A folic acid-enriched diet attenuates prostate involution in response to androgen deprivation.

BACKGROUND: Serum folate concentrations in the United States have risen since dietary folic acid fortification was first mandated in 1998. Although maternal folic acid offers protection against neural tube defects in conceptuses, its impact on other organ systems and life stages have not been fully examined. Here, we used a mouse model to investigate the impact of a Folic acid (FA) enriched diet on prostate homeostasis and response to androgen deprivation. METHODS: Male mice were fed a control diet (4 mg FA/kg feed) or a folic acid supplemented diet (24 mg FA/kg feed) beginning at conception and continuing through early adulthood, when mice were castrated. RESULTS: We made the surprising observation that dietary FA supplementation confers partial resistance to castration-mediated prostate involution. At 3, 10, and 14 days post-castration, FA enriched diet fed mice had larger prostates as assessed by wet weight, taller prostatic luminal epithelial cells, and more abundant RNAs encoding prostate secretory proteins than castrated control diet fed mice. Diet did not significantly affect prostate weights of intact mice or serum testosterone concentrations of castrated mice. RNA-Seq analysis revealed that the FA enriched diet was associated with a unique prostate gene expression signature, affecting several signaling and metabolic pathways. CONCLUSIONS: Continuous exposure to a FA enriched diet slows prostate involution in response to androgen deprivation. Prostates from FA diet mice have increased secretory gene expression and increased luminal cell heights. The influence of dietary FA supplementation on the prostate response to androgen deprivation raises a future need to consider how dietary folic acid supplementation affects efficacy of androgen-reducing therapies for treating prostate disease.

Ulmus macrocarpa Hance improves benign prostatic hyperplasia by regulating prostatic cell apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulmus macrocarpa Hance (UMH), of the family Ulmaceae, is a deciduous tree, widely distributed throughout Korea. UMH has been used as a traditional oriental medicine in Korea for the treatment of urological disorders, including bladder outlet obstruction (BOO), lower urinary tract syndrome (LUTS), diuresis, and hematuria. To date, its possible protective effects against benign prostatic hyperplasia (BPH) have not been analyzed. AIM OF THE STUDY: This study investigated the effects of UMH on the development of BPH using a rat model of testosterone propionate (TP)-induced BPH. MATERIALS AND METHODS: BPH was induced by daily subcutaneous injections of testosterone propionate (TP) for four weeks. UMH was administrated daily by oral gavage at a dose of 150 mg/kg during the four weeks of TP injections. Animals were sacrificed, and their prostates were weighed and subjected to histopathological examination, TUNEL assay, and western blot analysis. RESULTS: Treatment of BPH-model rats with UMH significantly reduced prostate weight, serum testosterone concentration and dihydrotestosterone (DHT) concentration in prostate tissue. TP-induced prostatic hyperplasia and the expression of proliferating cell nuclear antigen (PCNA) were significantly attenuated in UMH-treated rats. In addition, UMH administration markedly induced the activation of caspases-3, - 8, and - 9 in prostate tissues of BPH rats, accompanied by upregulation of expression of Fas, Fas-associated protein with death domain (FADD), and Fas ligand (FasL) and a reduction in the ratio of B-cell lymphoma 2 (Bcl-2) to Bcl-2-associated X protein (Bax). CONCLUSIONS: UMH effectively inhibited the proliferation and promoted the apoptosis of prostate cells, suggesting it may be useful for the treatment of BPH.

Isosamidin, an extract of Peucedanum japonicum, inhibits phenylephrine-mediated contractions of the human prostate in vitro.

Isosamidin is a pharmacologically active compound extracted from Peucedanum japonicum which is used as a health food in East Asia. Our preliminary animal data suggested that isosamidin may have sufficient potency to treat patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia or overactive bladder. However, the efficacy of isosamidin in humans is unknown. Here, we examined whether isosamidin inhibits agonist-stimulated contractions in isolated human bladder and prostate tissue strips in vitro. Human bladder and prostate strips obtained from 9 to 10 male patients, respectively, were suspended in organ baths. After administration of isosamidin (10, 30, and 100 µM), concentration-response curves to agonists (acetylcholine or phenylephrine) were constructed by cumulatively increasing agonist concentration. Isosamidin inhibited phenylephrine-stimulated contractions of isolated human prostate tissue strips in a concentration-dependent manner, with significant differences observed between control and 100 µM isosamidin. In contrast, isosamidin had no effect on acetylcholine-stimulated contractions of isolated human bladder tissue strips. Isosamidin may have pharmacological potency in the treatment of male patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Clinical studies are needed to confirm the efficacy and safety of isosamidin in humans.

