Prostatic Zinc Research Articles

Zinc metabolism in healthy men and in patients with chronic bacterial prostatitis

Introduction: Zinc is a vital trace element, which regulates metabolism of a prostate gland. It has been established that a low plasma zinc level in men increases the risk of chronic prostatitis and vice versa, chronic prostatitis is often accompanied by zinc deficiency in the prostate gland. The purpose of this study is to research the features and possible correlations of zinc metabolism disorders at systemic (in blood) and local (in prostatic fluid) levels in healthy men and patients with chronic bacterial prostatitis (CBP).
 Materials and methods: Ninety patients with CBP (main group) and thirty healthy men (control group) were random­ized by age (mean age 38.5±2.9 years) and examined. In addition to standard examinations, the zinc levels in blood serum and prostatic fluid were determined, and the oxidative status of the prostate gland was assessed (the level of reac­tive oxygen species (ROS), conjugated dienes, malondialdehyde, superoxide dismutase (SOD) activity in the prostatic fluid) according to standard methods.
 Results and discussion: In patients with CBP, the absolute deficiency of plasma and prostatic zinc was detected 2.89 and 2.5 times more often, respectively, than in healthy men (p < 0.05). At the same time, both the patients with CBP and healthy men had significant correlations between plasma zinc and zinc in prostatic fluid (r = 0.345; n = 37; p = 0.001 and r = 0.156; n = 30; p = 0.001; respectively). A significant positive correlation between the zinc level and the activity of SOD in prostatic fluid was revealed only in the patients with CBP (r = 0.389; n = 90; p = 0.001).
 Conclusion: Zinc concentration in blood plasma does not objectively reflect zinc metabolism disorders in the prostate gland, and therefore the determination of zinc in prostatic fluid is the most reliable and sensitive method for assessing zink disorders in patients with CBP.

Development of Zinc-Specific iCEST MRI as an Imaging Biomarker for Prostate Cancer.

The healthy prostate contains the highest concentration of mobile zinc in the body. As this level decreases dramatically during the initial development of prostate cancer, in vivo detection of prostate zinc content may be applied for diagnosis of prostate cancer. Using 19 F ion chemical exchange saturation transfer magnetic resonance imaging (iCEST MRI) and TF-BAPTA as a fluorinated Zn-binding probe with micromolar sensitivity, we show that iCEST MRI is able to differentiate between normal and malignant prostate cells with a 10-fold difference in contrast following glucose-stimulated zinc secretion in vitro. The iCEST signal decreased in normal prostate cells upon downregulation of the ZIP1 zinc transporter. In vivo, using an orthotopic prostate cancer mouse model and a transgenic adenocarcinoma of the mouse prostate (TRAMP) model, a gradual decrease of >300 % in iCEST contrast following the transition of normal prostate epithelial cells to cancer cells was detected.

Development of Zinc‐Specific iCEST MRI as an Imaging Biomarker for Prostate Cancer

AbstractThe healthy prostate contains the highest concentration of mobile zinc in the body. As this level decreases dramatically during the initial development of prostate cancer, in vivo detection of prostate zinc content may be applied for diagnosis of prostate cancer. Using 19F ion chemical exchange saturation transfer magnetic resonance imaging (iCEST MRI) and TF‐BAPTA as a fluorinated Zn‐binding probe with micromolar sensitivity, we show that iCEST MRI is able to differentiate between normal and malignant prostate cells with a 10‐fold difference in contrast following glucose‐stimulated zinc secretion in vitro. The iCEST signal decreased in normal prostate cells upon downregulation of the ZIP1 zinc transporter. In vivo, using an orthotopic prostate cancer mouse model and a transgenic adenocarcinoma of the mouse prostate (TRAMP) model, a gradual decrease of >300 % in iCEST contrast following the transition of normal prostate epithelial cells to cancer cells was detected.

Synchrotron Radiation X-ray Fluorescence Elemental Mapping in Healthy versus Malignant Prostate Tissues Provides New Insights into the Glucose-Stimulated Zinc Trafficking in the Prostate As Discovered by MRI.

