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.

Beta-Sitosterol Alters Collagen Distribution in Prostate Fibroblasts.

Herbal supplements containing several types of plant sterols, vitamins, and minerals, are marketed for prostate health. In the majority of these supplements, the most abundant plant sterol is saw palmetto extract or its' principal component, beta-sitosterol. In terms of prostate health, previous work almost exclusively focused on the effects of beta-sitosterol on prostatic epithelium, with little attention paid to the effects on prostatic stroma. This omission is a concern, as the abnormal accumulation of collagen, or fibrosis, of the prostatic stroma has been identified as a factor contributing to lower urinary tract symptoms and dysfunction in aging men. To address whether beta-sitosterol may be promoting prostatic fibrosis, immortalized and primary prostate stromal fibroblasts were subjected to immunoblotting, immunofluorescence, qRT-PCR, ELISA, and image quantitation and analysis techniques to elucidate the effects of beta-sitosterol on cell viability and collagen expression and cellular localization. The results of these studies show that beta-sitosterol is nontoxic to prostatic fibroblasts and does not stimulate collagen production by these cells. However, beta-sitosterol alters collagen distribution and sequesters collagen within prostatic fibroblasts, likely in an age-dependent manner. This is a significant finding as prostate health supplements are used predominantly by middle aged and older men who may, then, be affected disproportionately by these effects.

The effect of Ganoderma lucidum polysaccharide extract on sensitizing prostate cancer cells to flutamide and docetaxel: an in vitro study.

Ganoderma lucidum polysaccharide is the most widely used complementary therapy in cancer. The present study aims to investigate the possible interaction between Ganoderma lucidum polysaccharide and Docetaxel (a chemotherapy drug) and the first-line medication for prostate cancer treatment (Flutamide) and sensitizing the cells to these treatments. The cytotoxic effects of Ganoderma lucidum polysaccharide in combination with Docetaxel and Flutamide on prostate cancer cells were investigated by the MTT test, Hoechst staining, and flow cytometry. In addition, the expression of genes related to apoptosis, angiogenesis, Epithelial-Mesenchymal Transition pathway (EMT), and prostate cancer biomarkers by Real-Time PCR was investigated. The results demonstrated that IC50 values for Ganoderma lucidum polysaccharide (30 µM and 20 µM), Docetaxel (10 µM and 5 µM), and Flutamide (20 µM and 12 µM) with MTT were confirmed by flow cytometry in a dose and time-dependent manner. Regarding the high efficacy of Ganoderma lucidum polysaccharide in combination with Flutamide and Docetaxel, 10 µM and 5 µM Flutamide were used instead of 20 µM and 12 µM and 5 µM and 2 µM Docetaxel was used instead of 10 µM and 5 µM in PC3 and LNCap, respectively. Moreover, for the first time, it was shown that Ganoderma lucidum polysaccharide alone and in combination with Docetaxel and Flutamide significantly augmented apoptosis, reduced cell migration and colonization, and downregulated expression of KLK2 and EMT pathway genes in both PC3 and LNCap cell line (P < 0.01). Ganoderma lucidum polysaccharide synergistically increased the effect of Docetaxel and Flutamide and increased the sensitivity of the prostate cancer cell lines to these drugs. Therefore, it may provide a new therapeutic strategy against prostate cancer.

Therapeutic potential of pomegranate juice-derived nanovesicles in nude mouse benign prostatic hyperplasia (BPH) xenograft model.

Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms affect a large percentage of the male population and places a substantial burden on the world health system. Current therapies include 5-alpha reductase inhibitors and alpha-blockers that are only partially effective and pose a huge economic burden, emphasizing the urgent need for effective, economical therapies. We isolated nanovesicles from pomegranate juice (Punica Granatum) (referred to as 'POM-NVs') and report to our knowledge for the first time, that these vesicles possess therapeutic potential against BPH. Following extensive characterization of POM-NVs, we tested their therapeutic potential in vitro using BPH1 cell line and identified a potential anti-proliferative and pro-apoptotic effect. We further tested these vesicles using a clinically relevant xenograft mouse BPH model derived from human BPH tissues. Remarkably, POM-NVs could reverse the BPH phenotype conferred by TGF-ß mediated signaling and induced epithelial-to-mesenchymal (EMT) reversal, leading to the restoration of prostate epithelial states in vivo and in vitro. Furthermore, these vesicles attenuated bone morphogenic protein 5 (BMP5) signaling, a cardinal alteration that is instrumental in driving BPH. Considering the large incidences of BPH and its associated economic burdens, our study has important implications and can potentially improve the clinical management of BPH.

