Development Of Benign Prostatic Hyperplasia Research Articles

Integrating spatial transcriptomics and single-cell RNA-sequencing reveals the alterations in epithelial cells during nodular formation in benign prostatic hyperplasia

ObjectiveProliferative nodular formation represents a characteristic pathological feature of benign prostatic hyperplasia (BPH) and serves as the primary cause for prostate volume enlargement and consequent lower urinary tract symptoms (LUTS). Its specific mechanism is largely unknown, although several cellular processes have been reported to be involved in BPH initiation and development and highlighted the crucial role of epithelial cells in proliferative nodular formation. However, the technological limitations hinder the in vivo investigation of BPH patients.MethodsThe robust cell type decomposition (RCTD) method was employed to integrate spatial transcriptomics and single cell RNA sequencing profiles, enabling the elucidation of epithelial cell alterations during nodular formation. Immunofluorescent and immunohistochemical staining was performed for verification.ResultsThe alterations of epithelial cells during the formation of nodules in BPH was observed, and a distinct subgroup of basal epithelial (BE) cells, referred to as BE5, was identified to play a crucial role in driving this progression through the hypoxia-induced epithelial-mesenchymal transition (EMT) signaling pathway. BE5 served as both the initiating cell during nodular formation and the transitional cell during the transformation from luminal epithelial (LE) to BE cells. A distinguishing characteristic of the BE5 cell subgroup in patients with BPH was its heightened hypoxia and upregulated expression of FOS. Histological verification results confirmed a significant association between c-Fos expression and key biological processes such as hypoxia and cell proliferation, as well as the close relationship between hypoxia and EMT in BPH tissues. Furthermore, a strong link between c-Fos expression and the progression of BPH was also been validated. Additionally, notable functional differences were observed in glandular and stromal nodules regarding BE5 cells, with BE5 in glandular nodules exhibiting enhanced capacities for EMT and cell proliferation characterized by club-like cell markers.ConclusionsThis study elucidated the comprehensive landscape of epithelial cells during in vivo nodular formation in patients, thereby offering novel insights into the initiation and progression of BPH.

Effects of Taraxaci Herba (Dandelion) on Testosterone Propionate-Induced Benign Prostatic Hyperplasia in Rats.

Benign prostatic hyperplasia (BPH) is the non-malignant enlargement of the prostate, associated with lower urinary tract symptoms (LUTSs). Taraxaci Herba (TH), commonly known as dandelion, has traditionally been utilized in East Asia to treat symptoms related to LUTSs. Based on this traditional use, our study aimed to explore the inhibitory effects of TH on BPH progression using a testosterone propionate-induced rat model. To induce BPH, male Sprague Dawley rats were castrated and injected subcutaneously with testosterone propionate (3 mg/kg/day) for 28 days. Concurrently, TH extract was administered orally at doses of 100 and 300 mg/kg/day throughout the four-week period of testosterone propionate injections. The TH extract significantly reduced both the absolute and relative weights of the prostate, along with histopathological changes in the gland. Moreover, it lowered serum levels of testosterone and dihydrotestosterone and reduced the expression of the androgen receptor in the prostate. Additionally, the TH extract modulated the protein expressions of Bax and Bcl-2, which are key regulators of apoptosis in prostate cells. Collectively, our findings suggest that TH inhibits BPH development partially by modulating androgen signaling and inducing apoptosis within the prostate.

Abstract 6276: In vitro neuroendocrine differentiation of BPH-1 cells under beta-adrenergic stimulation

Abstract Recent studies have shown that adrenergic fibers from the sympathetic nervous system (SNS), acting through stromal β2-adrenergic receptors, play an important role in the initial phases of cancer development by promoting tumor cell survival. Recent epidemiological data suggest that β-blocker intake is associated with improved survival of prostate cancer patients. Hypertension and high blood pressure have been suggested to increase prostate cancer development suggesting that the use of β-blockers in these patients could also reduce prostate cancer risk. β-adrenoceptors signal through the cAMP/PKA pathway that is known to promote neuroendocrine differentiation (NED) in LNCaP prostate cancer cell line. While neuroendocrine (NE) cells expressing synaptophysin (SYN) represent a minor cell population in the epithelial compartment of normal prostate glands, the population of NE-like cells, exhibiting NE phenotypes and expressing NE markers, is increased in, and correlates with, cancer progression, androgen-independent state and poor prognosis. Expression of the routine tissue biomarker of prostate cancer AMACR in NE-like cells discriminates them from NE cells. Our aim was to investigate whether NED could also be associated with benign prostatic hyperplasia (BPH) as recent studies showed that an increase in neuroendocrine cell density occurred before development of BPH in hypertensive rats. Our results showed that a 10-day treatment with 100µM IBMX (blocking cAMP degradation) and 10µM forskolin (FSK, adenylate cyclase activator) to trigger sustained activation of the cAMP/PKA pathway led to an increase in SYN and AMACR expression in BPH-1 cells (qPCR and WB). Similar results were observed by combining the effect of the β-adrenoceptor agonist isoproterenol (1µM) and FSK. The same treatments reduced BPH-1 cell proliferation rates by 40% and 60%, respectively, as expected for NED. Effects on AMACR and SYN expression and cell proliferation were fully reversed by the β-blocker carvedilol (5µM). This data suggests that β-adrenoceptors could be linked to the development of NE-like cells in BPH, a non-lethal disease affecting the transition zone (TZ). As 20% of the prostate cancer occur in this TZ, this observation may need further investigation. Citation Format: Natascha Pigat, Laura N. Garrido, Coline Lefevre, Manon Baures, Vincent Goffin, Anne-Sophie Armand, Thierry Capiod. In vitro neuroendocrine differentiation of BPH-1 cells under beta-adrenergic stimulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6276.