Specific effects of prenatal DEHP exposure on neuroendocrine gene expression in the developing hypothalamus of male rats.

Endocrine disrupting chemicals may disrupt developing neuroendocrine systems, especially when the exposure occurs during a critical period. This study aimed to investigate whether prenatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a major component of plasticizers used worldwide, disrupted the development of a network of genes important for neuroendocrine function in male rats. Pregnant rats were treated with corn oil (vehicle control), 2, 10 or 50 mg/kg DEHP by gavage from gestational day 14 to 19. The neuroendocrine gene expressions were quantified using a 48-gene Taqman qPCR array in the whole hypothalamus of neonatal rats (postnatal day 1) and in the anteroventral periventricular nucleus (AVPV), medial preoptic nucleus (MPN) and arcuate nucleus (ARC) of adult rats (postnatal day 70). Immunofluorescent signals of ERα and CYP19 were detected using the confocal microscopy in adult AVPV, MPN and ARC. The results showed that prenatal DEHP exposure perturbed somatic and reproductive development of offspring. Eleven genes were down-regulated in neonatal hypothalamus and showed non-monotonic dose-response relationships, that the 10 mg/kg DEHP dosage was associated with the greatest number of gene expression changes. Different from this, 14 genes were altered in adult AVPV, MPN and ARC and most of alterations were found in the 50 mg/kg DEHP group. Also, 50 mg/kg DEHP reduced ERα expression in the ARC, but no alterations were observed in CYP19 expression. These results indicated that prenatal DEHP exposure may perturb hypothalamic gene programming and the influences are permanent. The effects showed dependence on developmental stages and nuclei region.

Iodine prevents the increase of testosterone-induced oxidative stress in a model of rat prostatic hyperplasia.

Oxidative stress and inflammation are involved in the development and/or progression of benign prostatic hyperplasia (BPH). Molecular iodine (I2) induces antiproliferative and apoptotic effects in prostate cancer cells, but it is unknown if I2 regulates oxidative stress in the normal and/or tumoral prostate. The purpose of this study was to analyze the effects of I2 and celecoxib (Cxb) on oxidative stress and inflammation in a model of prostatic hyperplasia. Cxb was used as positive control of cyclooxygenase-2 (COX-2) inhibition. Prostatic hyperplasia was induced in male Wistar rats (170g) with testosterone (5mg/kg/week, for three weeks). One week before hyperplasia induction, I2 (25mg/day/rat) or Cxb (1.25mg/day/rat) was supplied for four weeks in the drinking water. Prostatic hyperplasia was evaluated by histological analysis, DNA content, and/or proliferating cell nuclear antigen (PCNA) expression. Lipoperoxidation (malondialdehyde) and nitrite (NO2-) levels were analyzed by colorimetric methods, while nitric oxide synthase (NOS), COX, and myeloperoxidase (MPO) enzymes were analyzed using RT-PCR, immunoblotting, and/or enzymatic assays. Levels of 15-F2t-isoprostanes, prostaglandins (PGE2), leukotrienes (LTB4), and tumor necrosis factor alpha (TNFα) were measured by ELISA. Control testosterone-treated animals exhibited hyperplasia in the dorsolateral prostate, as well as increments in almost all oxidative parameters except for COX-1, TNFα, or MPO. I2 and Cxb prevented epithelial hyperplasia (DNA content) and oxidative stress induction generated by testosterone in almost the same intensity, and the minimum I2 dose required was 2.5mg/rat. The antioxidant capacity of I2 was also analyzed in a cell-free system, showing that this element inhibited the conversion of nitrate (NO3-) to NO2-. I2 did not modify the prostatic oxidative state in testosterone untreated rats. In summary, our data showed that antiproliferative and antioxidant effects of I2 involve the inhibition of NOS and the COX-2 pathway. Further studies are necessary to analyze the therapeutic and/or adjuvant effects of I2 with first-line medications used to treat BPH.

Systems analysis of the prostate transcriptome in African-American men compared with European-American men.