Investigations into the Signaling Pathways Involving Glucose-Stimulated Zinc Secretion (GSZS) from Prostate Epithelial Cells In Vitro and In Vivo.

PURPOSE: Recently, we reported that exposure of prostate cells in vitro or the in vivo prostate to high glucose results in release of Zn2+ ions, a process now referred to as glucose-stimulated zinc secretion (GSZS). To our knowledge, the metabolic event(s) that trigger GSZS remain largely unknown. Here, we explore several signaling pathways both in vitro using a prostate epithelial cell line and in vivo from the rat prostate. METHODS: PNT1A cells grown to confluence were washed and tagged with ZIMIR to monitor zinc secretion by optical methods. The expression levels of GLUT1, GLUT4, and Akt in cells cultured in either zinc-rich or zinc-poor media and after exposure to high versus low glucose were determined. Zinc secretion from the rat prostate in vivo as detected by MRI was compared in control animals after injection of glucose, deoxyglucose, or pyruvate to initiate zinc secretion and in animals pre-treated with WZB-117 (a GLUT1 inhibitor) or S961 (a peripheral insulin receptor inhibitor). RESULTS: PNT1A cells exposed to high levels of glucose secrete zinc whereas cells exposed to an equivalent amount of deoxyglucose or pyruvate do not. Expression of Akt was dramatically altered by zinc supplementation of the culture media but not after exposure to glucose while GLUT1 and GLUT4 levels were less affected. Rats pre-treated with WZB-117 prior to imaging showed a reduction in GSZS from the prostate compared to controls whereas rats pre-treated with S961 showed no difference. Interestingly, in comparison to PNT1A cells, pyruvate and deoxyglucose also stimulate zinc secretion in vivo likely through indirect mechanisms. CONCLUSIONS: GSZS requires metabolism of glucose both in vitro (PNT1A cells) and in vivo (rat prostate). Pyruvate also stimulates zinc secretion in vivo but likely via an indirect pathway involving rapid production of glucose via gluconeogenesis. These combined results support the conclusion that glycolytic flux is required to trigger GSZS in vivo.

YY1 complex in M2 macrophage promotes prostate cancer progression by upregulating IL-6.

BACKGROUND: Tumor-associated macrophages are mainly polarized into the M2 phenotype, remodeling the tumor microenvironment and promoting tumor progression by secreting various cytokines. METHODS: Tissue microarray consisting of prostate cancer (PCa), normal prostate, and lymph node metastatic samples from patients with PCa were stained with Yin Yang 1 (YY1) and CD163. Transgenic mice overexpressing YY1 were constructed to observe PCa tumorigenesis. Furthermore, in vivo and in vitro experiments, including CRISPR-Cas9 knock-out, RNA sequencing, chromatin immunoprecipitation (ChIP) sequencing, and liquid-liquid phase separation (LLPS) assays, were performed to investigate the role and mechanism of YY1 in M2 macrophages and PCa tumor microenvironment. RESULTS: YY1 was highly expressed in M2 macrophages in PCa and was associated with poorer clinical outcomes. The proportion of tumor-infiltrated M2 macrophages increased in transgenic mice overexpressing YY1. In contrast, the proliferation and activity of anti-tumoral T lymphocytes were suppressed. Treatment targeting YY1 on M2 macrophages using an M2-targeting peptide-modified liposome carrier suppressed PCa cell lung metastasis and generated synergistic anti-tumoral effects with PD-1 blockade. IL-4/STAT6 pathway regulated YY1, and YY1 increased the macrophage-induced PCa progression by upregulating IL-6. Furthermore, by conducting H3K27ac-ChIP-seq in M2 macrophages and THP-1, we found that thousands of enhancers were gained during M2 macrophage polarization, and these M2-specific enhancers were enriched in YY1 ChIP-seq signals. In addition, an M2-specific IL-6 enhancer upregulated IL-6 expression through long-range chromatin interaction with IL-6 promoter in M2 macrophages. During M2 macrophage polarization, YY1 formed an LLPS, in which p300, p65, and CEBPB acted as transcriptional cofactors. CONCLUSIONS: Phase separation of the YY1 complex in M2 macrophages upregulated IL-6 by promoting IL-6 enhancer-promoter interactions, thereby increasing PCa progression.

