Rat Prostate Research Articles

Enhanced penetration of moxifloxacin into rat prostate tissue evidenced by microdialysis

Moxifloxacin is reported to have increased distribution into the prostate compared with older fluoroquinolones such as norfloxacin and ciprofloxacin, being able to reach tissue-to-plasma concentration ratios greater than unity. However, most of these studies use tissue homogenates derived from biopsy samples, which can lead to overestimation of free concentrations as fluoroquinolones tend to accumulate in the intracellular space. The aim of this study was to investigate moxifloxacin pharmacokinetics in rat prostate interstitial fluid by microdialysis. Tissue pharmacokinetics was assessed by implanting a small microdialysis catheter in the prostate gland. Blood samples were simultaneously collected for assessing plasma pharmacokinetics. Analysis of plasma (N=154) and microdialysis (N=344) concentrations after a single intravenous dose of 6 or 12mg/kg moxifloxacin was conducted in the non-linear mixed-effect modelling software NONMEM v.6 as well by a non-compartmental approach. Moxifloxacin showed a significant tissue distribution in the prostate (AUCprostate,ISF/fu·AUCplasma=1.24±0.37), 59% higher than the value obtained for levofloxacin in a previous study. A three-compartment model with non-linear kinetics could adequately describe moxifloxacin pharmacokinetics in terms of curve fitting and precision in parameter estimation. The developed pharmacokinetic model indicates that passive diffusion and active transport are the mechanisms involved in moxifloxacin distribution to the prostate. These findings suggest that moxifloxacin could be a better alternative to levofloxacin for the treatment of chronic bacterial prostatitis owing to its enhanced tissue penetration and higher AUCtissue/MIC ratios, even though it is not yet approved by the US FDA for this indication.

Dietary zinc deficiency effects dorso-lateral and ventral prostate of Wistar rats: histological, biochemical and trace element study.

Zinc deficiency has become a global problem affecting the developed and developing countries due to inhibitors in the diet which prevents its absorption or due to a very low concentration of bioavailable zinc in the diet. Being present in high concentration in the prostate and having diverse biological function, we investigated the effects of dietary zinc deficiency for 2 and 4 weeks on dorso-lateral and ventral prostate. Sixty prepubertal rats were divided into three groups: zinc control (ZC), pair fed (PF) and zinc deficient (ZD) and fed on 100 μg/g (zinc control and pair fed groups) and 1 μg/g (zinc deficient) diet. Zinc deficiency was associated with degenerative changes in dorso-lateral and ventral prostate as made evident by karyolysis, karyorhexis, cytoplasmolysis, loss of cellularisation, decreased intraluminar secretion and degeneration of fibromuscular stroma. In response, protein carbonyl, nitric oxide, acid phosphatase, 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase increased, exhibiting variable level of significance. Total protein and total zinc concentration in dorso-lateral and ventral prostate as well as in serum decreased (P < 0.001). Decrease (P < 0.001) was recorded in serum FSH and testosterone after 2 and 4 weeks of zinc deficiency. The changes were more prominent after 4 weeks of synthetic zinc deficient diet. The results indicate that zinc deficiency during prepubertal period affects the prostate structure, total protein concentration, enhanced protein carbonyl concentration, nitric oxide as well as acid phosphatase activities and impaired hydroxysteroid dehydrogenase activities. Evidently these changes could be attributed to dysfunction of dorso-lateral and ventral prostate after dietary zinc deficiency as well as impairment of metabolic and secretory activity, reduced gonadotropin levels by hypothalamus -hypophysial system which is indicative of a critical role of zinc in maintaining the prostate integrity.

Expression of nerve growth factor in the prostate of male rats in response to chronic stress and sympathetic denervation.

Nerve growth factor (NGF) has been found in the normal prostate of the Wistar rat and is regarded as an important prostatic mitogen. We have previously shown that chronic stress induced epithelial hyperplasia while sympathetic denervation caused atrophy in the male Wistar rat prostate. NGF may have been a contributing mechanism to the hyperplasia and atrophy response that was observed. The aim of the present study was to investigate the expression of NGF in the prostate of the male rat in response to chronic stress and denervation. Two weeks of restraint water-immersion stress were used to induce a chronic stress model in Wistar rats. Denervation of the peripheral sympathetic nerve was induced by 6-hydroxydopamine. The expression levels of NGF in the dissected prostate lobes were examined by immunohistochemistry. After 14 days of stress, proliferation of the epithelium in the ventral lobes was observed, whereas the dorsolateral lobes were almost unaffected. NGF immunoreactive protein was localized to the columnar secretory epithelium lines of the prostate tissue. Stress and denervation led to an increase in NGF expression in the ventral lobes. In conclusion, NGF was involved in the hyperplasia and atrophy in the prostate of the male rat in response to chronic stress and sympathetic denervation, and thus may be a contributing factor in the pathophysiology of the prostate.

Effects of maternal diabetes on male offspring: high cell proliferation and increased activity of MMP-2 in the ventral prostate.