AIM: African-Americans (AA) have increased prostate cancer risk and a greater mortality rate than European-Americans (EA). AA exhibit a high prevalence of vitamin D deficiency. We examined the global prostate transcriptome in AA and EA, and the effect of vitamin D3 supplementation. PATIENTS & METHODS: Twenty-seven male subjects (ten AA and 17 EA), slated to undergo prostatectomy were enrolled in the study. Fourteen subjects received vitamin D3 (4000 IU daily) and 13 subjects received placebo for 2 months prior to surgery. RESULTS: AA show higher expression of genes associated with immune response and inflammation. CONCLUSION: Systems level analyses support the concept that Inflammatory processes may contribute to disease progression in AA. These transcripts can be modulated by a short course of vitamin D3 supplementation.

The body has a brake: micrin is a postulated new gonadal hormone curbing tissue overgrowth and restricting reproduction.

There is evidence for an unrecognised classical hormone secreted by the mammalian gonad. This postulated hormone--'micrin' (pronounced 'my-crin')--represents the body's brake against tissue overgrowth. When oestrogens are administered in high doses to female rats there is a considerable (non-artefactual) increase in the relative size and weight of organs such as the pituitary, adrenals, uterus and liver--suggesting an organotrophic (organ-building) role for endogenous oestrogens. This effect is exaggerated if the animals are first ovariectomized, indicating the removal of a negative ovarian factor, micrin. These organ enlargements can be reduced by pretreating the rats with large doses of antioestrogens such as clomiphene and tamoxifen. This antiestrogenic blockade of exogenous oestrogens is itself blunted by prior removal of the ovaries. It is proposed that antioestrogens (e.g. tamoxifen in breast cancer treatment) antagonize the organotrophic effects of oestrogens by competing for the oestrogen receptor peripherally and centrally and via an increase in the secretion of ovarian micrin. It is deduced that micrin is the testicular 'inhibin' proposed in the 1930s, not the molecule that now bears that name, which acts at the pituitary tier as a downregulator of follicle-stimulating hormone. The hallmark of micrin deficiency in the male rat is a pituitary hypertrophy that follows castration. This is reversible with a steroid-depleted aqueous bovine testicular extract, the micrin within which suppresses the hypothalamus, normalizing the pituitary. Micrin probably acts as a brake on peripheral tissues directly but also indirectly at the meta-level via the hypothalamic-pituitary axis, resetting a hypothalamic 'organostat' controlling organ and tissue masses, part of the 'organotrophic system' of internal size regulation. Besides endocrine (circulating) micrin from the gonads there is probably paracrine (locally acting) micrin produced in the brain. This is involved in a somatic cueing system for puberty: the brake comes off at an appropriate body tissue mass disinhibiting the hypothalamus and accelerating the organism towards sexual maturity and full adult stature. This suggests the use in reproductive disorders of micrin-related drugs. These could also be inhibitors of breast, prostate and other cancers, while protecting the bone marrow via a trophic effect on the adrenals (the lack of which protection causes lethal bone marrow depression in oestrogen-treated ferrets and dogs). Benign prostatic hyperplasia is asserted to be a micrin deficiency disorder, involving insufficiently opposed androgen. The rise in cancers with age could be associated with a reduction in micrin protection and a relative lack of this hormone could partly explain why men die younger than women. Micrin is dissimilar in activity to any known molecule and could usefully be isolated, characterised and exploited therapeutically.

Androgenic effect of honeybee drone milk in castrated rats: roles of methyl palmitate and methyl oleate.

ETHNOPHARMACOLOGICAL RELEVANCE: Numerous honeybee (Apis mellifera) products have been used in traditional medicine to treat infertility and to increase vitality in both men and women. Drone milk (DM) is a relatively little-known honeybee product with a putative sexual hormone effect. The oestrogenic effect of a fraction of DM has recently been reported in rats. However, no information is available on the androgenic effects of DM. The purpose of the present study was to determine the androgen-like effect of DM in male rats and to identify effective compounds. MATERIALS AND METHODS: A modified Hershberger assay was used to investigate the androgenic effect of crude DM, and the plasma level of testosterone was measured. The prostatic mRNA and protein expression of Spot14-like androgen-inducible protein (SLAP) were also examined with real-time PCR and Western blot techniques. GC-MS and NMR spectroscopic investigations were performed to identify the active components gained by bioactivity-guided fractionation. RESULTS: The crude DM increased the relative weights of the androgen-dependent organs and the plasma testosterone level in castrated rats and these actions were flutamide-sensitive. DM increased the tissue mRNA and protein level of SLAP, providing further evidence of its androgen-like character. After bioactivity-guided fractionation, two fatty acid esters, methyl palmitate (MP) and methyl oleate (MO), were identified as active compounds. MP alone showed an androgenic effect, whereas MO increased the weight of androgen-sensitive tissues and the plasma testosterone level only in combination. CONCLUSION: The experimental data of DM and its active compounds (MO and MP) show androgenic activity confirming the traditional usage of DM. DM or MP or/and MO treatments may project a natural mode for the therapy of male infertility.