Whole-exome sequencing of Nigerian benign prostatic hyperplasia reveals increased alterations in apoptotic pathways.

Through whole-exome sequencing of 60 formalin-fixed paraffin-embedded Nigerian (NGRn) benign prostatic hyperplasia (BPH) samples, we identified germline and somatic alterations in apoptotic pathways impacting BPH development and progression. Prostate enlargement is a common occurrence in male aging; however, this enlargement can lead to lower urinary tract symptoms that negatively impact quality of life. This impact is disproportionately present in men of African ancestry. BPH pathophysiology is poorly understood and studies examining non-European populations are lacking. In this study, NGRn BPH, normal prostate, and prostate cancer (PCa) tumor samples were sequenced and compared to characterize genetic alterations in NGRn BPH. Two hundred and two nonbenign, ClinVar-annotated germline variants were present in NGRn BPH samples. Six genes [BRCA1 (92%), HSD3B1 (85%), TP53 (37%), PMS2 (23%), BARD1 (20%), and BRCA2 (17%)] were altered in at least 10% of samples; however, compared to NGRn normal and tumor, the frequency of alterations in BPH samples showed no significant differences at the gene or variant level. BRCA2_rs11571831 and TP53_rs1042522 germline alterations had a statistically significant co-occurrence interaction in BPH samples. In at least two BPH samples, 173 genes harbored somatic variants known to be clinically actionable. Three genes (COL18A1, KIF16B, and LRP1) showed a statistically significant (p < 0.05) higher frequency in BPH. NGRn BPH also had five gene pairs (PKD1/KIAA0100, PKHD1/PKD1, DNAH9/LRP1B, NWD1/DCHS2, and TCERG1/LMTK2) with statistically significant co-occurring interactions. Two hundred and seventy-nine genes contained novel somatic variants in NGRn BPH. Three genes (CABP1, FKBP1C, and RP11-595B24.2) had a statistically significant (p < 0.05) higher alteration frequency in NGRn BPH and three were significantly higher in NGRn tumor (CACNA1A, DMKN, and CACNA2D2). Pairwise Fisher's exact tests showed 14 gene pairs with statistically significant (p < 0.05) interactions and four interactions approaching significance (p < 0.10). Mutational patterns in NGRn BPH were similar to COSMIC (Catalog of Somatic Mutations in Cancer) signatures associated with aging and dysfunctional DNA damage repair. NGRn BPH contained significant germline alteration interactions (BRCA2_rs11571831 and TP53_rs1042522) and increased somatic alteration frequencies (LMTK2, LRP1, COL18A1, CABP1, and FKBP1C) that impact apoptosis. Normal prostate development is maintained by balancing apoptotic and proliferative activity. Dysfunction in either mechanism can lead to abnormal prostate growth. This work is the first to examine genomic sequencing in NGRn BPH and provides data that fill known gaps in the understanding BPH and how it impacts men of African ancestry.

Untargeted metabolomics reveals that declined PE and PC in obesity may be associated with prostate hyperplasia.

Recent studies have shown that obesity may contribute to the pathogenesis of benign prostatic hyperplasia (BPH). However, the mechanism of this pathogenesis is not fully understood. A prospective case-control study was conducted with 30 obese and 30 nonobese patients with BPH. Prostate tissues were collected and analyzed using ultra performance liquid chromatography ion mobility coupled with quadrupole time-of-flight mass spectrometry (UPLC-IMS-Q-TOF). A total of 17 differential metabolites (3 upregulated and 14 downregulated) were identified between the obese and nonobese patients with BPH. Topological pathway analysis indicated that glycerophospholipid (GP) metabolism was the most important metabolic pathway involved in BPH pathogenesis. Seven metabolites were enriched in the GP metabolic pathway. lysoPC (P16:0/0:0), PE (20:0/20:0), PE (24:1(15Z)/18:0), PC (24:1(15Z)/14:0), PC (15:0/24:0), PE (24:0/18:0), and PC (16:0/18:3(9Z,12Z,15Z)) were all significantly downregulated in the obesity group, and the area under the curve (AUC) of LysoPC (P-16:0/0/0:0) was 0.9922. The inclusion of the seven differential metabolites in a joint prediction model had an AUC of 0.9956. Thus, both LysoPC (P-16:0/0/0:0) alone and the joint prediction model demonstrated good predictive ability for obesity-induced BPH mechanisms. In conclusion, obese patients with BPH had a unique metabolic profile, and alterations in PE and PC in these patients be associated with the development and progression of BPH.

