology (PD11)1 Sep 2021PD11-10 PROSTATE-SPECIFIC DELETION OF Cdh1 IN MICE MIMICS PROSTATIC PERFUSION OF BENIGN PROSTATIC HYPERPLASIA (BPH) PATIENTS Pradeep Tyagi, Laura Pascal, Lesley Foley, Robin Frederick, T. Kevin Hitchens, Anthony Kanai, Naoki Yoshimura, and Zhou Wang Pradeep TyagiPradeep Tyagi More articles by this author , Laura PascalLaura Pascal More articles by this author , Lesley FoleyLesley Foley More articles by this author , Robin FrederickRobin Frederick More articles by this author , T. Kevin HitchensT. Kevin Hitchens More articles by this author , Anthony KanaiAnthony Kanai More articles by this author , Naoki YoshimuraNaoki Yoshimura More articles by this author , and Zhou WangZhou Wang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001986.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although BPH is an age-related comorbidity of cardiovascular disease and hypertension, the investigation into the direction of the relationship will require animal models. Recently, the downregulation of E-cadherin in hyperplastic nodules of BPH patients was mechanistically linked to the prostatic inflammation and vascular defects by the recapitulation of BPH phenotype following deletion of E-cadherin gene (Cdh1-/- ) in prostatic epithelium of adult mouse (Endocrinology 2021; 162(1) : bqaa212). Since the injected T1 shortening agent, Gadobutrol only resides in vascular and extracellular space, we enquired the effect of Cdh1-/-on dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). METHODS: Tamoxifen injection at 7 weeks of age generated PSA-CreERT2/Cdh1-/- mice and then anaesthetized 21-23 weeks old Cdh1-/- and wild type controls (n=3) were injected Gadobutrol 0.1mm/kg for T1 weighted DCE-MRI of prostate in 9 axial slices with number of excitations (NEX)=1 and temporal resolution of 12s in voxel size of 0.156x0.156x0.8mm3 at small animal 7T scanner followed by Masson’s trichome staining. RESULTS: Although ventral lobes of Cdh1-/- mice were similar in size to age matched controls, the kinetic modelling of DCE-MRI (repetition TR/echo time TE - 200/5.23ms) determined that clearance of Gadobutrol was four fold slower from ventral lobe of Cdh1-/- mice with efflux rate constant Kep of 0.17±1.48 min-1 vs 0.88±0.08 min-1 in controls. The prostate permeability metric, Kep of Cdh1-/- mice is determined by the widened and elongated venules (# telangiectasia) and the higher density of collagen (blue stain) in ventro/lateral lobes on Masson's trichrome staining, which retains the Gadobutrol even 30min after injection to increase T1 contrast more than adjacent dorsal lobes and ventral lobe of control mice in high resolution post-contrast images (TR/TE 2000/20ms; NEX=4). CONCLUSIONS: The link between the vascular defects and expanded extracellular space of prostate in Cdh1-/- mice with the slower clearance of Gadobutrol implicates a bidirectional relationship between prostatic inflammation and prostatic vasculature defects that are characteristic of BPH. Findings suggest that E-cadherin downregulation could be a driving force in human BPH development and progression. Source of Funding: UPMC Hillman Pilot Funding; DK112079; CA211242 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e201-e202 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Pradeep Tyagi More articles by this author Laura Pascal More articles by this author Lesley Foley More articles by this author Robin Frederick More articles by this author T. Kevin Hitchens More articles by this author Anthony Kanai More articles by this author Naoki Yoshimura More articles by this author Zhou Wang More articles by this author Expand All Advertisement Loading ...