Sperm retrieval in anejaculatory diabetic men who failed in drug treatment and penile vibratory stimulation during blood sugar under control.

Ejaculatory dysfunction is an uncommon cause of male infertility. The aim of this study was to explore non-invasive methods for sperm retrieval in anejaculatory diabetic men who failed in drug treatment and penile vibratory stimulation during blood sugar under control. Among 21 anejaculatory diabetic men who had failed in drug treatment and penile vibratory stimulation, sperm was collected by retrograde ejaculation in 10 patients (group A), and in eight patients, sperm was collected by prostatic massage (group B). We compared the outcome of subsequent assisted reproductive treatment between the two groups; the rate of fertility in group A and in group B was 78.3% and 66.6% respectively, and the rate of good embryo was 56.6% and 48.8% respectively. Eight singleton pregnancies were achieved in the 18 anejaculatory diabetic men, 5 in group A and 3 in group B, the rate of pregnancy between the two groups was 50% and 37.5% respectively. There was no significant difference in the rate of fertility, good embryo rate and pregnancy outcome between the two groups.

Relaxant effects of Aike Mixture on isolated bladder and prostatic urethral smooth muscle of rabbits.

OBJECTIVE: To observe the relaxant effect of Aike Mixture (AKM) on isolated bladder and prostatic urethral smooth muscle of rabbits. METHODS: The isolated bladder and prostatic urethral smooth muscle from male rabbits were placed in a Magnus bath and smooth muscle contraction was measured using a biological signal acquisition and analysis system. The effects of AKM in combination with methoxyamine, carbachol and CaCl2 on the contractile tension of muscle strips were determined by cumulative dosing. RESULTS: AKM dose-dependently reduced contractile tension of bladder trigone smooth muscle (r=0.831, P<0.05), reduced contractile wave amplitude (r=0.837, P<0.05) and decreased contractile frequency (r=-0.917, P<0.01). AKM significantly inhibited the increases in smooth muscle contraction induced by methoxyamine, carbachol and CaCl2. CONCLUSION: AKM dose-dependently inhibited the contraction of rabbit isolated bladder and prostatic urethral smooth muscle by antagonizing α1-adrenergic receptors and M-cholinergic receptors.

Effect of Boerhaavia diffusa in experimental prostatic hyperplasia in rats.

OBJECTIVE: Present investigation was undertaken to study the effectiveness of hydroalcoholic extract of roots of Boerhaavia diffusa in experimental benign prostatic hyperplasia (BPH) in rats using various animal models. MATERIALS AND METHODS: BPH in rats was induced by subcutaneous injection of testosterone (5 mg/kg) daily for 28 days. Rats were divided in to five groups (six rats each). A negative control group received arachis oil (1 ml/kg s.c.) and four groups were injected testosterone. These four groups were further divided into reference group (finasteride 1 mg/kg), model group (testosterone), study group A (B. diffusa 100 mg/kg), and study group B (B. diffusa 250 mg/kg). On the 29(th) day, rats were sacrificed and body weight, prostate weight, bladder weight, and serum testosterone level were measured and histological studies were carried out. Further in vitro analysis of B. diffusa extract on contractility of isolated rat vas deferens and prostate gland, produced by exogenously administered agonists were carried out. All results were expressed as mean ± SEM. 0 Data were analyzed by one-way analysis of variance followed by Tukey's test. RESULTS: B. diffusa (100 mg/kg) treatment for 28 days resulted in significant inhibition of prostate growth (P < 0.05). Drug extract did not have significant change on serum testosterone level. Histopathological analysis of prostate gland supported above results. Results of in vitro experiment suggest that extracts had attenuated the contractile responses of isolated vas deferens and prostate gland to exogenously applied agonists. CONCLUSION: The results suggested that treatment with B. diffusa may improve symptoms of disease and inhibit the increased prostate size. In vitro study implies that herbal extracts has the machinery to produce beneficial effect on prostatic smooth muscle, which would relieve the urinary symptoms of disease. B. diffusa could be a potential source of new treatment of prostatic hyperplasia.