FERTILITY FACTORS. D-HORMONE IN PREVENTION OF REPRODUCOPATHIES CAUSED BY BENIGN PROSTATIC HYPERPLASIA (Literature review)

In accordance with the statistical data, the spreading of benign prostatic hyperplasia (BPH) is increasing, because modern stressful lifestyle causes sex hormones disbalances and other dyshormonal conditions which lead to pathologies’ development at younger ages. The pathogenesis of BPH is connected with disturbances of regulation in the hypothalamo-hypophyseal system and with the changes of the regulatory signals intensity which go to the reproductive organs. The central pathogenic links of this pathology’ development are: the declining of efficacy of hypothalamus functioning regulation which carries out on the basis of feedback; the changes of the pituitary gland cells sensitivity to the releasing hormones of hypothalamus and disbalance of sex hormones. In addition to gonadotropins prolactin has a significant impact on the BPH development. Its hypersecretion causes the development of hyperplastic age-related changes in prostate gland. The introduction of dopamine receptors antagonists such as sulpiride causes the increasing of prolactin concentration and declining of gonadotropins releasing. “Sulpiride model” is broadly used in the experimental endocrinology for studying prostate-active drugs and is characterized by sex hormones disbalance' and inflammation processes’ development. The development of the pathology is linked with the disturbance of testosterone synthesis in the testicles, insufficiency of prostate gland functioning and increasing of prolactin and estradiol concentrations which provoke proliferative changes. The androgens disbalance is the main cause of BHP development, therefore, the “Testosterone model” based on testosterone’ and estradiol’ slow releasing implants is broadly used for modeling of urination disturbance in rats which imitates the same condition in elderly men with benign prostatic hyperplasia. The prostatitis, which developed under the condition of BHP, causes the disturbances of spermatogenesis during experimental modeling and in the clinical practice when spermatopathies, sexual disturbances and hypofertility are diagnosed in patients. The traditional BHP therapeutic methods are not always effective and the new therapeutic approaches of hypofertility caused by prostate gland pathologies are developed by investigators. Thus, there are data about correlation between increased vitamin D consumption and decreasing of BHP spreading, between gland volume and cells proliferation in patients with this pathology. Vitamin D level influences the quantity and quality of ejaculate. The deficiency of vitamin D is associated with lower proportion of sex hormones in young men and choriogonin sensitivity of Leydig's cells to be diminished. It has been experimentally shown that cholecalciferol regulates steroid hormones genesis, mitigates the age-related declining of testicles activity, protects the testicles in old animals and the unchanged spermatogenesis in normal males which received vitamin D3 can be considered to be the result of estrogens and androgens balance. The androgens receptors as well as vitamin D receptors have been found in prostate gland in health males and in those with hyperplasia. In addition to its classical function in calcium homeostasis and bones health, vitamin D inhibits tumor growth in different tissues including prostate gland. Vitamin D metabolites have been determined to be anti-inflammatory, proapoptotic and antiproliferative. D-hormone application potentiates the specific properties of prostate gland protectors, recovers reproductive capacity under the condition of experimental chronic prostatitis of inflammatory genesis as well as traumatic. All facts listed above allow to confirm the positive role of D-hormone in the regulation of prostate gland and reproductive function in patients with BHP and recovering of fertility under the condition of this pathology. The literature search for this review has been carried out on databases PubMed, Science Direct, Europa PMC, BMC, MedLine etc.

YAP1 Recognizes Inflammatory and Mechanical Cues to Exacerbate Benign Prostatic Hyperplasia via Promoting Cell Survival and Fibrosis.

Chronic prostatic inflammation promotes cell survival and fibrosis, leading to benign prostatic hyperplasia (BPH) with aggravated urinary symptoms. It is investigated whether yes-associated protein 1 (YAP1), an organ size controller and mechanical transductor, is implicated in inflammation-induced BPH. The correlation between YAP1 expression and fibrosis in human and rat BPH specimens is analyzed. Furthermore, the effects of YAP1 activation on prostatic cell survival and fibrosis, as well as the underlying mechanism, are also studied. As a result, total and nuclear YAP1 expression, along with downstream genes are significantly upregulated in inflammation-associated human and rat specimens. There is a significant positive correlation between YAP1 expression and the severity of fibrosis or clinical performance. YAP1 silencing suppresses cell survival by decreasing cell proliferation and increasing apoptosis, and alleviates fibrosis by reversing epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition in prostatic BPH-1 and WPMY-1 cells. Mechanistically, inflammatory stimulus and rigid matrix stiffness synergistically activate the RhoA/ROCK1 pathway to provoke cytoskeleton remodeling, thereby promoting YAP1 activation to exacerbate BPH development. Overall, inflammation-triggered mechanical stiffness reinforcement activates the RhoA/ROCK1/F-actin/YAP1 axis, thereby promoting prostatic cell survival and fibrosis to accelerate BPH progression.