Kolaviron modulates angiogenesis, apoptosis and inflammatory signaling in rat model of testosterone propionate-induced benign prostate hyperplasia.

Benign prostatic hyperplasia (BPH) is a non-malignant disease of the prostate characterized by uncontrolled proliferation of the prostate gland. Inflammation and oxidative stress have been reported to play a role in the development of BPH. Kolaviron, a bioflavonoid complex of Garcinia kola seed, has been shown to possess anti-inflammatory effect. In this study, we investigated the effect of Kolaviron on testosterone propionate (TP)-induced BPH in rats. Fifty male rats were assigned in 5 groups. Groups 1 and 2 were orally exposed to corn oil (2 ml/kg) and Kolaviron (200 mg/kg/day, p.o) for 28 days. Group 3 rats received TP (3 mg/kg/day, s.c) for 14 days while Groups 4 and 6 were treated with Kolaviron (200 mg/kg/day, p.o) and Finasteride (5 mg/kg/day, p.o), respectively, for 14 days prior to TP (3 mg/kg, s.c) co-exposure for the remaining 14 days. Administration of Kolaviron to TP-treated rats reverted histological alteration and significantly decreased prostate weight, prostate index, 5α-reductase, dihydrotestosterone, androgen receptor expression, tumor necrosis factor α, interleukin-1ß, cyclooxygenase-2, prostaglandin E2, 5-lipoxygenase leukotriene B4, inducible nitric oxide synthase and nitric oxide concentration. In addition, Kolaviron alleviated TP-induced oxidative stress and reduced the expression of Ki-67, VEGF, and FGF to almost control levels. Furthermore, Kolaviron promoted apoptosis in TP-treated rats through downregulation of BCL-2 and upregulation of P53 and Caspase 3 expressions. Overall, Kolaviron prevented BPH via regulation of androgen/androgen receptor signaling, anti-oxidative and anti-inflammatory mechanisms.

Distinct Roles of SELENOF in Different Human Cancers.

SELENOF, previously known as SEP15, is a selenoprotein that contains selenium in the form of the amino acid selenocysteine. Like other selenoproteins, the role for SELENOF in carcinogenesis has been investigated due to its altered expression compared to the corresponding normal tissue, its molecular function, and the association of genetic variations in the SELENOF gene to cancer risk or outcome. This review summarizes SELENOF's discovery, structure, cellular localization, and expression. SELENOF belongs to a new family of thioredoxin-like proteins. Published data summarized here indicate a likely role for SELENOF in redox protein quality control, and in the regulation of lipids, glucose, and energy metabolism. Current evidence indicates that loss of SELENOF contributes to the development of prostate and breast cancer, while its loss may be protective against colon cancer. Additional investigation into SELENOF's molecular mechanisms and its impact on cancer is warranted.

[Effect of electroacupuncture on the morphology of prostate and degranulation of mast cells in rats with chronic nonbacterial prostatitis].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on the morphology of prostate and degranulation of mast cells in prostate of rats with chronic nonbacterial prostatitis (CNP). METHODS: Male SD rats were randomly divided into sham operation group, model group and EA group, with 8 rats in each group. CNP model was established by surgical castration combined with 17-ß estradiol injection once daily for 30 days. EA was applied to "Zhongji" (CV3), "Guanyuan" (CV4) and bilateral "Dahe" (KI12) for 20 min, once daily for 8 days. The mechanical pain threshold of scrotum skin area was tested before modeling, after modeling and after intervention. The pathological morphology of the prostate was observed by HE staining. Collagenous fiber was observed by Masson staining. The infiltration of mast cells was observed by toluidine blue staining. The contents of interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) in prostate were determined by ELISA. The protein expression levels of tryptase and transforming growth factor ß1 (TGF-ß1) in prostate were detected by Western blot. RESULTS: A normal appearance with little inflammatory cell infiltration was observed in the prostate of the sham operation group. Gland atrophy, epithelial destruction, hyperemia and edema, diffuse inflammatory cell infiltration and visible collagen fiber deposition were observed in prostate of the model group. The degree of infiltration of inflammatory cells and collagen fiber deposition were reduced in the EA group. Compared with the sham operation group, mechanical pain threshold was decreased (P<0.01), while the collagen volu-me fraction (CVF) of prostate, the degranulated rate of mast cells, the protein expression levels of tryptase and TGF-ß1, and the contents of IL-6 and TNF-α were increased (P<0.01) in the model group. Following EA intervention, compared with the model group, the mechanical pain threshold was increased (P<0.01), CVF of the prostate, the degranulated rate of mast cells, the protein expression levels of tryptase and TGF-ß1, and the contents of IL-6 and TNF-α were decreased (P<0.05, P<0.01) in the EA group. CONCLUSION: EA can relieve pain and reduce inflammation and fibrosis of prostate in CNP rats, which may be related to inhibiting the degranulation of prostate mast cells and down-regulating the expression of inflammatory factors and TGF-ß1.