Outcomes in men with large prostates (≥ 60 cm(3)) treated with definitive proton therapy for prostate cancer.

Large prostate size is associated with higher rates of genitourinary and gastrointestinal toxicities after definitive treatment for prostate cancer, and because of this many men will undergo cytoreduction with androgen deprivation therapy (ADT) before definitive therapy, which results in its own unique toxicities and worsens quality of life. This series investigates genitourinary and gastrointestinal toxicity in men with large prostates (> 60 cm(3)) undergoing definitive proton therapy (PT) for prostate cancer. Material and methods. From 2006 to 2010, 186 men with prostates ≥ 60 cm(3) were treated with definitive PT (median dose, 78 CGE) for low- (47%), intermediate- (37%) and high-risk (16%) prostate cancer. Median prostate size was 76 cm(3) (range, 60-143 cm(3)) and pretreatment IPSS was > 15 in 27%. At baseline, 51% were managed for obstructive symptoms with transurethral resection of the prostate (TURP) (9.7%) or medical management with α blockers (32%), 5 α-reductase inhibitors (15%), and/or saw palmetto (11%). Fourteen men received ADT for cytoreduction. Results. Median follow-up was two years. Grade 3 genitourinary toxicities occurred in 14 men, including temporary catheterization (n = 7), TURP (n = 6), and balloon dilation for urethral stricture (n = 1). Multivariate analysis demonstrated pretreatment medical management (p = 0.0065) and pretreatment TURP (p = 0.0002) were significantly associated with grade 3 genitourinary toxicity. One man experienced grade 3 gastrointestinal toxicity and 15 men had grade 2 gastrointestinal toxicities. On multivariate analysis, dose > 78 CGE was associated with increased grade 2 + gastrointestinal toxicity (p = 0.0142). Conclusion. Definitive management of men with large prostates without ADT was associated with low rates of genitourinary and gastrointestinal toxicity.

Qianliening capsule () inhibits human prostate cell growth via induction of mitochondrion-dependent cell apoptosis.

OBJECTIVE: To investigate the molecular mechanisms by which Qianliening Capsule (, QC) treats benign prostatic hyperplasia (BPH). METHODS: Human prostate stromal cell line WPMY-1 was treated with 0, 1, 3 and 5 mg/mL of QC for 24, 48 and 72 h, respectively, in the presence of 10 ng/mL basic fibroblast growth factor (bFGF). The viability of WPMY-1 cells was determined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell morphology was observed by phase-contrast microscopy. 4',6-diamidino-2-phenylindole (DAPI) staining and fluorescence activated cell sorting (FACS) analysis with Annexin-V/propidium iodide (PI) staining were performed to determine cell apoptosis. The loss of mitochondrial membrane potential was examined by FACS analysis with 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyarine iodide (JC-1) staining. Activation of caspase-3 and -9 was evaluated by colorimetric assay. The mRNA and protein expression levels of Bcl-2 and Bax were measured by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting, respectively. RESULTS: Upon bFGF stimulation, the viability of WPMY-1 cells was increased to 122%-118% compared with the control cells (P <0.05). However, treatment with 1-5 mg/mL of QC for 24, 48 and 72 h decreased the viability of bFGF-stimulated cells to 80%-92%, 59%-82%, 36%-62% compared with the untreated cells (P <0.05). In addition, QC treatment reduced WPMY-1 cell density in a dose-dependent manner. Moreover, QC treatment dose-dependently induced the loss of plasma membrane asymmetry, the nuclear condensation and fragmentation, collapse of mitochondrial membrane potential, activation of caspase-9 and caspase-3, and increase of pro-apoptotic Bax/Bcl-2 ratio. CONCLUSION: Promoting mitochondrion-dependent apoptosis of prostate stromal cells might be one of the mechanisms by which QC treats BPH.

The effect of estrogen supplementation on cell proliferation and expression of c-kit positive cells in the rat prostate.