MP17-07 COSTS AND OUTCOMES ASSOCIATED WITH THE MANAGEMENT OF PATIENTS ACUTELY PRESENTING WITH NONNEUROGENIC URINARY RETENTION

You have accessJournal of UrologyHealth Services Research: Value of Care: Cost and Outcomes Measures I (MP17)1 Sep 2021MP17-07 COSTS AND OUTCOMES ASSOCIATED WITH THE MANAGEMENT OF PATIENTS ACUTELY PRESENTING WITH NONNEUROGENIC URINARY RETENTION David Friedlander, Davis Viprakasit, and Matthew Nielsen David FriedlanderDavid Friedlander More articles by this author , Davis ViprakasitDavis Viprakasit More articles by this author , and Matthew NielsenMatthew Nielsen More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002002.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Benign prostatic hyperplasia (BPH) is a common and costly clinical condition effecting men worldwide. The most severe sequela of progressive BPH is nonneurogenic acute urinary retention (AUR), affecting 33% of men >80 years of age. Little is known about non-clinical factors that influence rates of BPH progression and overall clinical outcomes following an episode of AUR. We sought to identify clinical and non-clinical predictors of post-AUR patterns of care and associated costs. METHODS: All-payer data from the 2016 Healthcare Cost and Utilization Project State Databases from Florida and New York were used to identify 30,827 men ≥40 years of age acutely presenting with AUR and track subsequent acute care encounters over a 1-year period. Patient demographics, regional data, and procedural information were collected, and episode-based costs were calculated. Multivariable logistic and gamma generalized linear regression were utilized to identify predictors of acute care revisit/subsequent bladder outlet procedure and episode-based costs, respectively. RESULTS: Of the 30,827 patients presenting with AUR, 5,409 (7.5%) experienced at least one additional hospital revisit for AUR, whereas 1,987 (6.4%) subsequently underwent a bladder outlet procedure. Older age (≥80 vs. <70: OR 1.31, 95% CI 1.20-1.42; p <0.001), Medicare vs. private insurance (OR 1.16, 95% CI 1.05-1.29; p=0.005), Black vs. White race (OR 1.18, 95% CI 1.07-1.30; p=0.001), and higher education level (OR 1.13, 95% CI 1.01-1.26; p=0.03) were all associated with increased odds of hospital revisit for recurrent AUR. Regarding subsequent bladder outlet procedure, increasing number of revisits (OR 4.39, 95% CI 3.94-4.89; p <0.001), age (≥80 vs. <70: OR 0.53, 95% CI 0.44-0.63; p <0.001), comorbidity status (CCI ≥3 vs. 0: OR 0.31, 95% CI 0.26-0.36; p <0.001), and insurance type (Medicaid vs. private: OR 0.52, 95% CI 0.36-0.73; p <0.001) all influenced odds of subsequent surgery. Mean unadjusted costs associated with an outlet procedure and revisit were $6,245.58 and $15,675.90, respectively. Mean episode-based costs were higher among individuals who did not undergo a subsequent bladder outlet procedure ($16,223.38, 95% CI $15,423.61-$17,023.15 vs. $17,690.54, 95% CI $17,402.93-$17,978.15; p=0.04). CONCLUSIONS: AUR is a common and costly sequela of BPH, and both clinical and non-clinical factors influence the frequency and type of follow-up care received by patients with AUR. Surgical intervention following AUR may be protective against costly revisits resulting from recurrent AUR. Source of Funding: n/a © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e310-e310 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information David Friedlander More articles by this author Davis Viprakasit More articles by this author Matthew Nielsen More articles by this author Expand All Advertisement Loading ...

SIRT3 affects mitochondrial metabolic reprogramming via the AMPK–PGC‐1α axis in the development of benign prostatic hyperplasia

