Omentin-1 inhibits the development of benign prostatic hyperplasia by attenuating local inflammation.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a prevalent disease affecting elderly men, with chronic inflammation being a critical factor in its development. Omentin-1, also known as intelectin-1 (ITLN-1), is an anti-inflammatory protein primarily found in the epithelial cells of the small intestine. This study aimed to investigate the potential of ITLN-1 in mitigating BPH by modulating local inflammation in the prostate gland. METHODS: Our investigation involved two in vivo experimental models. Firstly, ITLN-1 knockout mice (Itln-1-/-) were used to study the absence of ITLN-1 in BPH development. Secondly, a testosterone propionate (TP)-induced BPH mouse model was treated with an ITLN-1 overexpressing adenovirus. We assessed BPH severity using prostate weight index and histological analysis, including H&E staining, immunohistochemistry, and enzyme-linked immunosorbent assay. In vitro, the impact of ITLN-1 on BPH-1 cell proliferation and inflammatory response was evaluated using cell proliferation assays and enzyme-linked immunosorbent assay. RESULTS: In vivo, Itln-1-/- mice exhibited elevated prostate weight index, enlarged lumen area, and higher TNF-α levels compared to wild-type littermates. In contrast, ITLN-1 overexpression in TP-induced BPH mice resulted in reduced prostate weight index, lumen area, and TNF-α levels. In vitro studies indicated that ITLN-1 suppressed the proliferation of prostate epithelial cells and reduced TNF-α production in macrophages, suggesting a mechanism involving the inhibition of macrophage-mediated inflammation. CONCLUSION: The study demonstrates that ITLN-1 plays a significant role in inhibiting the development of BPH by reducing local inflammation in the prostate gland. These findings highlight the potential of ITLN-1 as a therapeutic target in the management of BPH.

Exploring the mechanism of action of Qian Lie Xing Fang during the treatment of benign prostatic hyperplasia via network pharmacology and molecular dynamics simulation analyses.

This study aimed to explore the historical research progress on benign prostatic hyperplasia from the perspective of traditional Chinese medicine theory and the treatment of benign prostatic hyperplasia (BPH) with Qian Lie Xing Fang (QLXF) via the warming and tonifying of kidney yang, promotion of blood circulation, and clearing of meridians. First, network pharmacology analysis was used to screen and identify possible pathways for BPH treatment with QLXF. Subsequently, molecular docking analysis helped explore the mechanism of action by which the components of QLXF affected androgen receptor (AR) and type 5 phosphodiesterase inhibitor (PDE-5) levels. Targets for treatment with QLXF were identified from the online Mendelian inheritance in man and DisGeNET databases. BPH-related genes were identified using GeneCards and online Mendelian inheritance in man databases, and their intersection was used to construct a protein-protein interaction network analysis graph. Subsequently, gene ontology and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were performed. The semiflexible docking of the ingredients of QLXF acting on the 2 targets was performed via molecular docking and molecular dynamics simulation, to elucidate the mechanism of action by which the active ingredients affect AR and PDE-5 levels further. This enabled us to explore the pattern of interactions between small active ingredient molecules, the target protein, and the stability after binding at the microscopic level. Gene ontology enrichment analysis showed that QLXF affected several processes, such as DNA transcription factor binding, kinase binding, protein homodimerization activity, protein structure domain-specific binding, and protein-coupled amine receptor activity in BPH patients. KEGG results showed that chemical carcinogenic reactive oxidative species and the JAK-STAT, Pl3k-Akt, FoxO, NF-κB, and other pathways were significantly enriched. Conducting molecular docking studies to investigate the interaction of active components from QLXF with AR and PDE-5, it was found that MOL002260 may possess the potential to inhibit PDE-5 activity, while MOL010578 may exhibit the capability to inhibit AR activity. QLXF is closely associated with various biological processes and KEGG signaling pathways related to BPH. The active ingredients of QLXF were investigated for their interactions with AR and PDE-5, with a primary focus on the small molecules MOL002260 and MOL010578.