Dysregulation of the PRUNE2/PCA3 genetic axis in human prostate cancer: from experimental discovery to validation in two independent patient cohorts.

Background: We have previously shown that the long non-coding (lnc)RNA prostate cancer associated 3 (PCA3; formerly prostate cancer antigen 3) functions as a trans-dominant negative oncogene by targeting the previously unrecognized prostate cancer suppressor gene PRUNE2 (a homolog of the Drosophila prune gene), thereby forming a functional unit within a unique allelic locus in human cells. Here, we investigated the PCA3/PRUNE2 regulatory axis from early (tumorigenic) to late (biochemical recurrence) genetic events during human prostate cancer progression. Methods: The reciprocal PCA3 and PRUNE2 gene expression relationship in paired prostate cancer and adjacent normal prostate was analyzed in two independent retrospective cohorts of clinically annotated cases post-radical prostatectomy: a single-institutional discovery cohort (n=107) and a multi-institutional validation cohort (n=497). We compared the tumor gene expression of PCA3 and PRUNE2 to their corresponding expression in the normal prostate. We also serially examined clinical/pathological variables including time to disease recurrence. Results: We consistently observed increased expression of PCA3 and decreased expression of PRUNE2 in prostate cancer compared with the adjacent normal prostate across all tumor grades and stages. However, there was no association between the relative gene expression levels of PCA3 or PRUNE2 and time to disease recurrence, independent of tumor grades and stages. Conclusions: We concluded that upregulation of the lncRNA PCA3 and targeted downregulation of the protein-coding PRUNE2 gene in prostate cancer could be early (rather than late) molecular events in the progression of human prostate tumorigenesis but are not associated with biochemical recurrence. Further studies of PCA3/PRUNE2 dysregulation are warranted. Funding: We received support from the Human Tissue Repository and Tissue Analysis Shared Resource from the Department of Pathology of the University of New Mexico School of Medicine and a pilot award from the University of New Mexico Comprehensive Cancer Center. RP and WA were supported by awards from the Levy-Longenbaugh Donor-Advised Fund and the Prostate Cancer Foundation. EDN reports research fellowship support from the Brazilian National Council for Scientific and Technological Development (CNPq), Brazil, and the Associação Beneficente Alzira Denise Hertzog Silva (ABADHS), Brazil. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of New Mexico Comprehensive Cancer Center (CA118100) and the Rutgers Cancer Institute of New Jersey (CA072720).

Blockage of MDM2-mediated p53 ubiquitination by yuanhuacine restrains the carcinogenesis of prostate carcinoma cells by suppressing LncRNA LINC00665.

Prostate cancer (PCa) is a challenging issue for men's health worldwide due to its uncontrolled proliferation and high metastatic potential. Increasing evidence has supported plant extracts and natural plant derivatives as promising antitumor therapy with less toxic side effects. Yuanhuacine is an active component isolated from Daphne genkwa and can effectively suppress the tumorigenesis of several cancers. However, its role in PCa remains unclear. In this study, yuanhuacine dose-dependently inhibited the proliferation and induced apoptosis of PCa cells. Moreover, yuanhuacine also restrained the invasion and migration of PCa cells. Mechanically, yuanhuacine decreased the ubiquitination and degradation of p53 protein, and ultimately increased p53 levels, which was regulated by inhibiting the phosphorylation and total protein levels of mouse double minute 2 (MDM2). Moreover, elevation of MDM2 reversed the suppressive efficacy of yuanhuacine in PCa cell viability, invasion, and migration. The network pharmacologic and bioinformatics analysis confirmed that MDM2 might be a common target of D. genkwa and LINC00665. Furthermore, yuanhuacine inhibited LINC00665 expression. Upregulation of LINC00665 reversed yuanhuacine-mediated inhibition in MDM2 protein expression and suppressed p53 levels by enhancing its ubiquitination in yuanhuacine-treated cells. Importantly, the inhibitory effects of yuanhuacine on cell viability and metastatic potential were offset after LINC00665 elevation. Together, the current findings highlight that yuanhuacine may possess tumor-suppressive efficacy by inhibiting LINC00665-mediated MDM2/p53 ubiquitination signaling. Therefore, this study indicates that yuanhuacine may be a promising candidate for the treatment of PCa.