Possible therapeutic role of zinc oxide nanoparticles versus vanillic acid in testosterone-induced benign prostatic hyperplasia in adult albino rat: A histological, immunohistochemical and biochemical study

BackgroundThe search for alternative therapies for treatment of Benign prostatic hyperplasia (BPH) has been increasingly studied to avoid the common adverse effects of the usual regimens. Therefore, this study aimed at delineating possible mechanisms of benign prostatic hyperplasia (BPH) and possible therapeutic role of zinc oxide nanoparticles (ZnO-NPs) versus vanillic acid. MethodsForty rats were divided into five groups: control, sham control, Testosterone-induced BPH, BPH and Zn-NPs, and BPH and vanillic acid. Light microscopic, immune-histochemical; PCNA, Bcl-2, Bax, caspase-3, p-Akt and p-mTOR, histomorphometric analysis, MDA/SOD and GPx and were done. Gene expression of p-Akt, p-mTOR and survivin were evaluated. ResultsApplication of zinc oxide nanoparticles as well as vanillic acid significantly reduced prostatic index, epithelial thickness, stromal collagen fibers, expression of PCNA, Bcl2, p-Akt, p-mTOR and MDA tissue level (p < 0.05). Whereas expression of Bax and caspase 3, and tissue levels of SOD and GPx were significantly increased in groups treated with Zno-Nps and vanillic acid compared to that of BPH group. Zinc oxide nanoparticles showed a better effect than vanillic acid in alleviating BPH. ConclusionThese findings suggested that ZnO-NPs as well as VA ameliorated the histolo-pathological and biochemical effects of induced BPH, moreover they improved the proapoptotic and antioxidant parameters which ere induced in BPH. It is recommended to search for new agents to prevent the development and progression of BPH.

Mechanism of RhoA regulating benign prostatic hyperplasia: RhoA-ROCK-β-catenin signaling axis and static & dynamic dual roles

BackgroundThe pathogenesis of benign prostatic hyperplasia (BPH) has not been fully elucidated. Ras homology family member A (RhoA) plays an important role in regulating cell cytoskeleton, growth and fibrosis. The role of RhoA in BPH remains unclear.MethodsThis study aimed to clarify the expression, functional activity and mechanism of RhoA in BPH. Human prostate tissues, human prostate cell lines, BPH rat model were used. Cell models of RhoA knockdown and overexpression were generated. Immunofluorescence staining, quantitative real time PCR (qRT-PCR), Western blotting, cell counting kit-8 (CCK-8), flow cytometry, phalloidine staining, organ bath study, gel contraction assay, protein stability analysis, isolation and extraction of nuclear protein and cytoplasmic protein were performed.ResultsIn this study we found that RhoA was localized in prostate stroma and epithelial compartments and was up-regulated in both BPH patients and BPH rats. Functionally, RhoA knockdown induced cell apoptosis and inhibited cell proliferation, fibrosis, epithelial-mesenchymal transformation (EMT) and contraction. Consistently, overexpression of RhoA reversed all aforementioned processes. More importantly, we found that β-catenin and the downstream of Wnt/β-catenin signaling, including C-MYC, Survivin and Snail were up-regulated in BPH rats. Downregulation of RhoA significantly reduced the expression of these proteins. Rho kinase inhibitor Y-27632 also down-regulated β-catenin protein in a concentration-dependent manner. However, overexpression of β-catenin did not affect RhoA-ROCK levels, suggesting that β-catenin was the downstream of RhoA-ROCK regulation. Further data suggested that RhoA increased nuclear translocation of β-catenin and up-regulated β-catenin expression by inhibiting its proteasomal degradation, thereby activating Wnt/β-catenin signaling. Overexpression of β-catenin partially reversed the changes in cell growth, fibrosis and EMT except cell contraction caused by RhoA downregulation. Finally, Y-27632 partially reversed prostatic hyperplasia in vivo, further suggesting the potential of RhoA-ROCK signaling in BPH treatment.ConclusionOur novel data demonstrated that RhoA regulated both static and dynamic factors of BPH, RhoA-ROCK-β-catenin signaling axis played an important role in the development of BPH and might provide more possibilities for the formulation of subsequent clinical treatment strategies.