BACKGROUND: Benign prostatic hyperplasia (BPH) is associated with the proliferation of prostate tissue and an increase in smooth muscle tone. However, the way in which the hormonal environment affects cell proliferation and prostatic interstitial cells (PIC) responsible for the maintenance of the smooth muscle tone is not clear. The present study investigated the effect of estrogen supplementation on cell proliferation, androgen/estrogen ratio, and expression and/or distribution of PIC. METHODS: Male Sprague-Dawley rats were anesthetized with isoflurane/oxygen breathing mixture and subcutaneously implanted with silastic capsules. These capsules were either empty or filled with a 10 or 20 mg of crystalline estrogen. RESULTS: Estrogen exerted a potent effect on ventral prostate weight, which was manifested as a significant decrease between controls and the E(10)- and E(20)-treated rats. Active cell proliferation detected as Ki67-positive nuclei was observed in the stromal and epithelial cells of the ventral prostatic lobes from estrogen-treated rats and controls. Estrogen supplementation caused a significant and dose-dependent increase in prostatic estradiol and 5alpha-dihydrotestosterone (DHT) concentration but the ratios of either DHT/E(2) or E(2)/DHT were not significantly affected. PIC were observed in the region between the fibromuscular stroma and the glandular epithelium in all three experimental groups. E(20)-treated rats showed a higher expression of PIC than controls and E(10)-treated rats. CONCLUSIONS: The present study provides novel information regarding the synergistic role of estrogens and androgens in the prostate: estrogen may prevent prostatic hyperplasia via mechanisms other than affecting cell proliferation or DHT/estrogen ratio.

Attenuated proliferation and trans-differentiation of prostatic stromal cells indicate suitability of phosphodiesterase type 5 inhibitors for prevention and treatment of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is characterized by tissue overgrowth and stromal reorganization primarily due to cellular proliferation and fibroblast-to-myofibroblast trans-differentiation. To evaluate the potential of phosphodiesterase type 5 (PDE5) inhibitors like tadalafil for prevention and treatment of BPH, we analyzed the role of the nitric oxide/cyclic GMP (cGMP)/PDE5 pathway for cellular proliferation and TGFbeta1-induced fibroblast-to-myofibroblast trans-differentiation in primary prostate stromal cells. Inhibition by tadalafil of PDE5, which is mainly expressed in the stromal compartment of the prostate, reduced proliferation of primary prostate stromal cells and to a lesser extent of primary prostate basal epithelial cells. Attenuated proliferation due to elevated intracellular cGMP levels was confirmed by inhibition of the cGMP-dependent protein kinase G by its inhibitor KT2358. Moreover, tadalafil strongly attenuated TGFbeta1-induced fibroblast-to-myofibroblast trans-differentiation. The inhibitory effect on trans-differentiation was also observed after small interfering RNA-mediated PDE5 knockdown. As confirmed by the MAPK kinase 1 inhibitor PD98059, this effect was mediated via MAPK kinase 1 signaling. We conclude that BPH patients might benefit from adjuvant therapies with PDE5 inhibitors that inhibit stromal enlargement due to cell proliferation, as well as TGFbeta1-induced trans-differentiation processes.

Promoter demethylation and chromatin remodeling by green tea polyphenols leads to re-expression of GSTP1 in human prostate cancer cells.

Epigenetic silencing of gluthathione-S-transferase pi (GSTP1) is recognized as being a molecular hallmark of human prostate cancer. We investigated the effects of green tea polyphenols (GTPs) on GSTP1 re-expression and further elucidated its mechanism of action and long-term safety, compared with nucleoside-analog inhibitor of DNA methyltransferase (DNMT), 5-aza-2'-deoxycitidine. Exposure of human prostate cancer LNCaP cells to 1-10 microg/ml of GTP for 1-7 days caused a concentration- and time-dependent re-expression of GSTP1, which correlated with DNMT1 inhibition. Methyl-specific-PCR and sequencing revealed extensive demethylation in the proximal GSTP1 promoter and regions distal to the transcription factor binding sites. GTP exposure in a time-dependent fashion diminished the mRNA and protein levels of MBD1, MBD4 and MeCP2; HDAC 1-3 and increased the levels of acetylated histone H3 (LysH9/18) and H4. Chromatin immunoprecipitation assays demonstrated that cells treated with GTP have reduced MBD2 association with accessible Sp1 binding sites leading to increased binding and transcriptional activation of the GSTP1 gene. Exposure of cells to GTP did not result in global hypomethylation, as demonstrated by methyl-specific PCR for LINE-1 promoter; rather GTP promotes maintenance of genomic integrity. Furthermore, exposure of cells to GTP did not cause activation of the prometaststic gene S100P, a reverse response noted after exposure of cells to 5-aza-2'deoxycitidine. Our results, for the first time, demonstrate that GTP has dual potential to alter DNA methylation and chromatin modeling, the 2 global epigenetic mechanisms of gene regulation and their lack of toxicity makes them excellent candidates for the chemoprevention of prostate cancer.