[Rauwolfia extract inhibits the proliferation of prostate cells in rats with benign prostatic hyperplasia].

OBJECTIVE: To investigate the effects of different concentrations of Rauwolfia extract (RE) on the proliferation of prostate cells in the rat model of benign prostatic hyperplasia (BPH). METHODS: We randomly divided 48 male SD rats into six groups of an equal number, BPH model control, finasteride, low-concentration RE, medium-concentration RE, high-concentration RE and normal control, and established a BPH model in the former five groups by subcutaneous injection of testosterone propionate following castration. We treated the rats of the finasteride and RE groups intragastrically with finasteride solution at 5 mg/kg and RE at 5, 10 and 20 mg/kg respectively, and those of the model control and normal control groups with an equal dose of normal saline, all once a day for 28 consecutive days. Then, we killed all the animals, collected their prostate tissue, obtained the wet weight and volume of the prostate, the prostate index and the contents of serum T and dihydrotestosterone (DHT), observed the morphological changes of the prostate tissue by HE staining, counted the glands in the prostate tissue, measured the intraglandular area, and determined the expressions of PCNA and α-SMA by immunohistochemistry. RESULTS: Compared with the rats of the normal control group, the BPH model controls showed significantly increased wet weight (ï¼»0.923 ± 0.15ï¼½ vs ï¼»1.455 ± 0.52ï¼½ g, P < 0.05), volume (ï¼»1.035 ± 0.29ï¼½ vs ï¼»1.687 ± 0.31ï¼½ ml, P < 0.05) and index of the prostate (ï¼»0.23 ± 0.04ï¼½% vs ï¼»0.37 ± 0.15ï¼½%, P < 0.05), dilation, hyperemia and edema of the prostatic stroma and vessels, and proliferation rate of the prostatic cells, but remarkably decreased number of glands (ï¼»20.35 ± 3.83ï¼½ vs ï¼»12.56 ± 2.58ï¼½, P < 0.05), epithelial thickness (ï¼»39.76 ± 5.20ï¼½ vs ï¼»19.52 ± 1.52ï¼½ µm, P < 0.05) and intraglandular area (ï¼»12.3 ± 1.21ï¼½ vs ï¼»5.96 ± 0.34ï¼½ ×103µm2, P < 0.05). In comparison with the BPH model controls, the animals treated with RE, especially in the high-concentration RE group, exhibited marked decreases in the weight (ï¼»1.455 ± 0.52ï¼½ vs ï¼»0.862 ± 0.31ï¼½ g, P < 0.05), volume ( ï¼»1.687 ± 0.31ï¼½ vs ï¼»0.952 ± 0.28ï¼½ ml, P < 0.05) and index of the prostate (ï¼»0.37 ± 0.15ï¼½% vs ï¼»0.22 ± 0.07ï¼½%, P < 0.05), dramatic improvement in the number of glands (ï¼»12.56 ± 2.58ï¼½ vs ï¼»18.36 ± 1.25ï¼½, P < 0.05), epithelial thickness (ï¼»39.76 ± 5.20ï¼½ vs ï¼»19.04 ± 3.89ï¼½ µm, P < 0.05) and intraglandular area (ï¼»5.96 ± 0.34ï¼½ vs ï¼»10.25 ± 0.98ï¼½ ×103µm2, P<0.05ï¼½, P < 0.05), remarkable down-regulation of the expressions of PCNA and α-SMA, and significant reduction of the contents of serum T (ï¼»19.147 ± 3.214ï¼½ vs ï¼»6.016 ± 1.978ï¼½ ng/ml, P < 0.05) and DHT (ï¼»9.052 ± 0.633ï¼½ vs ï¼»2.532 ± 0.386ï¼½ ng/ml, P < 0.05). CONCLUSION: Rauwolfia extract can inhibit the proliferation of prostate cells and relieve BPH symptoms in a concentration-dependent manner in rats with BPH.