Efficacy of Buzhong Yiqi decoction on benign prostatic hyperplasia and its possible mechanism.

OBJECTIVE: To explored the mechanism of Buzhong Yigi decoction ( BZYQD) in inhibiting prostatic cell proliferation effect. METHODS: The compounds of BZYQD consisted with eight herbs were searched in TCMSP databases and the putative targets of BZYQD were collected in Drugbank database. Then, "Benign prostatic hyperplasia" (BPH) was used to find the targets based on the GeneCards, Online Mendelian Inheritance in Man (OMIM) and Therapeutic Target Database (TTD) databases, and they were further used to collect further collect the intersection targets between BZYQD and BPH by counter-selection. Next, Herb-Compound-Target-Disease network was constructed by Cytoscape software and protein interaction network was built by Search tool for recurring instances of neighbouring genes (STRING) database. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were analyzed by Database for Annotation, Visualization and Integrated Discovery (DAVID) database to predict the mechanism of the intersection targets. Mitogen activated protein kinase 8 (MAPK8), interleukin 6 (IL-6) and quercetin were chosen to perform molecular docking. Then 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was to detect the bility of BPH-1 (BPH epithelial cell line) by treated with quercetin at the concentrations of 15, 30, 60, 120 µM for 12, 24, 48, 72 h. The production of IL-6, tumor necrosis factor-α (TNF-α), IL-1ß and were mRNA expression detected by enzyme-linked immunosorbent assay kit and quantitative real-time polymerase chain reaction. Western blot was used to detect the expression of phospho-p38 mitogen-activated protein kinase (p-P38) and matrix metalloprotein-9 (MMP-9). RESULTS: A total 151 chemical ingredients of 8 herbs and 1756 targets in BZYQD, 105 common targets of BZYQD and BPH which mainly involving with MAPK8, IL-6, and so on. GO enrichment analysis got 352 GO entries (0.05) which included 208 entries of biological process, 64 entries of cell component and 80 entries of molecular function. KEGG pathway Enrichment analyses got 20 significant pathways which mainly involved with MAPK signaling way. MTT assay indicated quercetin inhibited the viability of BPH-1 cells by time-and dose-dependent manner. Quercetin decreased the IL-6, TNF-α and IL-1ß production and mRNA expression, and the expression of p-P38 and MMP-9 were also obviously reduced after treated with quercetin. CONCLUSIONS: BZYQD inhibited BPH through suppressing inflammatory response which might involving with regulating the MAPK signaling way.

Anti-androgenic potential of the fruit extracts of certain Egyptian Sabal species and their genetic variability studies: a metabolomic-molecular modeling approach.

This work aimed to evaluate the anti-androgenic activity of S. blackburniana Glazebrook, S. causiarum (O. F. Cook) Becc, and S. palmetto (Walter) Lodd. Ex Schult fruit extracts in rats using Hershberger assay. Furthermore, to annotate secondary metabolites using LC-HRMS technique, to investigate underlying mechanisms responsible for 5-α-reductase inhibitory activity in silico and to compare cytotoxic effects in vitro against human prostatic stromal myofibroblast (WPMY-1) and human benign prostatic hyperplasia (BPH-1) cell lines using MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (spectrophotometrically). The results showed significant anti-androgenic implications with varying degrees, markedly decreased sex organ weights, reduction in testosterone and increase in LH and FSH serum levels. Genetic diversity study ensured the correct genotype and revealed outperformance of SCoT compared with CBDP markers to interpret polymorphism among selected species. S. blackburniana exhibited selective cytotoxic activity against BPH-1 compared to finasteride. Molecular docking of 59 dereplicated metabolites belonging to various chemical classes revealed that helasaoussazine, pinoresinol and tetra-O-caffeoylquinic acid are the top inhibitors of 5-α-reductase-2. Our study provides an insight into the anti-androgenic activity of selected species of Egyptian Sabal supported by docking study for the first time, demonstrates safety toward liver and kidney and highlights a new potential therapeutic candidate for anti-androgenic related disease such as benign prostatic hyperplasia.