High glucose promotes benign prostatic hyperplasia by downregulating PDK4 expression

As men age, a growing number develop benign prostatic hyperplasia (BPH). According to previous research, diabetes may be a risk factor. Pyruvate dehydrogenase kinase 4 (PDK4) is closely related to glucose metabolism and plays a role in the onset and progression of numerous illnesses. This study aimed to determine the direct effects of high glucose environment on prostate epithelial cells, in particular by altering PDK4 expression levels. In this investigation, normal prostatic epithelial cells (RWPE-1) and human benign prostatic hyperplasia epithelial cells (BPH-1) were treated with 50 mM glucose to show the alteration of high glucose in prostate cells. PDK4-target siRNA, PDK4-expression plasmid were used to investigate the effects of PDK4. Rosiglitazone (RG), a PPARγ agonist, with the potential to up-regulate PDK4 expression was also used for treating prostate cells. The expression of PDK4 in human prostate samples was also analyzed. The effects of high glucose therapy on BPH-1 and RWPE-1 cells were demonstrated to enhance proliferation, epithelial-mesenchymal transition (EMT), suppress apoptosis, and down-regulate PDK4 expression. Additionally, diabetes-related BPH patients had reduced PDK4 expression. Following the application of PDK4-target siRNA, a comparable outcome was seen. The PDK4-expression plasmid therapy, however, produced the opposite results. RG with the ability to elevate PDK4 expression might be used to treat BPH. Changes in the metabolism of lipids and glucose may be the cause of these consequences. These findings showed that high glucose treatment might facilitate BPH development, and may be related to the down-regulation of PDK4. PDK4 might be a potential therapeutic target of BPH.

Tissue immunoexpression of IL-6 and IL-18 in aging men with BPH and MetS and their relationship with lipid parameters and gut microbiota - derived short chain fatty acids.

Recent studies indicate that inflammation is one of the causes of the development of benign prostatic hyperplasia (BPH). Inflammation may result from past infections, metabolic disorders, but also from the state of functioning of the intestinal microbiota. The aim of the study was to assess whether the diagnostic lipid parameters for metabolic syndrome and short-chain fatty acids (SCFAs) are related to the immunoexpression of interleukins in prostate tissue with benign hyperplasia. The study involved 103 men with BPH, who were divided into two groups depending on the presence of MetS. We analysed tissue immunoexpression of two proinflammatory interleukins: IL-6, which is known to be involved in the development of BPH, and IL-18, which has not been analysed so far. The results of our study indicate that men with BPH + MetS in the stroma of the prostate have a significantly higher overall percentage of IL-6+ cells compared to men without MetS (p = 0.034). The analysis of IL-18 immunoexpression in prostate tissue indicated that in men with BPH + MetS, the glandular part of the prostate had a significantly higher percentage of cells with strong IL-18 expression (p = 0.040). We also noticed a relationship between tissue expression of IL-6 and IL-18 and lipid parameters (TG and HDL). We conclude that lipid disorders occurring in men with BPH increase inflammation in the prostate gland. Moreover, it has also been demonstrated for the first time that, indirectly, through SCFAs, the gut microbiota can act to prevent or create an inflammatory microenvironment in the prostate gland.

Diagnostic efficacy of systemic immune-inflammation biomarkers in benign prostatic hyperplasia using receiver operating characteristic and artificial neural network

Benign prostatic hyperplasia (BPH) is a chronic, progressive disease characterized by mesenchymal cell-predominance and stromal and glandular cell-hyperproliferation. Although, the precise cause of BPH is unknown, it is believed to be associated with hormonal changes in aging men. Despite androgens and ageing are likely to play a role in the development of BPH, the pathophysiology of BPH remains uncertain. This paper aims to evaluate the diagnostic efficacy of platelet-to-lymphocyte ratio (PLR), neutrophil–lymphocyte ratio (NLR) and systemic immune-inflammation index in in diagnosing BPH. A single-center-randomized-retrospective study was carried out at Alzahraa university hospital between January 2022 and November 2022 on 80 participants (40 non-BPH subjects and 40 patients with symptomatic enlarged prostate) who visited the outpatient clinic or admitted to the urology department. The BPH cases were evaluated by digital rectal examination (DRE), International Prostate Symptom Score (IPSS), prostate size, prostate specific antigen (PSA), TRUS biopsy in elevated PSA > 4 ng/ml, PLR, NLR and systemic immune inflammatory (SII). The diagnosing efficiency of the selected parameters was evaluated using Receiver Operating Characteristic (ROC) and Artificial Neural Network (ANN) showing excellent discrimination with 100% accuracy and AUC = 1 in the ROC curves. Moreover, the accuracy rate of the ANN exceeds 99%. Conclusion: PLR, NLR and SII can be significantly employed for diagnosing BPH.