Inhibition of α1-Adrenergic, Non-Adrenergic and Neurogenic Human Prostate Smooth Muscle Contraction and of Stromal Cell Growth by the Isoflavones Genistein and Daidzein.

Isoflavone-rich legumes, including soy, are used for food production, as dietary supplements and in traditional medicine. Soy consumption correlates negatively with benign prostatic hyperplasia (BPH) and voiding symptoms. However, isoflavone effects on the prostate are hardly known. Here, we examined the effects on human prostate smooth muscle contractions and stromal cell growth, which are driving factors of voiding symptoms in BPH. Smooth muscle contractions were induced in prostate tissues from radical prostatectomy. Growth-related functions were studied in cultured stromal cells (WPMY-1). Neurogenic, α1-adrenergic and non-adrenergic contractions were strongly inhibited with 50 µM and by around 50% with 10 µM genistein. Daidzein inhibited neurogenic contractions using 10 and 100 µM. Agonist-induced contractions were inhibited by 100 µM but not 10 µM daidzein. A combination of 6 µM genistein with 5 µM daidzein still inhibited neurogenic and agonist-induced contractions. Proliferation of WPMY-1 cells was inhibited by genistein (>50%) and daidzein (<50%). Genistein induced apoptosis and cell death (by seven-fold relative to controls), while daidzein induced cell death (6.4-fold) without apoptosis. Viability was reduced by genistein (maximum: 87%) and daidzein (62%). In conclusion, soy isoflavones exert sustained effects on prostate smooth muscle contractions and stromal cell growth, which may explain the inverse relationships between soy-rich nutrition, BPH and voiding symptoms.

Protective Effects of PollenAid Plus Soft Gel Capsules' Hydroalcoholic Extract in Isolated Prostates and Ovaries Exposed to Lipopolysaccharide.

Pollen extract represents an innovative approach for the management of the clinical symptoms related to prostatitis and pelvic inflammatory disease (PID). In this context, the aims of the present work were to analyze the phenolic composition of a hydroalcoholic extract of PollenAid Plus soft gel capsules, and to evaluate the extract's cytotoxic effects, in human prostate cancer PC3 cells and human ovary cancer OVCAR-3 cells. Additionally, protective effects were investigated in isolated prostate and ovary specimens exposed to lipopolysaccharide (LPS). The phytochemical investigation identified catechin, chlorogenic acid, gentisic acid, and 3-hydroxytyrosol as the prominent phenolics. The extract did not exert a relevant cytotoxic effect on PC3 and OVCAR-3 cells. However, the extract showed a dose-dependent inhibition of pro-inflammatory IL-6 and TNF-α gene expression in prostate and ovary specimens, and the extract was effective in preventing the LPS-induced upregulation of CAT and SOD gene expression, which are deeply involved in tissue antioxidant defense systems. Finally, a docking approach suggested the capability of catechin and chlorogenic acid to interact with the TRPV1 receptor, playing a master role in prostate inflammation. Overall, the present findings demonstrated anti-inflammatory and antioxidant effects of this formulation; thus, suggesting its capability in the management of the clinical symptoms related to prostatitis and PID.

Permixon®, hexane-extracted Serenoa repens, inhibits human prostate and bladder smooth muscle contraction and exerts growth-related functions in human prostate stromal cells.

AIMS: Recently, the European Association of Urology recommended hexane-extracted fruit of Serenoa repens (HESr) in their guidelines on management of non-neurogenic male lower urinary tracts symptoms (LUTS). Despite previously lacking recommendations, Permixon® is the most investigated HESr in clinical trials, where it proved effective for male LUTS. In contrast, underlying mechanisms were rarely addressed and are only marginally understood. We therefore investigated effects of Permixon® on human prostate and detrusor smooth muscle contraction and on growth-related functions in prostate stromal cells. MAIN METHODS: Permixon® capsules were dissolved using n-hexane. Contractions of human prostate and detrusor tissues were induced in organ bath. Proliferation (EdU assay), growth (colony formation), apoptosis and cell death (flow cytometry), viability (CCK-8) and actin organization (phalloidin staining) were studied in cultured human prostate stromal cells (WPMY-1). KEY FINDINGS: Permixon® inhibited α1-adrenergic and thromboxane-induced contractions in prostate tissues, and methacholine-and thromboxane-induced contractions in detrusor tissues. Endothelin-1-induced contractions were not inhibited. Neurogenic contractions were inhibited in both tissues in a concentration-dependent manner. In WPMY-1 cells, Permixon® caused concentration-dependent breakdown of actin polymerization, inhibited colony formation, reduced cell viability, and proliferation, without showing cytotoxic or pro-apoptotic effects. SIGNIFICANCE: Our results provide a novel basis that allows, for the first time, to fully explain the ubiquitous beneficial effects of HESr in clinical trials. HESr may inhibit at least neurogenic, α1-adrenergic and thromboxane-induced smooth muscle contraction in the prostate and detrusor, and in parallel, prostate stromal cell growth. Together, this may explain symptom improvements by Permixon® in previous clinical trials.