Prostatic zinc content is a known biomarker for discriminating normal healthy tissue from benign prostatic hyperplasia (BPH) and prostate cancer (PCa). Given that zinc content is not readily measured without a tissue biopsy, we have been exploring noninvasive imaging methods to detect these diagnostic differences using a zinc-responsive MRI contrast agent. During imaging studies in mice, we observed that a bolus of glucose stimulates secretion of zinc from the prostate of fasted mice. This discovery allowed the use of a Gd-based zinc sensor to detect differential zinc secretion in regions of healthy versus malignant prostate tissue in a transgenic adenocarcinoma mouse model of PCa. Here, we used a zinc-responsive MRI agent to detect zinc release across the prostate during development of malignancy and confirm the loss of total tissue zinc by synchrotron radiation X-ray fluorescence (μSR-XRF). Quantitative μSR-XRF results show that the lateral lobe of the mouse prostate uniquely accumulates high concentrations of zinc, 1.06 ± 0.08 mM, and that the known loss of zinc content in the prostate is only observed in the lateral lobe during development of PCa. Additionally, we confirm that lesions identified by a loss of zinc secretion indeed represent malignant neoplasia and that the relative zinc concentration in the lesion is reduced to 0.370 ± 0.001 mM. The μSR-XRF data also provided insights into the mechanism of zinc secretion by showing that glucose promotes movement of zinc pools (∼1 mM) from the glandular lumen of the lateral lobe of the mouse prostate into the stromal/smooth muscle surrounding the glands. Co-localization of zinc and gadolinium in the stromal/smooth muscle areas as detected by μSR-XRF confirm that glucose initiates secretion of zinc from intracellular compartments into the extracellular spaces of the gland where it binds to the Gd-based agent and albumin promoting MR image enhancement.

The effects of Pueraria mirifica extract, diadzein and genistein in testosterone-induced prostate hyperplasia in male Sprague Dawley rats.

Pueraria mirifica (PM) is a medicinal plant native to Thailand contained high amount of phytoestrogen and possesses anticancer activity. This study reports the effect of P. mirifica extract, phytoestrogen of diadzein and genistein for its benign prostate hyperplasia properties in testosterone-induced prostate hyperplasia in male Sprague Dawley rats. The P. mirifica extract was evaluated for its total phenols, flavonoid and antioxidant activity using DPPH, FRAP and metal chelating assay. The assessment of P. mirifica, diadzein and genistein against benign prostate hyperplasia was determined in testosterone-induced prostate hyperplasia in male Sprague Dawley rats. The total phenol was higher than flavonoid but showed low antioxidant activity of DPPH, FRAP and metal chelating. The aqueous PM extract at 1000mg/kg significantly increased testosterone levels in testosterone-induced rats by 13% while diadzein and genistein increased it by 11% and 17% respectively. However, levels of FSH, LH, triglyceride and HDL are not affected by the oral administration of PM, diadzein and genistein to the rats. Similarly, total protein, albumin, globulin, total bilirubin, conjugated bilirubin, alkaline phosphatase, alanine aminotransferase, AST, and G-glutamyltransferase showed no significant difference as compared with negative control rats. The body weight of the rats, testis, kidney and liver showed no toxic effect. The zinc content increased significantly and the zinc transporter gen of ZnT4 and ZIP4 highly expressed suggesting that the PM, diadzein and genistein plays essential role in modulating prostate zinc homeostasis. Similarly, the expression of IL-6, AR and ER was significantly reduced indicating functioning in regulation of prostate growth and acts as anti-inflammatory role in preventing BPH. In conclusion, the results indicated that PM reduced BPH and contributed to the regulation in the zinc transport expression of the prostate cells in the benign prostate hyperplasia (BPH).