Inhibition of integrin receptors reduces extracellular matrix levels, ameliorating benign prostate hyperplasia

Although a high prevalence of benign prostate hyperplasia (BPH) has been documented, the risk factors are poorly understood. Metabolic syndrome increases the risk of BPH. Succinylation, a type of posttranslational modification, mostly targets metabolic processes. The level of succinylation was investigated in 4 BPH patients and 4 healthy controls. Additionally, 176 patients with BPH were analyzed by using pan-antisuccinyllysine antibody blotting. TMT-labeling proteomic and sc-RNAseq Cellchat analyses were employed to identify key signaling factors involved in the development of BPH. In vivo and in vitro experiments were used to confirm the role of integrin receptors. The global succinylation level in BPH was higher than that in the healthy prostate. Positive correlations of prostate volume with IHC score sand urodynamics testing were found in large clinical cohorts. The extracellular matrix (ECM), metabolic processes and immune signaling were involved in succinylation in BPH, as indicated by using TMT-labeling proteomic analysis, and this finding was also confirmed by sc-RNAseq CellChat analysis. The proteins upregulated in SIRT5 knockout WPMY-1 cells were also enriched in the extracellular matrix and metabolic processes. More importantly, integrin receptor inhibition in a mouse model of BPH significantly ameliorated prostate hyperplasia. High levels of succinylation modifications were found in BPH, and succinylated proteins influenced the activation of the ECM. Inhibition of ECM signaling further ameliorated prostate hyperplasia in mice.

Inhibitory Effects of Pueraria mirifica Aqueous Extracts on 5α-reductase and Prostate Histomorphometry in Testosterone-induced Benign Prostatic Hyperplasia Sprague Dawley Rats

Introduction: Benign prostatic hyperplasia (BPH) is the most prevalent prostatic disease in ageing men, characterised by an excessive proliferation of the prostatic epithelial and stromal cells. Despite the extensive choices of pharmaceutical therapies, the current treatments possess side effects, necessitating the search for new alternative options, including herbal substances such as Pueraria mirifica. This tuberous root of P. mirifica is a medicinal plant that contains numerous phytoestrogens, traditionally used for health rejuvenation in aged men and women. This study was carried out to access the inhibitory effect of 5α-reductase of P. mirifica and its histoprotective effect in a rat model of testosterone-induced BPH. Methods: Adult Sprague Dawley (12 weeks) were subcutaneously injected with testosterone propionate (3 mg/kg) daily to induce BPH. Rats (n=6) in all groups (aqueous extract of P. mirifica (APM): 10, 100, and 1000 mg/kg, p.o.; finasteride: 2mg/kg, p.o., BPH model, and sham groups) were treated for 30 days. The determination of serum dihydrotestosterone (DHT) level, prostatic index and prostate structural changes were investigated. Results: APM and finasteride-treated groups showed significantly lesser prostatic weight and prostatic index, serum DHT levels compared to the model group (p&lt;0.05). Furthermore, there was a significantly lower prostate score with improved prostate histomorphology, demonstrating fewer epithelial involutions of glandular tissues and improved stromal and epithelial cells. Conclusion: In conclusion, the aqueous extract of P. mirifica tuberous root mitigates the development of BPH and it can be inferred that aqueous extract of P. mirifica tuberous root may possess the active agents for anti-BPH treatment.

Multidirectional Effects of Terpenoids from Sorbus intermedia (EHRH.) PERS Fruits in Cellular Model of Benign Prostate Hyperplasia.

Benign prostatic hyperplasia (BPH) is a common urological disease affecting aging men. Its pathogenesis is regarded as complex and multifactorial, with sex hormones and inflammation as key contributory factors. In the current study, we investigated the anti-BPH potential of terpenoids present in the fruits of Sorbus intermedia (EHRH.) PERS. Not only the effects on testosterone-stimulated normal prostate epithelial PNT2 cells, namely suppression of 5-α-reductase activity, PSA secretion, and cell proliferation, were determined but also the inhibitory activity on heat-induced protein denaturation, hyaluronidase, as well as IL-6, TNF-α, and NO release in LPS-treated macrophages. Sorbus terpenoids significantly inhibited 5-α-reductase activity and reduced PSA secretion in PNT2 cells, reversing the stimulatory effect of testosterone. PNT2 cell proliferation was also found to be attenuated. Subsequently, all compounds reduced the release of pro-inflammatory mediators in RAW 264.7 cells. In addition, ursolic acid (UA) and its aldehyde (UAL) were the most potent hyaluronidase inhibitors of all compounds, with IC50 values of 225.75 µg/mL and 369.77 µg/mL, respectively. For better understanding and interpretation of the overall effect of Sorbus terpenoids on different aspects of BPH pathogenesis and development, cluster analysis was applied.