SNAT2 is responsible for hyperosmotic induced sarcosine and glycine uptake in human prostate PC-3 cells.

Solute carriers (SLC) are important membrane transport proteins in normal and pathophysiological cells. The aim was to identify amino acid SLC(s) responsible for uptake of sarcosine and glycine in prostate cancer cells and investigate the impact hereon of hyperosmotic stress. Uptake of 14C-sarcosine and 3H-glycine was measured in human prostate cancer (PC-3) cells cultured under isosmotic (300 mOsm/kg) and hyperosmotic (500 mOsm/kg) conditions for 24 h. Hyperosmotic culture medium was obtained by supplementing the medium with 200 mM of the trisaccharide raffinose. Amino acid SLC expression was studied using RT-PCR, real-time PCR, and western blotting. siRNA knockdown of SNAT2 was performed. Experiments were conducted in at least 3 independent cell passages. The uptake of Sar and Gly was increased approximately 8-ninefold in PC-3 cells after 24 h hyperosmotic culture. PAT1 mRNA and protein could not be detected, while SNAT2 was upregulated at the mRNA and protein level. Transfection with SNAT2-specific siRNA reduced Vmax of Sar uptake from 2653 ± 38 to 513 ± 38 nmol mg protein-1 min-1, without altering the Km value (3.19 ± 0.13 vs. 3.42 ± 0.71 mM), indicating that SNAT2 is responsible for at least 80% of Sar uptake in hyperosmotic cultured PC-3 cells. SNAT2 is upregulated in hyperosmotic stressed prostate cancer cells and SNAT2 is responsible for cellular sarcosine and glycine uptake in hyperosmotic cultured PC-3 cells. Sar is identified as a substrate for SNAT2, and this has physiological implications for understanding cellular solute transport in prostate cancer cells.

Accumulation of Sulforaphane and Alliin in Human Prostate Tissue.

Diets rich in cruciferous vegetables have been associated with a lower risk of incidence and progression of prostate cancer. Sulforaphane, an isothiocyanate derived from 4-methylsulphinylbutyl glucosinolate (glucoraphanin) that accumulates in certain of these vegetables, notably broccoli, has been implicated in their protective effects. Likewise, the consumption of garlic and its sulphur-containing compounds such as alliin have been associated with a reduction in risk of prostate cancer. In this study, we tested whether consuming glucoraphanin derived from broccoli seeds and alliin derived from garlic resulted in the occurrence of these potential bioactive compounds in the prostate, which may contribute to our understanding of the putative protective effects of these dietary components. We recruited 42 men scheduled for a trans-perineal prostate biopsy into a randomised, double-blinded, 2 × 2-factorial dietary supplement four-week intervention study, and 39 completed the study. The two active interventions were supplements providing glucoraphanin from broccoli (BroccoMax®) and alliin from garlic (Kwai Heartcare®). Following the intervention, prostate biopsy tissue was analysed for the presence of sulforaphane and its thiol conjugates and for alliin and associated metabolites. Sulforaphane occurred in significantly higher levels in the prostate tissue (both within the transition and peripheral zone) of men consuming the glucoraphanin containing supplements (p < 0.0001) compared to men not consuming these supplements. However, while alliin and alliin-derived metabolites were detected within the prostate, there was no significant difference in the concentrations of these compounds in the prostate of men consuming supplements derived from garlic compared to men not consuming these supplements.

CircPDHX promotes prostate cancer cell progression in vitro and tumor growth in vivo via miR-497-5p/ACSL1 axis.