Vitamin D and testosterone co-ordinately modulate intracellular zinc levels and energy metabolism in prostate cancer cells

Vitamin D3 and its receptor are responsible for controlling energy expenditure in adipocytes and have direct roles in the transcriptional regulation of energy metabolic pathways. This phenomenon also has a significant impact on the etiology of prostate cancer (PCa). Using several in vitro models, the roles of vitamin D3 on energy metabolism and its implication in primary, early, and late invasive PCa were investigated. BODIPY staining and qPCR analyses show that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) up-regulates de novo lipogenesis in PCa cells by orchestrating transcriptional regulation that affects cholesterol and lipid metabolic pathways. This lipogenic effect is highly dependent on the interaction of several nuclear receptors and their corresponding ligands, including androgen receptor (AR), vitamin D receptor (VDR), and retinoid X receptor (RXR). In contrast, inhibition of peroxisome proliferator-activated receptor alpha (PPARα) signaling blocks the induction of the lipogenic phenotype induced by these receptors. Furthermore, 1,25(OH)2D3, T, and 9 cis-retinoic acid (9-cis RA) together redirect cytosolic citrate metabolism toward fatty acid synthesis by restoring normal prostatic zinc homeostasis that functions to truncate TCA cycle metabolism. 1,25(OH)2D3, T, and 9-cis RA also exert additional control of TCA cycle metabolism by down-regulating SLC25A19, which limits the availability of the co-factor thiamine pyrophosphate (TPP) that is required for enzymatic catalyzation of citrate oxidation. This extensive metabolic reprogramming mediated by 1,25(OH)2D3, T, and 9-cis RA is preserved in all in vitro cell lines investigated. These data suggest that 1,25(OH)2D3 and T are important regulators of normal prostatic energy metabolism. Based on the close association between energy metabolism and cancer progression, supplementation of vitamin D3 and testosterone can restrict the energy production that is required to drive PCa progression by maintaining proper zinc homeostasis and inhibiting TCA cycle activity in PCa cells.

AB010. Metabolic disturbance for prostate cancer therapy

Cancer metabolism is emerging with great interest as a therapeutic target for cancer management. Prostate cancer is especially unique in this aspect since benign prostate tissue exhibits truncated Krebs cycle to secret citrate due to high level of prostatic zinc concentration but prostate cancer cells fully oxidize citrate for energy production through Krebs cycle. In addition, most cancer cells maintain functional mitochondria with reprogrammed metabolism, and prostate cancers only present Warburg effect at the late stage of the diseases different from other solid tumors. These metabolic features warrant an advantage of targeting mitochondrial Krebs cycle for prostate cancer management. Despite prostate cancers exhibit massive genetic heterogenicity, metabolic abnormalities appear to be ubiquitous and constant as measured by in situ ion imaging of metabolites and lipids. Thus, it is possible to target Krebs cycle for a unified response. So far, multiple efforts have focused on single specific metabolic enzymes responsible for the altered Krebs cycle in human cancers, including metformin for ETC complex I, IDH1/2 inhibitors, PDH inhibitor CPI-613, MPC1/2 inhibitor UK5099, MCT1 inhibitor AZD3965, CPT1 inhibitors etomoxir/perhexiline/ST1326, FASN inhibitor orlistat/TVB-2640, MCD inhibitor CBM-301106, ACAA2 inhibitor trimetazidine. Ideally, a therapeutic drug for curing cancer should have a cancer preference with a minimum side effect on benign tissues. We previously demonstrated that a natural compound Alternol exerts a cancer-specific killing effect with very limited side effect. Through a comprehensive approach, we identified 4 Krebs cycle enzymes as Alternol-interacting proteins. Alternol disturbs their functions and reduces ATP production only in malignant cells or tissues while sparing benign cells. Therefore, it possesses great hope for a successful clinical implication.