Sirtuin 3 (SIRT3) has been reported to share an association with mitochondrial metabolic reprogramming. However, the molecular mechanism underlying is not well understood, especially in benign prostatic hyperplasia (BPH). Therefore, the purpose of this study was to research whether SIRT3 can affect the progression of BPH via the regulation of mitochondrial metabolic reprogramming. Following the development of a rat model of BPH using testosterone propionate (TP), we extracted prostate tissues from sham-operated and BPH rats. Subsequently, bioinformatics prediction was used to screen the genes differentially expressed in BPH. To verify the role played by SIRT3 in BPH, we injected AAV9-SIRT3 into rats, followed by TP treatment. Prostate epithelial cells (PEC) were treated with TP to assess the mitochondrial morphology, mitochondrial membrane potential, and expression of enzymes related to the oxidative phosphorylation pathway after SIRT3 expression alteration. Finally, we examined the expression of AMPK-PGC-1α pathway in tissues and cells. SIRT3 was reduced in the prostate tissues of BPH rats. After overexpression of SIRT3, mitochondrial morphology was more stable in prostate tissues of BPH rats and in TP-treated PEC, with significant increases in mitochondrial membrane potential and in the expression of oxidative phosphorylation-related enzymes in the cytoplasm. Moreover, SIRT3 significantly activated the AMPK-PGC-1α signaling pathway, which maintained the stability of mitochondrial membrane potential as well as mitochondrial structure, thus alleviating the symptoms of BPH. SIRT3 maintained the stability of mitochondrial membrane potential as well as mitochondrial structure by activating the AMPK-PGC-1α pathway, thereby alleviating the symptoms of BPH.

Effects of inflammatory prostatitis on the development and progression of benign prostatic hyperplasia: A literature review.

Benign prostatic hyperplasia is a major disease that affects the quality of life of middle-aged and older men. Although >70% of men aged >70years have pathological benign prostatic hyperplasia, its pathogenesis and progression remain unclear. In this article, we reviewed the scientific literature on this condition and examined the development of lower urinary tract symptoms. Clinically, the weight of the prostate is not always proportional to the severity of the symptoms, and many factors can influence the progression of benign prostatic hyperplasia. Other than androgens, chronic inflammation can play an essential role in its development and the induction of symptoms, especially in symptomatic hyperplasia, because inflammatory cell infiltration is frequently observed in the prostate. Inflammation-induced changes in the prostate environment lead to changes in gene expression and subsequent chronicity of inflammation. It has been suggested that chronic asymptomatic prostatitis might be associated with changes in prostate structure and subsequent symptoms. In animal studies, the administration of anti-inflammatory drugs in rats with chronic prostatitis prevented the infiltration of inflammatory cells and increased the gland-to-stroma ratio. It is hoped that future research on the molecular biology of asymptomatic prostatitis might help to develop new therapeutic strategies for lower urinary tract symptoms associated with symptomatic prostatitis. Our conclusions provide a comprehensive insight into the prevalence and development of benign prostate hyperplasia and the treatment methods that can be used to treat it.

Effects of Saussurea costus on apoptosis imbalance and inflammation in benign prostatic hyperplasia

Ethnopharmacological relevanceSaussurea costus (synonym: Aucklandia lappa Decne) is a medicinal plant distributed in Yunnan, Guangxi, and Sichuan in China. In traditional Korean medicine, the plant parts (especially the root—“radix aucklandiae”) is widely used to treat vomiting, diarrhea, and inflammation. However, little has been reported on its effect on benign prostatic hyperplasia (BPH), which is common in middle-aged men. Aim of the studyBPH is caused by apoptosis imbalance and inflammation due to aging of the prostate. Therefore, the aim of this was to prove the efficacy of S. costus by analyzing its effect on the biological mechanisms leading to BPH progression. Materials and methodsWistar rats were injected subcutaneously with a single dose of testosterone (125 mg/kg) to induce BPH, and were later administered with S. costus (20, 40 mg/kg). After 12 weeks, histological changes in the prostate and hormone regulation factors were assessed in all animals. Furthermore, apoptotic protein and apoptotic body values were analyzed to confirm the improvement of apoptosis imbalance, and inflammatory cytokines were analyzed to confirm the anti-inflammatory efficacy of S. costus. ResultsIn the serum and tissue of S. costus-treated BPH rats, a significant reduction in prostate weight, prostate index, and hormone regulation factors was observed. S. costus also increased the levels of apoptosis marker proteins and reduced the levels of inflammatory cytokines. It also decreased the expression of B-cell lymphoma 2 (BCL-2) and increased the expression of BCL-2 associated X protein (BAX) in the prostate. Histological changes such as epithelial thickness significantly increased in BPH induced group but significantly decreased in the S. costus-treated groups (p < 0.001). ConclusionsS. costus may prevent and treat BPH occurrence by modulating inflammation and apoptosis imbalance.