Purple Corn Extract Improves Benign Prostatic Hyperplasia by Regulating Prostate Cell Proliferation and Apoptosis.

Purple corn (Zea mays L.), utilized as a natural pigment in food production and processing, has been used to treat obesity, cystitis, and urinary tract infections. However, no reports of its use for benign prostatic hyperplasia (BPH) exist. Purple corn extract (PCE) contains anthocyanins, particularly cyanidin-3-O-glucoside, which have various pharmacological characteristics. Therefore, this study sought to elucidate the ameliorative effect of PCE on BPH in dihydrotestosterone (DHT)-stimulated WPMY-1 cells and testosterone propionate (TP)-induced rats. Expression levels of the upregulated androgen receptor (AR) and its related genes in DHT-stimulated WPMY-1 cells were reduced by PCE, and proapoptotic gene expression increased by modulating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling cascade. PCE reduced the weight of the enlarged prostate by inhibiting the androgen/AR signaling-related markers. Histological variations in the prostate epithelium caused by TP injection were restored by PCE. Thus, PCE alleviates BPH by modulating prostate cell proliferation and apoptosis.

Oral administration of berberine represses macrophage activation-associated benign prostatic hyperplasia: a pivotal involvement of the NF-κB.

Benign prostatic hyperplasia (BPH) is one of the most common chronic diseases in men over the age of 50. Clinical studies have suggested that chronic inflammation is associated with BPH pathoprogression. Berberine (BB) is a natural compound found in Berberis vulgaris, Coptis chinensis and Phellodendron amurense. Although several studies have documented that BB may be effective for inflammation, the effects of the oral administration of BB on BPH are not fully understood. The effects of BB on chronic prostatic inflammation were evaluated in a testosterone-induced BPH animal model. Orally administered BB alleviated the pathological alterations induced by BPH and significantly suppressed the expression of inflammatory markers while enhancing the expression of antioxidant factors. Furthermore, BB regulated the activation of macrophages via NF-κB signaling pathway inhibition in the BPH rat model. The effects and underlying signaling pathway of BB in RWPE-1 cells exposed to macrophage conditioned medium (CM) were also demonstrated in vitro. While CM stimulation induced prostatic cell proliferation and upregulated the expression of inflammatory factors, BB exerted anti-proliferation and anti-inflammatory effects in RWPE-1 cells. These findings propose that BB suppresses androgen-dependent BPH development by targeting NF-κB-mediated pro-inflammatory signaling.

Extracts of Phyllostachys pubescens Leaves Represses Human Steroid 5-Alpha Reductase Type 2 Promoter Activity in BHP-1 Cells and Ameliorates Testosterone-Induced Benign Prostatic Hyperplasia in Rat Model.

Benign prostatic hyperplasia (BPH) is the most common symptomatic abnormality of the human prostate characterized by uncontrolled proliferation of the prostate gland. In this study, we investigated the effect of bamboo, Phyllostachys pubescens, leaves extract (PPE) on human 5α-reductase type 2 (SRD5A2) gene promoter activity in human prostate cell lines and the protective effect of PPE on a testosterone-induced BPH rat model. PPE repressed human SRD5A2 promoter activity and its mRNA expression. The rats treated with PPE for 4 weeks showed a significantly attenuated prostate weight compared to vehicle control. PPE-treated rats also showed reduced serum dihydrotestosterone, testosterone, prostate-specific antigen, and SRD5A2 levels by testosterone injection. Quantitative real-time polymerase chain reaction showed that PPE treatment significantly decreased mRNA expression of SRD5A2, androgen receptor (AR), proliferating cell nuclear antigen (PCNA), and fibroblast growth factor 2 compared with the vehicle-treated, testosterone-injected rats in the prostate. Furthermore, PPE treatment showed reduced AR, PCNA, and tumor necrosis factor alpha expression in the prostate via immunohistofluorescence staining. In conclusion, oral administration of PPE prevented and inhibited the development and progression of enlarged prostate lesions in testosterone-induced animal models through various anti-proliferative and anti-inflammatory pharmacological effects and induced suppression of SRD5A2 gene expression.