Zinc Induces Lipopolysaccharide-Mediated Upregulation of Human β-defensin-2 in Human Prostate Epithelial Cells

Zinc is considered to be one of the most essential trace minerals for the immune system. High levels of prostatic zinc are associated with prostatic antimicrobial activities. Zinc-deficient individuals experience increased susceptibility to a variety of pathogens. Zinc appears to play a crucial role in maintaining prostate health. This study aimed to clarify the role of zinc in human prostate epithelial cell defense against bacterial infection. To explore the effect of zinc on lipopolysaccharide (LPS)-mediated induction of human β-defensin-2 (HBD-2), the normal human prostate epithelial cell lines (RWPE-1) were co-treated with zinc/LPS and HBD-2 mRNA expression was quantitated by the reverse transcription polymerase chain reaction (RT-PCR). We also conducted a Western blot analysis to determine whether zinc stimulates p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase-1 and -2 (ERK1/2) signaling pathways. To investigate the involvement of the p38MAPK and ERK1/2 signaling pathways in zinc-mediated upregulation of HBD-2, quantitative real-time PCR and immunocytochemical staining were then used to quantify HBD-2 mRNA expression and protein production, respectively, which was treated with either U0126 (ERK1/2 inhibitor) or SB203580 (p38MAPK inhibitor) prior to each analysis of HBD-2.

Single component image guided ‘On-demand’ drug delivery system for early stage prostate cancer

The early stage detection, diagnosis and treatment of prostate cancer are life-saving events in patients housing potentially invasive disease. The healthy human prostate accumulates the maximum amount of zinc compared to any soft tissue in the body. But in the contrary, an inability of cancer cells to accumulate zinc has been found with the development of malignancy resulting in a dramatic reduction in the zinc content of prostate tissue. In this current study, we designed and developed a dipicolylamine-coumarin-chlorambucil (Dpa-Cm-Cmbl) based system which can act as a sensor (for the prostatic zinc i.e. diagnosis) as well as photoresponsive drug delivery system (treatment). We demonstrated that Dpa-Cm-Cmbl being a single component system, first guided us to locate the diseased area by using cellular zinc concentration as a biomarker and in the next there was on-demand release of anticancer drug chlorambucil by employing the external stimulus light. In-vitro studies showed that Dpa-Cm-Cmbl presents excellent properties like detection of cancerous regions in the prostate, photoregulated drug delivery in controlled manner, biocompatibility and all together an efficient chemotherapy.

The effect of chronic prostatitis on zinc concentration of prostatic fluid and seminal plasma: a systematic review and meta-analysis

Background:Prostatitis is a common disease in urology departments. Prostatic zinc accumulation is connected with the secretory function of the prostate, and zinc concentrations present in prostatic diseases differ greatly from the normal level. Studies have investigated the effect of chronic prostatitis on zinc concentration of prostatic fluid and seminal plasma, but have shown inconsistent results. Hence, we performed a systematic literature review and meta-analysis to assess the effect of chronic prostatitis on the zinc concentration of prostatic fluid and seminal plasma.Methods:Systematic literature searches were conducted with PubMed, Embase, Science Direct/Elsevier, CNKI and the Cochrane Library up to March 2015 for case–control studies that involved the relationship between chronic prostatitis and zinc concentration of prostatic fluid and seminal plasma. Meta-analysis was performed with Review Manager and Stata software. Standard mean differences (SMDs) of zinc concentration were identified with 95% confidence intervals (95% CIs) in a random- or fixed-effects model.Results:Our results illustrated that the zinc concentrations in prostatic fluid and seminal plasma from chronic prostatitis patients were significantly lower than normal controls (SMD [95% CI] −246.71 [−347.97, −145.44], −20.74 [−35.11, −6.37], respectively).Limitations:The sample size of each study was relatively small, and a total of 731 chronic prostatitis patients and 574 normal controls were investigated in all fourteen studies. Several studies related to the subject were excluded due to lack of control data or means and standard deviations.Conclusions:The present study illustrates that there was a significant negative effect of chronic prostatitis on zinc concentrations of prostatic fluid and seminal plasma. Further studies with larger sample sizes are needed to better illuminate the negative impact of chronic prostatitis on zinc concentrations.

Evidence that Human Prostate Cancer is a ZIP1-Deficient Malignancy that could be Effectively Treated with a Zinc Ionophore (Clioquinol) Approach.