(065) The Impact of Testosterone-Replacement Therapy (TRT) on Benign Prostatic Hyperplasia (BPH) Incidence and Need for Interventions in Hypogonadal Men

Abstract Introduction Investigations on the application of testosterone-replacement therapy (TRT) in hypogonadal men with benign prostatic hyperplasia (BPH) show contrasting results. While some studies reported increased prostate-related events with TRT, recent evidence suggested that TRT can alleviate BPH symptoms in hypogonadal men. Objective Our main objective was to determine the impact of TRT on BPH incidence in a large cohort of hypogonadal men. We also evaluated the relationship between TRT in hypogonadal men and the need for BPH interventions. Methods This retrospective case-control study used the 2011-2020 IBM MarketScan database to identify males above 18 years old with a hypogonadism diagnosis, and determine if they received TRT. We used ICD-9, -10, CPT, HCPCS, and NDC codes to identify diagnoses, interventions, and medications. We excluded individuals who were diagnosed with congenital genetic disorders (e.g. chromosomal abnormalities), hypothalamic-pituitary disorders, or prostatic adenocarcinoma. BPH diagnosis was the primary outcome of this study, and BPH treatment was the secondary outcome. We ran cox proportional hazard (CPH) models from initial hypogonadism diagnosis to BPH occurrence to investigate the effect of TRT on the development of BPH. We also used CPH models from time of BPH diagnosis to first intervention, to evaluate the impact of TRT on BPH interventions. In all models we controlled for age, geographic region, population density, and comorbidities. We included TRT within the last 6 as a time-varying covariate in the models. For BPH occurrence there was non-proportionality in the effect of TRT. Thus, we ran two CPH models for BPH occurrence, one from first hypogonadism diagnosis to 912 days (2.5 years), and one from 2.5 years to the end of enrollment. Results In our total cohort of 882570 hypogonadal men, 157185 (17.8%) were diagnosed with BPH. Hyperlipidemia was the most common comorbidity detected in 84% and 68% of hypogonadal men with and without BPH respectively. For the first 2.5 years after hypogonadism diagnosis, there was no significant difference for development of BPH between patients on TRT and those who were not on TRT (HR 1.00, 95%CI 0.98-1.01, p=0.66). However, from 2.5 years onward, men who were on TRT had a 32% greater chance for development of BPH (HR 1.32, 95%CI 1.28-1.36, p&amp;lt;0.001). Hypogonadal men with BPH who received TRT showed no significant difference for BPH interventions compared to those who were not on TRT (HR 0.95, 95%CI 0.89-1, p=0.08). Conclusions In the long term, TRT can increase the risk of development of BPH in hypogonadal men. On the other hand, TRT in hypogonadal men with BPH does not change the need for BPH interventions. Our findings indicate that TRT should be used with caution in hypogonadal men who are at risk of developing BPH but further work is needed to clarify this relationship. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Educational/Research grant: Acerus, Coloplast, Endo, Boston Scientific; Consultant: Turtle Health; Hold equity: StreamDx, FirmTech, Maximus.

Biochemical evaluation of Ceiba pentandra leaf on the amelioration of testosterone induced-benign prostatic hyperplasia in Wister rats

Benign prostatic hyperplasia (BPH) is a considerable public health problem prevalent among older men. Despite its eminent prevalence, the etiology of BPH is not well understood. Accumulating evidence indicates that modifiable risk factors of cardiovascular disease may also increase the risk of BPH and potentially contribute to BPH development. This study evaluated the ameliorative effect of Ceiba pentandra leaf on some lipids profile indices and bilirubin concentration of rats induced BPH. Thirty six Wistar rats were divided randomly into six groups (n = 6). All the experimental groups except the normal control were induced benign prostatic hyperplasia using testosterone propionate and estradiol valerate at a dose of 400 µg and 80 µg respectively, for 21 days. After induction, rats in the negative control (BPH Control) group received no treatment. Rats in the standard control group received finasterides (1mg/kg body weight), while rats in the low dose extract, medium dose extract and high dose extract groups received the plant extract according to their body weights in kilogram at 500 mg/kg, 1000 mg/kg, and 1500 mg/kg respectively. Normal Control group received only feed without any special treatment. The animals in all the groups were allowed access to water and feed ad libitum for 28 days. The rats were anaesthetized after treatment period. Blood samples were collected and serum harvested for analyses using standard methods. Result showed that Ceiba pentandra leaf had ameliorative effect on the lipids profile analyzed.

Molecular mechanisms of Chengshi Beixie Fenqing Decoction based on network pharmacology: pivotal roles of relaxin signaling pathway and its associated target proteins against Benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is a common disease that affects the quality of life of middle-aged and older men. We investigated the therapeutical effects of Chengshi Beixie Fenqing Decoction (CBFD), a classic traditional Chinese medicine prescription, on BPH through in vivo model and network pharmacology. Bioactives in CBFD were detected through UPLC-Q-Tof-MS/MS and GC-MS, and filtered by the modified Lipinski’s rule. Target proteins associated with the filtered compounds and BPH are selected from public databases. Venn diagram identified the overlapping target proteins between the bioactives-interacted target proteins and the BPH-targeted proteins. The bioactive-protein interactive networking of BPH was analyzed through the KEGG pathway on STRING to identify potential ligand-target and visualized the rich factors on the R packet. After that, the molecular docking test (MDT) was performed between bioactives and target proteins. It showed that the mechanism of CBFD against BPH was related to 104 signaling pathways of 42 compounds. AKT1, 6-demethyl-4′-methyl-N-methylcoclaurine and relaxin signaling pathways were selected as a hub target, key bioactivitie and hub signaling pathway, respectively. In addition, three major compounds, 6-demethyl-4′-methyl-N-methylcoclaurine, isoliensinine and liensinine, had the highest affinity on MDT for the three crucial target proteins, AKT1, JUN and MAPK1. These proteins were associated with the relaxin signaling pathway, which regulated the level of nitric oxide and is implicated in both BPH development and CBFD. We concluded that the three key bioactivities found in Plumula nelumbinis of CBFD may contribute to improving BPH condition by activating the relaxin signaling pathways. Communicated by Ramaswamy H. Sarma