Pao Pereira extract suppresses benign prostatic hyperplasia by inhibiting inflammation-associated NFκB signaling.

BACKGROUND: Our previous study revealed the extract from the bark of an Amazonian tree Pao Pereira can suppress benign prostatic hyperplasia (BPH) in a rat model. Herein, we examined its inhibitory effects on human BPH cells and dissect its molecular mechanism. METHODS: We applied Pao extract to human BPH epithelial BPH-1 and prostate myofibroblast WPMY-1 cells. Cell viability, apoptosis and immunoblotting were performed, followed by gene expression profiling and gene set enrichment analysis (GSEA) to detect the differentially expressed genes and signaling pathway induced by Pao extract. Human ex vivo BPH explant organ culture was also used to examine the effects of Pao extract on human BPH tissues. RESULTS: Pao extract treatment inhibited viability and induced apoptosis in human BPH-1 and WPMY-1 cells. Gene expression profiling and the following validation indicated that the expression levels of pro-apoptotic genes (eg. PCDC4, CHOP and FBXO32) were induced by Pao extract in both two cell lines. GSEA further revealed that Pao extract treatment was negatively associated with the activation of NFκB signaling. Pao extract suppressed the transcriptional activity of NFκB and down-regulated its target genes involved in inflammation (CXCL5, CXCL6 and CXCL12) and extracellular matrix (ECM) remodeling (HAS2, TNC and MMP13) in both cultured cells and human ex vivo BPH explants. CONCLUSION: In both BPH epithelial and stromal cells, Pao extract induces apoptosis by upregulating the pro-apoptotic genes and inhibiting the inflammation-associated NFκB signaling via reducing phosphorylation of NFκB subunit RelA. Our data suggest that Pao extract may be a promising phytotherapeutic agent for BPH.

Clinical relevance of gene expression in localized and metastatic prostate cancer exemplified by FABP5.

PURPOSE: Fatty acid-binding protein 5 (FABP5), a transport protein for lipophilic molecules, has been proposed as protein marker in prostate cancer (PCa). The role of FABP5 gene expression is merely unknown. METHODS: In two cohorts of PCa patients who underwent radical prostatectomy (n = 40 and n = 57) and one cohort of patients treated with palliative transurethral resection of the prostate (pTUR-P; n = 50) FABP5 mRNA expression was analyzed with qRT-PCR. Expression was correlated with clinical parameters. BPH tissue samples served as control. To independently validate findings on FABP5 expression, three microarray and sequencing datasets were reanalyzed (MSKCC 2010 n = 216; TCGA 2015 n = 333; mCRPC, Nature Medicine 2016 n = 114). FABP5 expression was correlated with ERG-fusion status, TCGA subtypes, cancer driver mutations and the expression of druggable downstream pathway components. RESULTS: FABP5 was overexpressed in PCa compared to BPH in the cohorts analyzed by qRT-PCR (radical prostatectomy p = 0.003, p = 0.010; pTUR-P p = 0.002). FABP5 expression was independent of T stage, Gleason Score, nodal status and PSA level. FABP5 overexpression was associated with the absence of TMPRSS2:ERG fusion (p < 0.001 in TCGA and MSKCC). Correlation with TCGA subtypes revealed FABP5 overexpression to be associated with SPOP and FOXA1 mutations. FABP5 was positively correlated with potential drug targets located downstream of FABP5 in the PPAR-signaling pathway. CONCLUSION: FABP5 overexpression is frequent in PCa, but seems to be restricted to TMPRESS2:ERG fusion-negative tumors and is associated with SPOP and FOXA1 mutations. FABP5 overexpression appears to be indicative for increased activity in PPAR signaling, which is potentially druggable.