Despite decades of research, no efficacious chemotherapy exists for the treatment of prostate cancer. Malignant prostate zinc levels are markedly decreased in all cases of prostate cancer compared to normal/benign prostate. ZIP1 zinc transporter down regulation decreases zinc to prevent its cytotoxic effects. Thus, prostate cancer is a "ZIP1-deficient" malignancy. A zinc ionophore (e.g. Clioquinol) treatment to increase malignant zinc levels is a plausible treatment of prostate cancer. However, skepticism within the clinical/biomedical research community impedes significant progress leading to such a zinc treatment. This report reviews the clinical and experimental background, and presents new experimental data showing Clioquinol suppression of prostate malignancy; which provides strong support for a zinc ionophore treatment for prostate cancer. Evaluation of often-raised opposing issues is presented. These considerations lead to the conclusion that the compelling evidence dictates that a zinc-treatment approach for prostate cancer should be pursued with additional research leading to clinical trials.

Abstract 128: Exosomal miRNAs contribute to prostatic zinc homeostasis

Abstract A high level of zinc accumulation is required for normal prostatic function and secretion of prostatic fluid, and loss of zinc is a consistent marker of malignancy. We have recently shown that the reduction in expression of a major zinc transport protein, hZIP1, is due, in part, to aberrantly expressed microRNAs (miRs). MiR-183, 96 and 182, of the miR-183 family, target hZIP1 and other zinc transporters through binding the 3′ untranslated region (UTR) leading to decreased intracellular zinc in prostatic cells. Overexpression of miRs-183, 96 and 182 in prostate cancer is accompanied by decreased zinc concentration. African American men, as compared to Caucasian men, are at a higher risk of diagnosis and death from prostate cancer. African American men typically present with prostate tumors with higher Gleason grades at an earlier age than Caucasian men. This suggests that the prostatic tumors African American men suffer from are more aggressive and faster growing than the prostate tumors of Caucasian men and that there may be a strong biological component to this disparity. It has been previously shown that the prostatic lesions of African American men have a consistently lower zinc concentration than the lesions of their Caucasian peers and have comparatively reduced prostatic expression of hZIP1. We hypothesize that increased expression and exosomal secretion of miRs-183, 96 and 182 may be responsible for the greater degree of zinc depletion in the cancerous prostatic lesions of African American men, as compared to Caucasian men. Exosomes are small vesicles secreted from most cell types that have been repeatedly shown to be capable of carrying miRs to neighboring cells or the circulation. Our preliminary data shows that miRs-183, 96 and 182 are secreted in exosomes from primary prostate epithelial cells in culture, indicating a possible regulation of zinc via cell-to-cell transfer of exosomal miRs. Additionally, we found that the miR-183 family is more highly expressed in the prostatic tissues of African American men, which may contribute to the prostatic zinc disparity. Ongoing work will measure exosomal levels and activity of miR-183, 96 and 182 in primary prostatic epithelial cells from African American and Caucasian men and we have data to suggest that exosomes from African American men contain higher levels of miRs-183, 96 and 182. We will further determine the ability of exosomally derived miR-183, 96 and 182 to regulate zinc homeostasis in primary prostate epithelial cells. The identification of these miRNAs have important implications for patient care, in that African American men may benefit more from zinc supplementation than their Caucasian peers. As miRNA-targeted therapies emerge, these miRNAs may be targeted for prostate cancer treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 128. doi:1538-7445.AM2012-128

Abstract 3729: Resveratrol enhances the anti-proliferative response of zinc by increasing zinc-transporter protein ZIP1 in prostate cancer cells: A novel combinatorial approach for prostate cancer management