MP24-12 ASSOCIATION OF RARE MONOGENIC VARIANTS WITH DIAGNOSIS OF BPH USING WHOLE EXOME SEQUENCING IN THE UK BIOBANK

You have accessJournal of UrologyCME1 Apr 2023MP24-12 ASSOCIATION OF RARE MONOGENIC VARIANTS WITH DIAGNOSIS OF BPH USING WHOLE EXOME SEQUENCING IN THE UK BIOBANK Clark Judge, David Nusbaum, Jun Wei, Zhuqing Shi, Andrew Rifkin, S. Lilly Zheng, Brian Helfand, Alexander Glaser, and Jianfeng Xu Clark JudgeClark Judge More articles by this author , David NusbaumDavid Nusbaum More articles by this author , Jun WeiJun Wei More articles by this author , Zhuqing ShiZhuqing Shi More articles by this author , Andrew RifkinAndrew Rifkin More articles by this author , S. Lilly ZhengS. Lilly Zheng More articles by this author , Brian HelfandBrian Helfand More articles by this author , Alexander GlaserAlexander Glaser More articles by this author , and Jianfeng XuJianfeng Xu More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003249.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Benign prostatic hyperplasia (BPH) is a common condition that leads to bothersome lower urinary tract symptoms. Polygenic heritability of BPH has been demonstrated using genetic risk scores derived from common single nucleotide polymorphisms, but rare monogenic gene mutations associated with BPH have not been well described. The objective of this study was to determine the impact of rare monogenic variants on the development of BPH. METHODS: A total of 83,631 men from the UK Biobank (UKB) with whole exome sequencing data were included and categorized based on ICD10 diagnosis of BPH (N40). Of men with BPH, 9,697 were further characterized as undergoing transurethral resection of prostate (TURP). The robust SKAT-O, a novel gene-based analysis of pathogenic/likely pathogenic mutations that properly controls for type I error rates due to unbalanced case-control ratio, was used for association tests adjusting for age at recruitment and genetic background. RESULTS: Nineteen candidate genes were identified as associated with BPH in 9,697 cases compared to 73,934 controls at p<0.001 using SKAT-O (Table). However, none of these associations was significant after adjusting for multiple testing (FDR<0.05). For most of these genes, higher carrier rates in patients undergoing TURP was also found. CONCLUSIONS: In this large study of nearly 84,000 men, several candidate genes were identified. Confirmation in independent study populations is required. Identification of monogenic gene mutations associated with BPH may advance our understanding of disease etiology and identify potential therapeutic targets. Source of Funding: NA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e322 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Clark Judge More articles by this author David Nusbaum More articles by this author Jun Wei More articles by this author Zhuqing Shi More articles by this author Andrew Rifkin More articles by this author S. Lilly Zheng More articles by this author Brian Helfand More articles by this author Alexander Glaser More articles by this author Jianfeng Xu More articles by this author Expand All Advertisement PDF downloadLoading ...

Expression and functional activity of myosin II in hyperplastic prostates of varying volumes

Prostate volume (PV) differs dramatically among benign prostatic hyperplasia (BPH) patients. Estimation of PV is important to guide the most appropriate pharmacologic or interventional treatment approach. However, the underlying pathophysiological mechanisms for the differences in PV remain unknown. We recently found that the myosin II system might participate in the etiology and development of BPH via static and dynamic factors. Our present study aims to explore the expression and functional activities of myosin II isoforms including smooth muscle (SM) myosin II (SMM II) and non-muscle myosin II (NMM II) in hyperplastic prostates with varied PV. Human hyperplastic prostates and the testosterone-induced rat BPH model were employed for this study. Hematoxylin and Eosin (H&E), Masson's trichrome, immunohistochemical staining, in vitro organ bath, RT-polymerase chain reaction (PCR) and Western-blotting were performed. Also, a BPH tissue microarray (TMA) was constructed to determine the correlations between myosin II isoforms with clinical parameters of BPH patients. With the increase of PV, the expression of NMMHC-A, NMMHC-C, SM-A and LC17b isoforms were increased, and the contractility of prostate smooth muscle was enhanced but force developed more slowly. Consistently, NMMHC-A, NMMHC-C, SM-A and LC17b were correlated positively with PV. Similar outcomes were also observed in the BPH rat model with different PVs. Alterations in the expression and function of myosin the II system may be involved in the pathophysiological mechanism of PV differences between BPH patients.