Regulation of microRNAs by rape bee pollen on benign prostate hyperplasia in rats.

The miRNAs are dysregulated in BPH. Rape bee pollen (RBP) is used to improve benign prostatic hyperplasia (BPH). Whether RBP treats BPH by regulating the dysregulated miRNAs remains unclear. Here, we identified miRNAs regulated along with the improvement of BPH by RBP in posterior lobes of prostate in rats. Firstly, to screened miRNAs might relate to improvement of BPH by RBP, we compared differentially expressed miRNAs between BPH model group and RBP group by high-throughput sequencing. As a result, 10 known miRNAs and 17 novel miRNA were up-regulated in RBP group, and 6 known and 13 novel miRNAs were down-regulated. Secondly, among the known miRNAs, we identified those that might relate to BPH by RT-qPCR, while only rno-miR-184 was screened, so we compared it among normal control group, BPH model group and RBP group. The results showed that rno-miR-184 was significantly lower expressed in BPH group, but up-regulated along with the improvement of BPH by RBP. Moreover, expression level of rno-miR-184 was no difference between RBP group and normal control level. Therefore, we considered that RBP might improve BPH through regulating expression of miRNAs like rno-miR-184 in prostate in rats.

Pao Pereira Extract Attenuates Testosterone-Induced Benign Prostatic Hyperplasia in Rats by inhibiting 5α-Reductase.

Benign prostatic hyperplasia (BPH) is one of the most common diseases in the urinary system of elderly men. Pao extract is an herbal preparation of the bark of the Amazon rainforest tree Pao Pereira (Geissospermum vellosii), which was reported to inhibit prostate cancer cell proliferation. Herein we investigated the therapeutic potential of Pao extract against BPH development in a testosterone-induced BPH rat model. The administration of testosterone induced the prostate enlargement, compared with the sham operated group with vehicle treatment. The BPH/Pao group showed reduced prostate weight comparable with BPH/finasteride group. Notably, Pao treatment did not significantly reduce body weights and sperm number of rats, compared with the control group. Furthermore, Pao extract treatment reduced the proliferative index in prostate glands and testosterone-induced expression levels of AR, as well as androgen-associated proteins such as SRD5A1 and PSA. Moreover, Pao extract and its active component, flavopereirine, induced cytotoxicity on human prostate epithelial RWPE-1 cells in a dose- and time- dependent manner with G2/M arrest. Consistently, Pao extract and flavopereirine suppressed the expression levels of SRD5A1, AR and PSA, respectively. Together, these data demonstrated that Pao extract suppresses testosterone-induced BPH development through inhibiting AR activity and expression, and suggested that Pao extract may be a promising and relative safe agent for BPH.

Bakuchiol suppresses oestrogen/testosterone-induced Benign Prostatic Hyperplasia development through up-regulation of epithelial estrogen receptor ß and down-regulation of stromal aromatase.

Estrogens and androgens play critical roles during benign prostatic hyperplasia (BPH) development. Estrogen receptors (ERs), androgen receptor (AR) and aromatase, the key conversion enzyme of androgen to estrogen, are thought to be the effective targets for BPH treatment. Bakuchiol (Ba)-containing herb Psoralea corylifolia has been long-termed used for BPH patients in traditional Chinese medicine while the role and regulatory mechanism of Ba involved remain unclear. Human prostatic cell lines WPMY-1 and BPH-1 and oestrodial/testosterone-induced BPH rats were used as the in vitro and in vivo models. Ba significantly inhibited the proliferation of WPMY-1 and BPH-1 cells. In E2/T-induced BPH model, Ba treatment also significantly inhibited the enlargement of prostate, decreased PI values, reduced the thickness of periglanular smooth muscle layer, and down-regulated the expressions of PCNA and smooth muscle cell marker α-SMA, all of which were highly induced in BPH rats. Moreover, the basal and PGE2-induced expressions of aromatase were reduced in Ba-stimulated WPMY-1 cells, while the expression of ERß was highly increased in Ba-stimulated BPH-1 cells, both of which are consistent with the findings in Ba group in vivo. Ba induced ERE activity in BPH-1 cells as E2 did; however, silence of ERß not ERα, blocked Ba-induced ERE activity while E2 still exhibited the significant ERE activity, indicating the regulation of estrogen signaling by Ba is particularly via ERß. In conclusion, by down-regulation of stromal aromatase and up-regulation of epithelial ERß, Ba contributes to the balance of estrogen and androgen signaling and further inhibits BPH development.