Abstract Prostate Cancer (PCa) is one of the most prevalent cancers in males across the globe. In the United States alone, 240,890 new PCa cases and 33,720 related deaths are predicted for the year 2011. Studies suggest that the essential trace element zinc is extremely important in prostate cell functions and survival. Prostate tissue can accumulate zinc at up to ten-fold higher concentration than other organs. However, the cancerous prostatic cells lose the ability to accumulate zinc and lower levels of prostatic zinc have been associated with PCa development and progression. Based on several studies, it has been suggested that lower expression of zinc transporter protein ZIP1 is associated with this neoplastic transformation and restoration of adequate zinc levels in premalignant/malignant prostate cells can abort prostate malignancy. In addition, zinc has been shown to function as an anti-proliferative agent against PCa. However, because of low ZIP1 in cancerous cells, active transport of zinc into the cells is compromised. Thus, zinc supplementation is not effective since very high concentrations of zinc are needed to achieve enough zinc inside cancerous cells. Therefore new means to enhance the bioaccumulation of sufficient zinc in the prostate tissue could be useful towards PCa management. In this study, we tested the hypothesis that grape antioxidant resveratrol will enhance zinc bioaccumulation via increasing ZIP1 in prostate, to impart a superior anti-proliferative response against PCa cells. Our data demonstrated that ZIP1 protein was markedly downregulated in human PCa tissue as compared to normal prostate tissue. Employing androgen-responsive 22Rα1 and LNCaP as well as androgen-unresponsive DU145 cell lines, we observed that a combination of resveratrol and zinc resulted in a remarkable increase in ZIP1 mRNA and protein expression in PCa cells. Further, a combination of resveratrol and zinc was found to impart a superior anti-proliferative response (inhibition of cell growth/viability and induction of apoptosis) in PCa cells, compared to either of the agent alone. Furthermore, we also found that resveratrol-zinc combination resulted in an increase in the levels of metallothioneins (MT1A, MT1X, MT2A and MT3), which play critical role in regulation of intracellular zinc levels. Taken together, our data indicate that resveratrol enhances the cellular transport of zinc via enhancing ZIP1 transporter protein and a combination of resveratrol and zinc may be a useful approach for PCa management. However, further in vivo studies are needed in appropriate animal model(s) with relevance to human disease to determine the clinical benefits of resveratrol and zinc combination against PCa. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3729. doi:1538-7445.AM2012-3729

The Effect of Age on 12 Chemical Element Contents in the Intact Prostate of Adult Men Investigated by Inductively Coupled Plasma Atomic Emission Spectrometry

The effect of age on 12 chemical element contents in intact prostate of 64 apparently healthy, 13-60-year-old men (mean age 36.5 years) was investigated by inductively coupled plasma atomic emission spectrometry. Mean values (M ± SΕΜ) for mass fraction (milligrams/kilogram, on dry weight basis) of Ba, Ca, Cu, Fe, K, Mg, Na, P, S, Sr, and Zn were: Ba 1.18 ± 0.12, Ca 2,178 ± 160, Cu 10.7 ± 0.9, Fe 122 ± 5, K 12,530 ± 360, Mg 1,100 ± 70, Na 10,470 ± 320, P 7,580 ± 300, S 8,720 ± 180, Sr 1.85 ± 0.28, and Zn 782 ± 97, respectively. The upper limit of mean content of V was ≤0.22 mg/kg. A tendency of age-related increase in Ca, Fe, Na, and Zn mass fraction as well an increase in Zn/Ba, Zn/Ca, Zn/Cu, Zn/Fe, Zn/K, Zn/Mg, Zn/Na, Zn/P, Zn/S, and Zn/Sr ratios in prostate was observed. A significant positive correlation was seen between the prostatic zinc and Ca, Cu, Fe, Mg, Na, and P contents.

MiR-183-96-182 Cluster Is Overexpressed in Prostate Tissue and Regulates Zinc Homeostasis in Prostate Cells