BACKGROUND: Circular RNAs (circRNAs) have been proved could regulate many cancers, including prostate cancer (PCa). In this paper, we reconnoitered the roles of circRNA pyruvate dehydrogenase complex component X (circPDHX) in PCa. METHODS: The circPDHX, microRNA (miR)-497-5p and acyl-CoA synthetase long chain family member 1 (ACSL1) contents were detected by quantitative real-time PCR and Western blot analysis. Cell proliferation was measured by cell counting kit-8 assay, 5-Ethynyl-2'-deoxyuridine assay, and colony formation assay. Cell migration was examined by wound healing assay. The apoptosis was detected by flow cytometry assay. The ELISA kits were applied to quantify the fatty acid metabolites. Furthermore, the interplay between miR-497-5p and circPDHX or ACSL1 was detected by dual-luciferase reporter assay and RIP assay. The role of circPDHX in PCa was supplementary substantiated in vivo. RESULTS: CircPDHX and ACSL1 contents were upregulated, and the miR-497-5p level was downregulated in PCa. CircPDHX deficiency attenuated PCa cell proliferation, migration, and fatty acid metabolites, while intensified cell apoptosis. CircPDHX bound to miR-497-5p to adjust ACSL1. Moreover, miR-497-5p inhibited the PCa progression by regulating ACSL1. In the meantime, circPDHX deficiency repressed PCa tumor growth in vivo. CONCLUSION: CircPDHX stimulated PCa development via miR-497-5p/ACSL1, which presented a new thought for PCa treatment.

Ellagic acid improves benign prostate hyperplasia by regulating androgen signaling and STAT3.

Benign prostate hyperplasia (BPH) is an age-related disease in men characterized by the growth of prostate cells and hyperproliferation of prostate tissue. This condition is closely related to chronic inflammation. In this study, we highlight the therapeutic efficacy of ellagic acid (EA) for BPH by focusing on the AR signaling axis and STAT3. To investigate the effect of EA on BPH, we used EA, a phytochemical abundant in fruits and vegetables, to treat testosterone propionate (TP)-induced BPH rats and RWPE-1 human prostate epithelial cells. The EA treatment reduced prostate weight, prostate epithelial thickness, and serum DHT levels in the TP-induced BPH rat model. In addition, EA improved testicular injury by increasing antioxidant enzymes in testis of the BPH rats. EA reduced the protein levels of AR, 5AR2, and PSA. It also induced apoptosis by regulating Bax, Bcl_xL, cytochrome c, caspase 9, and caspase 3 with increasing mitochondrial dynamics. Furthermore, EA reduced the expression of IL-6, TNF-α, and NF-κB, as well as phosphorylation of STAT3 and IκBα. These findings were also confirmed in TP-treated RWPE-1 cells. Overall, our data provide evidence of the role of EA in improving BPH through inhibition of AR and the STAT3 pathway.

Estrogen and G protein-coupled estrogen receptor accelerate the progression of benign prostatic hyperplasia by inducing prostatic fibrosis.

Benign prostatic hyperplasia (BPH) is the most common and progressive urological disease in elderly men worldwide. Epidemiological studies have suggested that the speed of disease progression varies among individuals, while the pathophysiological mechanisms of accelerated clinical progression in some BPH patients remain to be elucidated. In this study, we defined patients with BPH as belonging to the accelerated progressive group (transurethral resection of the prostate [TURP] surgery at ≤50 years old), normal-speed progressive group (TURP surgery at ≥70 years old), or non-progressive group (age ≤50 years old without BPH-related surgery). We enrolled prostate specimens from the three groups of patients and compared these tissues to determine the histopathological characteristics and molecular mechanisms underlying BPH patients with accelerated progression. We found that the main histopathological characteristics of accelerated progressive BPH tissues were increased stromal components and prostatic fibrosis, which were accompanied by higher myofibroblast accumulation and collagen deposition. Mechanism dissection demonstrated that these accelerated progressive BPH tissues have higher expression of the CYP19 and G protein-coupled estrogen receptor (GPER) with higher estrogen biosynthesis. Estrogen functions via GPER/Gαi signaling to modulate the EGFR/ERK and HIF-1α/TGF-ß1 signaling to increase prostatic stromal cell proliferation and prostatic stromal fibrosis. The increased stromal components and prostatic fibrosis may accelerate the clinical progression of BPH. Targeting this newly identified CYP19/estrogen/GPER/Gαi signaling axis may facilitate the development of novel personalized therapeutics to better suppress the progression of BPH.