hnRNPM, a potential mediator of YY1 in promoting the epithelial-mesenchymal transition of prostate cancer cells.

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

Association of receptor expression with prostate volume in benign prostatic hyperplasia.

BACKGROUND: The expression of androgen (AR) and estrogen receptors (ER-A, ER-B) in Prostate cancer is well documented, but there are limited data about the same in patients with BPH. Hence the present study was designed to analyse the gene and protein expression of androgen and estrogen receptors in patients with BPH. MATERIALS AND METHODS: Prostatic tissues were obtained from 27 BPH patients aged between 55 to 85 years by transurethral resection of prostate. Based on prostate volume, BPH patients were divided into two groups, Group A (≤30mL) and Group B (>30mL). The mRNA and protein expression of AR, ER-A and B were assessed by Quantitative real time PCR, Western blotting and Immunohistochemistry. RESULTS: AR gene (P < 0.05) and protein expression (P = 0.03) and ER-A gene (P < 0.05) and protein expression (P = 0.02) was significantly higher in BPH patients with larger prostate size compared to smaller prostate size. Immunohistochemistry showed that AR expression was predominate in ductal cells of larger volume prostate tissues while AR expression in stromal tissue was the dominant finding in patients with smaller prostate size. Also serum estradiol was significantly increased in patients with larger prostate size (P = 0.03). CONCLUSION: Androgen and Estrogen receptor expression increases with increase in prostate volume in BPH cases.

Correlation between 5-α reductase type 2 protein expression and methylation of 5-α reductase type 2 promotor gene of benign prostatic hyperplasia.

PURPOSE: The enzyme 5-α reductase type 2 (5-AR 2) plays a key role in the development and maintenance of the prostate gland. We evaluated the level 5-AR 2 protein expression and the relationship between methylation of the 5-AR 2 gene-promoter and 5-AR 2 protein expression of benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A total of 37 prostate samples were evaluated. These included 22 samples from men undergoing transurethral prostate resections and 15 non-cancerous transition-zone human prostate tissue samples taken following radical prostatectomy. We quantified 5-AR 2 protein expression and gene-promoter methylation status using common assay procedures. Clinical variables included age, body mass index (BMI), prostate-specific antigen (PSA) levels, lipid profiles, and prostate volumes. Univariate and multivariate statistical analyses were performed followed by stepwise logistic regression modeling. RESULTS: We were able to extract DNA from 36 of the 37 tissue samples and 10 of these (28%) did not express the 5-AR 2 protein. In total, 26 patients (72%) had methylated 5-AR 2 promoter-regions. There was a strong correlation between methylation of the 5-AR 2 promoter-regions and low-absent 5-AR 2 protein expression (p = 0.0003). Increasing age significantly predicted methylation status and protein expression level (p = 0.013). CONCLUSIONS: The level of 5-AR 2 protein expression varies among prostate tissue samples. Methylation of the 5-AR 2 gene-promoter may account for low or absent expression of 5-AR 2 in adult human prostate tissues. Increased age correlates with increased 5-AR 2 gene-promoter methylation and decreased protein expression in men with BPH.

Human-like hyperplastic prostate with low ZIP1 induced solely by Zn deficiency in rats.