Decreased zinc levels are a hallmark of prostate cancer tumors as zinc uniquely concentrates in healthy prostate tissue. Increased dietary zinc correlates with decreased risk of advanced prostate cancer and decreased mortality from prostate cancer. The mechanisms of prostatic zinc homeostasis are not known. Lower zinc levels in the tumor are correlated directly with decreased expression of the zinc transporter hZIP1. We report identification of a microRNA cluster that regulates multiple zinc transporters, including hZIP1. Screening in laser capture microdissected prostate cancer tumors identified miR-182 as a potential regulator of hZIP1. Regulation of hZIP1 by miR-182 via two binding sites was confirmed in primary prostate cell cultures. miR-96 and miR-183 are expressed as a cluster with miR-182 and share similar sequences. Array profiling of tissue showed that miR-183, -96, and -182 are higher in prostate cancer tissue compared with normal prostate. Overexpression of the entire miR-183-96-182 cluster suppressed five additional zinc transporters. Overexpression of miR-183, -96, and -182 individually or as a cluster diminished labile zinc pools and reduced zinc uptake, demonstrating this miR cluster as a regulator of zinc homeostasis. We observed regulation of zinc homeostasis by this cluster in prostate cells and HEK-293 cells, suggesting a universal mechanism that is not prostate-specific. To our knowledge, this is the first report of a miR cluster targeting a family of metal transport proteins. Individually or as a cluster, miR-183, -96, and -182 are overexpressed in other cancers too, implicating this miR cluster in carcinogenesis.

The Br, Fe, Rb, Sr, and Zn contents and interrelation in intact and morphologic normal prostate tissue of adult men investigated by energy‐dispersive X‐ray fluorescent analysis

A method for radionuclide‐induced (109Cd) energy‐dispersive X‐ray fluorescent (EDXRF) was used to determine Br, Fe, Rb, Sr, and Zn contents in intact and morphologic normal prostate tissues. Prostates were removed at necropsy from 64 men (mean age 36.5 years, range 13–60) who had died suddenly. All materials were divided into two parts. One part was morphologically examined, whereas chemical element contents of the other were estimated. Mean values (M ± SΕΜ) for mass fraction of Br, Fe, Rb, Sr, and Zn (mg kg−1 on dry‐weight basis) in the intact and morphologic normal prostate tissue were 35.5 ± 4.0, 107 ± 5.4, 17.1 ± 0.8, 1.9 ± 0.3, and 850 ± 79, respectively. Mean values (M ± SΕΜ) for Zn/Fe, Zn/Rb, and Zn/Sr ratios of mass fraction were 8.72 ± 0.80, 57.4 ± 7.2, and 567 ± 82, respectively. A strongly pronounced tendency of age‐related exponential increase in Zn mass fraction as well an increase in Zn/Fe, Zn/Rb, and Zn/Sr ratios in prostate was observed. A significant positive correlation was seen between the prostatic zinc and iron contents (p ≤ 0.05, r = 0.22) and between the prostatic zinc and bromine contents (p ≤ 0.01, r = 0.43). Copyright © 2011 John Wiley & Sons, Ltd.

Effect of red maca (Lepidium meyenii) on prostate zinc levels in rats with testosterone-induced prostatic hyperplasia

Lepidium meyenii (maca) is a plant that grows exclusively above 4000 m in the Peruvian central Andes. Red maca (RM) extract significantly reduced prostate size in rats with benign prostatic hyperplasia (BPH) induced by testosterone enanthate (TE). Zinc is an important regulator of prostate function. This study aimed to determine the effect of RM on prostate zinc levels in rats with BPH induced by TE. Also, the study attempted to determine the best marker for the effect of RM on sex accessory glands. Rats treated with RM extract from day 1 to day 14 reversed the effect of TE administration on prostate weight and zinc levels. However, RM administered from day 7 to day 14 did not reduce the effect of TE on all studied variables. Finasteride (FN) reduced prostate, seminal vesicle and preputial gland weights in rats treated with TE. Although RM and FN reduced prostate zinc levels, the greatest effect was observed in TE-treated rats with RM from day 1 to day 14. In addition, prostate weight and zinc levels showed the higher diagnosis values than preputial and seminal vesicle weights. In conclusion, RM administered from day 1 to day 14 reduced prostate size and zinc levels in rats where prostatic hyperplasia was induced with TE. Also, this experimental model could be used as accurately assay to determine the effect of maca obtained under different conditions and/or the effect of different products based on maca.