Extracts of bark from the traditional Chinese herb Phellodendron amurense inhibit contractility of the isolated rat prostate gland.

AIM OF THE STUDY: To assess the effectiveness of the traditional Chinese herb Phellodendron amurense in treating urological disorders. MATERIALS AND METHODS: Prostate smooth muscle relaxant activity of an extract from the bark of Phellodendron amurense was tested on contractions of isolated rat prostate gland induced by electrical nerve stimulation and direct muscle stimulation. RESULTS: Electrical field stimulation (0.5 ms, 60V, 1-20 Hz) induced nerve mediated contractions of isolated rat prostate were inhibited by Phellodendron amurense extract dissolved in either dimethylsulfoxide (DMSO), acetic acid or water (P

Thermal therapy in urologic systems: a comparison of arrhenius and thermal isoeffective dose models in predicting hyperthermic injury.

The Arrhenius and thermal isoeffective dose (TID) models are the two most commonly used models for predicting hyperthermic injury. The TID model is essentially derived from the Arrhenius model, but due to a variety of assumptions and simplifications now leads to different predictions, particularly at temperatures higher than 50 degrees C. In the present study, the two models are compared and their appropriateness tested for predicting hyperthermic injury in both the traditional hyperthermia (usually, 43-50 degrees C) and thermal surgery (or thermal therapy/thermal ablation, usually, >50 degrees C) regime. The kinetic parameters of thermal injury in both models were obtained from the literature (or literature data), tabulated, and analyzed for various prostate and kidney systems. It was found that the kinetic parameters vary widely, and were particularly dependent on the cell or tissue type, injury assay used, and the time when the injury assessment was performed. In order to compare the capability of the two models for thermal injury prediction, thermal thresholds for complete killing (i.e., 99% cell or tissue injury) were predicted using the models in two important urologic systems, viz., the benign prostatic hyperplasia tissue and the normal porcine kidney tissue. The predictions of the two models matched well at temperatures below 50 degrees C. At higher temperatures, however, the thermal thresholds predicted using the TID model with a constant R value of 0.5, the value commonly used in the traditional hyperthermia literature, are much lower than those predicted using the Arrhenius model. This suggests that traditional use of the TID model (i.e., R=0.5) is inappropriate for predicting hyperthermic injury in the thermal surgery regime (>50 degrees C). Finally, the time-temperature relationships for complete killing (i.e., 99% injury) were calculated and analyzed using the Arrhenius model for the various prostate and kidney systems.

Gene expression profile of primary prostate epithelial and stromal cells in response to sulforaphane or iberin exposure.

BACKGROUND: Broccoli consumption has been associated with a reduced risk of prostate cancer. Isothiocyanates (ITCs) derived from glucosinolates that accumulate in broccoli are dietary compounds that may mediate these health effects. Sulforaphane (SF, 4-methylsulphinylbutyl ITC) derives from heading broccoli (calabrese) and iberin (IB, 3-methylsulphinypropyl ITC) from sprouting broccoli. While there are many studies regarding the biological activity of SF, mainly undertaken with cancerous cells, there are few studies associated with IB. METHODS: Primary epithelial and stromal cells were derived from benign prostatic hyperplasia tissue. Affymetrix U133 Plus 2.0 whole genome arrays were used to compare global gene expression between these cells, and to quantify changes in gene expression following exposure to physiologically appropriate concentrations of SF and IB. Ontology and pathway analyses were used to interpret results. Changes in expression of a subset of genes were confirmed by real-time RT-PCR. RESULTS: Global gene expression profiling identified epithelial and stromal-specific gene expression profiles. SF induced more changes in epithelial cells, whereas IB was more effective in stromal cells. Although IB and SF induced different changes in gene expression in both epithelial and stromal cells, these were associated with similar pathways, such as cell cycle and detoxification. Both ITCs increased expression of PLAGL1, a tumor suppressor gene, in stromal cells and suppressed expression of the putative tumor promoting genes IFITM1, CSPG2, and VIM in epithelial cells. CONCLUSION: These data suggest that IB and SF both alter genes associated with cancer prevention, and IB should be investigated further as a potential chemopreventative agent. Prostate 69: 1411-1421, 2009. (c) 2009 Wiley-Liss, Inc.