Prostate cancer is a leading cause of cancer death in men over 50 years of age, and there is a characteristic marked decrease in Zn content in the malignant prostate cells. The cause and consequences of this loss have thus far been unknown. We found that in middle-aged rats a Zn-deficient diet reduces prostatic Zn levels (P = 0.025), increases cellular proliferation, and induces an inflammatory phenotype with COX-2 overexpression. This hyperplastic/inflammatory prostate has a human prostate cancer-like microRNA profile, with up-regulation of the Zn-homeostasis-regulating miR-183-96-182 cluster (fold change = 1.41-2.38; P = 0.029-0.0003) and down-regulation of the Zn importer ZIP1 (target of miR-182), leading to a reduction of prostatic Zn. This inverse relationship between miR-182 and ZIP1 also occurs in human prostate cancer tissue, which is known for Zn loss. The discovery that the Zn-depleted middle-aged rat prostate has a metabolic phenotype resembling that of human prostate cancer, with a 10-fold down-regulation of citric acid (P = 0.0003), links citrate reduction directly to prostatic Zn loss, providing the underlying mechanism linking dietary Zn deficiency with miR-183-96-182 overexpression, ZIP1 down-regulation, prostatic Zn loss, and the resultant citrate down-regulation, changes mimicking features of human prostate cancer. Thus, dietary Zn deficiency during rat middle age produces changes that mimic those of human prostate carcinoma and may increase the risk for prostate cancer, supporting the need for assessment of Zn supplementation in its prevention.

Banana Flower Extract Suppresses Benign Prostatic Hyperplasia by Regulating the Inflammatory Response and Inducing G1 Cell-cycle Arrest.

BACKGROUND/AIM: The banana flower is used for ameliorating urinary disturbance. However, there is limited evidence to support the efficacy or mechanism of action of banana flower against benign prostatic hyperplasia (BPH). In the present study, the anti-BPH activity and mechanisms of banana flower extracts were investigated in vitro and in vivo. MATERIALS AND METHODS: The banana flower extract is a water-soluble extract obtained by sonication. MTT assay was used to examine whether banana flower extract exhibited cytotoxic effects on BPH-1 cells. The effect of banana flower extract on cell-cycle distribution was examined by flow cytometry. The expression of cell-cycle-regulatory molecules was determined by western blot analysis. Testosterone propionate (TP)-induced rat model of BPH was used to evaluate the anti-BPH activity of banana flower extract in vivo. RESULTS: Banana flower extract reduced epithelial cell line BPH-1 cell viability through cell-cycle arrest at G1 phase. Moreover, banana flower extract reduced the expression of cyclin D1 and cyclin-dependent kinase 6, while it increased the expression of p53 and p27. Interestingly, banana flower extract suppressed BPH-related inflammatory responses through suppressing cyclo-oxygenase-2 expression and prostaglandin E2 production. Finally, banana flower extract administered orally to male rats reduced prostatic weight and serum dihydrotestosterone level, and improved prostate gland morphology. High-performance liquid chromatography revealed that banana flower extract contains citric acid, taurine, pantothenic acid and nicotinic acid components. In summary, banana flower extract may be used as a therapeutic agent for BPH via anti-proliferative and anti-inflammatory activities.

Chrysin attenuates testosterone-induced benign prostate hyperplasia in rats.

Benign prostate hyperplasia (BPH) is a common age-related health problem affecting almost 3 out of 4 men in their sixties. Chrysin is a dietary phytoestrogen found naturally in bee propolis and various plant extracts. It possesses antioxidant, anti-inflammatory and anti-proliferative properties. The current study was conducted to explore the role chrysin plays in protection against testosterone-induced BPH in rats. On grounds of a preliminary experiment, a dose of chrysin (50 mg/kg) was chosen for further investigation. Testosterone significantly depleted glutathione, suppressed superoxide dismutase and catalase activities, and elevated lipid peroxidation. Moreover, it markedly scaled down the level of cleaved caspase-3 enzyme, reduced Bax/Bcl-2 ratio and mRNA expression of p53 and p21; conversely, protein expression of proliferating cell nuclear antigen was enhanced. Chrysin alleviated testosterone-induced oxidative stress and restored cleaved caspase-3 level, Bax/Bcl-2 ratio and mRNA expression of p53 and p21 to almost control levels. Chrysin prevented the increase in binding activity of nuclear factor kappa B (NF-κB) p65 subunit, mRNA expression of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 1 receptor (IGF-1R). These data highlight the protective role of chrysin against experimentally-induced BPH. This is attributed - at least partly - to its antioxidant, antiproliferative and proapoptotic properties.