Castration‐ and Aging‐Induced Changes in the Expression of Zinc Transporter and Metallothionein in Rat Prostate

Prostate tissue contains high concentrations of zinc. Zinc content in the prostate gland changes in prostatic disease, such as benign prostate hyperplasia and prostate cancer, which occur more frequently with increasing age. Prostate zinc content is also known to decrease after castration in animal models. It is not clear how prostate zinc content is regulated; therefore, to clarify the mechanisms underlying zinc homeostasis, we examined zinc content and the expression of zinc transporters and metallothioneins in the prostates of aged or castrated rats. Zinc concentration was measured by flame atomic absorption spectrometry. The mRNA expression of zinc transporters and metallothioneins was determined by real-time reverse transcriptase polymerase chain reaction analysis. The expression of the zinc transporter Slc30a2 (Znt2) in ventral prostate (VP) of aged rats (21 months) was approximately 21-fold higher than that in VP of young rats (4 months), and zinc levels in VP of young rats increased significantly compared with that in aged rats. Zinc content in lateral prostate (LP) and dorsal prostate did not differ between young and aged rats. Decreased metallothionein-3 (Mt3) expression was observed in LP of castrated rats, and this reduction was prevented by testosterone replacement. Zinc content and Mt3 expression levels correlated significantly in rat LP. Our findings suggest that Mt3 could play a critical role in zinc homeostasis in rat LP.

Evaluation of Chinese medicine Qian-Yu for chronic bacterial prostatitis in rats

Objectives:Qian-Yu (QY), a Chinese medicine formula, has anti-inflammatory and broad spectrum anti-bacterial activity. This study is undertaken to evaluate the anti-inflammatory effects of Qian-Yu (QY) in chronic bacterial prostatitis (CBP).Materials and Methods:The potential of QY in the treatment of CBP was evaluated using a CBP animal model by examining the anti-inflammatory activity. Its consequences were analyzed by immunological and histopathological methods. Experimental chronic bacterial prostatitis was induced by instillation of bacterial suspension of Escherichia coli 7.5 × 105 CFU/ml into the prostatic urethra. Animals were followed up for four weeks and then treated with either 7 mg/kg QY or 7 mg/kg positive control agent-Qianlietai (QLT) or 1 ml of phosphate-buffered saline (PBS) for the controls. Ten rats in each group were sacrificed at the end of four weeks. The inhibition of inflammation and its consequences were analyzed histologically. Prostatic IL-8, SIgA and zinc concentrations were measured by ELISA, RIA and ICP-AES, respectively. The data was expressed as mean ± S.D. Least-significant difference (LSD) of one-way ANOVA (SPSS 12.0) was used to determine the differences of scores.Results:The histopathology showed resolving prostatitis in QY-and QLT-treated groups and the immunology showed reduction of IL-8 and increment of SIgA contents in prostatic tissues as compared to the control groups. The prostatic zinc levels were higher in the QY-and QLT-treated groups than those in the controls. These results suggested that QY is effective in CBP treatment.

Zinc is decreased in prostate cancer: an established relationship of prostate cancer!

This minireview is prompted by the recent report of Banas et al. (J Biol Inorg Chem 15:1147-1155, 2010), which purports to show and concludes that zinc levels are increased in prostate cancer. Such a conclusion conflicts with the overwhelming corroborating clinical and experimental evidence that has amassed from numerous reports over the past approximately 60 years; these consistently show that prostate zinc levels are decreased in the development and progression of prostate cancer. We submit that this is an established relationship in prostate cancer that must be considered and described in any studies that purport to identify results that are inconsistent with this established relationship. In support of this relationship, we provide a minireview of the information that has led to the establishment of this relationship. As with most established clinical relationships, exceptions and anomalies often exist. However, these must be described and explained in the context of the established relationship, and not in the context of refutation of the established relationship, at least not until sufficient corroborating evidence overwhelms the existing evidence. This provides a background to address and to critique the report of Banas et al. Of broader and more serious implications are the widespread recalcitrance and/or lack of knowledge within the clinical and biomedical research community for recognition that zinc decrease in prostate cancer is an established relationship. This leads to misinformation and misinterpretations regarding clinical, experimental, and epidemiological issues that do not serve the best interests of the scientific, medical, and public communities.