Ageratum conyzoides L. inhibits 5-alpha-reductase gene expression in human prostate cells and reduces symptoms of benign prostatic hypertrophy in otherwise healthy men in a double blind randomized placebo controlled clinical study.

A double-blind, randomized, placebo-controlled clinical trial assessed the efficacy and safety of Ageratum conyzoides in treating benign prostatic hypertrophy (BPH). In this study, 109 men with medically diagnosed BPH, aged 41-76 years, were administered the investigational product, A. conyzoides extract at a dose of 250 mg/d or placebo, q.d. for 12 weeks. The primary outcome measures were the International Prostate Symptom Score (IPSS), daily urinary frequency and safety evaluations. The secondary outcome measures were testosterone, dihydrotestosterone, oestradiol, sex hormone binding globulin (SHBG), Dehydroepiandrosterone sulfate (DHEA-S) and cortisol levels, and prostate specific antigen (PSA), lipids, blood glucose, the Aging Male's Symptom (AMS) Score and sexual function assessed by Derogatis Interview for Sexual Functioning-Self Report (DISF-SR). The effect of A. conyzoides L extract on gene expression of 5-alpha-reductase in human prostate cells was also investigated to elucidate a potential mechanism of action. The clinical study, showed a significant reduction in total IPSS score (p < 0.01) and day- and night-time urinary frequency (P < 0.01) over time after treatment with A. conyzoides. Steroid hormones, SHBG, PSA levels, lipids, and blood glucose remained within healthy reference range in both groups. There were no changes in AMS or DISF-SR in either group. Gene arrays demonstrated that A. conyzoides extract was effective in reducing the expression of mRNA coding for 5-alpha-reductase types 2 and 1 in human prostate epithelial cells. The overall results indicate that A. conyzoides may be an effective treatment for reducing symptoms of BPH in healthy men, in part, through inhibition of 5-alpha-reductase enzyme activity. © 2017 BioFactors, 43(6):789-800, 2017.

In vivo evaluation of hot water extract of Acorus gramineus root against benign prostatic hyperplasia.

BACKGROUND: Acorus gramineus has been reported to exhibit various pharmacological effects including inhibition of cholesterol synthesis, enhancement of lipid metabolism, prevention of dementia and inhibition of mast cell growth. According to the Chinese compendium of materia media, it has been reported that Acorus spp. is effective for sedation, dementia prevention as well as diuretic effect. In addition, it showed more than equivalent activity compared to furosoemide, a drug known to be effective in diuretic action in animal model study. However, their effectiveness against benign prostatic hyperplasia (BPH) of Acorus gramineus has not been reported. This study was designed to evaluate the effect of Acorus gramineus root hot water extract (AG) against BPH in vivo. METHODS: Male rats, 10 weeks of age and weighing 405 g ± 10 g, were used for this study. Biomarkers were evaluated including prostate weight, prostate weight ratio, hormonal changes, 5-α reductase type II androgen receptor (AR) of the prostate gland and anti-oxidant activation factors related to BPH. These biomarkers were measured in vivo test. RESULTS: AG showed significant effect at the 250 and 500 mg/kg/day in rats. Groups treated with AG displayed significantly lower levels of prostate gland weight (0.79 g) compared to the BPH induced group (1.19 g). Also, dihydrotestosterone (DHT) level was decreased from 61.8 to 100% and androgen receptor expression level was decreased from 111 to 658%. Any hematological toxicity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level wasn't observed. CONCLUSION: This study indicated that AG was effective for reducing BPH symptoms. TRIAL REGISTRATION: Not applicable.