This study presents a comprehensive view of the histological and functional status of the prostate of adult rat offspring of mothers subjected to gestational diabetes induced by alloxan. The ventral prostate of male adult offspring of diabetic (DP) or normal (CP) mothers was evaluated for collagen fibres, cell death, fibroblasts, smooth muscle cells, cell proliferation, matrix metalloproteinases (MMPs), androgen receptors (AR), transforming growth factor β1 (TGFβ-1), catalase and total antioxidant activity. The prostates of DP animals were lower in weight than those of the CP group. The DP group also exhibited hyperglycaemia and hypotestosteronemia, higher cell proliferation and AR expression, a reduction in α-actin (possibly interfering with the reproductive function of the prostate), and enhanced activity of MMP-2, although the absolute content of MMP-2 was lower in this group. These findings were associated with increased TGFβ-1 and decreased collagen distribution. The prostates of DP rats additionally exhibited reductions in catalase and total antioxidant activity. Thus, rats developing in a diabetic intrauterine environment have glycaemic and hormonal changes that impact on the structure and physiology of the prostate in adulthood. The increased AR expression possibly leads to elevated cell proliferation. Stromal remodelling was characterized by enhanced activity of MMP-2 and collagen degradation, even with increased TGFβ-1 activation. These changes associated with increased oxidative stress might interfere with tissue architecture and glandular homeostasis.

Regucalcin is an androgen-target gene in the rat prostate modulating cell-cycle and apoptotic pathways.

Regucalcin (RGN) is a calcium (Ca(2+) )-binding protein underexpressed in prostate adenocarcinoma comparatively to non-neoplastic prostate or benign prostate hyperplasia cases. Moreover, RGN expression is negatively associated with the cellular differentiation of prostate adenocarcinoma, suggesting that loss of RGN may be associated with tumor onset and progression. However, the RGN actions over the control of prostate cell growth have not been investigated. Androgens are implicated in the promotion of prostate cell proliferation, thus we studied the in vivo effect of androgens on RGN expression in rat prostate. The role of RGN modulating cell proliferation and apoptotic pathways in rat prostate was investigated using transgenic animals (Tg-RGN) overexpressing the protein. In vivo stimulation with 5α-dihydrotestosterone (DHT) down-regulated RGN expression in rat prostate. Cell proliferation index and prostate weight were reduced in Tg-RGN, which was concomitant with altered expression of cell-cycle regulators. Tg-RGN presented diminished expression of the oncogene H-ras and increased expression of cell-cycle inhibitor p21. Levels of anti-apoptotic Bcl-2, as well as the Bcl-2/Bax protein ratio were increased in prostates overexpressing RGN. Both caspase-3 expression and enzyme activity were decreased in the prostates of Tg-RGN. Overexpression of RGN resulted in inhibition of cell proliferation and apoptotic pathways, which demonstrated its role maintaining prostate growth balance. Thus, deregulation of RGN expression may be an important event favoring the development of prostate cancer. Moreover, the DHT effect down-regulating RGN expression in rat prostate highlighted for the importance of this protein in prostatic physiology.

Anatomical and Immunohistochemical Characteristics of the Prostate Gland in the Greater Cane Rat (Thryonomys swinderianus)

This study examined the morphology and immunohistochemical features of the prostate gland in 15 captive-reared male greater cane rat of known reproductive and medical history. Samples of the glands were taken after gross examination and routinely prepared for both histological and ultrastructural analysis. Immunohistochemistry was also carried out on paraffin-embedded sections of the glands using rabbit polyclonal antibodies against oestrogen receptors (ERα and ERβ) and mouse monoclonal antibody for the progesterone receptor (PR). The prostate, which constitutes 0.04% of the body weight, was a paired, lobulated, brownish gland having three left and four right lobes that partly cover the pelvic urethra. Based on the amount and arrangement of the secretory epithelial folding and relative to their distances to the urethra, two histological zones, the central and peripheral, were identified. However, the epithelium of both zones was lined by predominantly simple cuboidal cells with occasional basal cells. The main ultrastructural features of these cuboidal cells were the presence of several nuclear pores on the nucleus, moderately well-developed, short microvilli and bleb-like apical projections, as well as inter-cellular lacunae seen between these cells and the basal cells. The cuboidal epithelial cells also showed positive nuclear staining for ERα and ERβ but not for PR. It is however interesting that the ERα-positive staining was more at the epithelial cells, which is uncommon. These findings highlight the peculiarities in the structure and ultrastructure as well as the unique expression of the oestrogen receptors in the prostate gland of the greater cane rat.

D-004 ameliorates phenylephrine-induced urodynamic changes and increased prostate and bladder oxidative stress in rats.

BackgroundLower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH) mainly depend on alpha1-adrenoreceptors (α1-ADR) stimulation, but a link with oxidative stress (OS) is also involved. D-004, a lipid extract of Roystonea regia fruits, antagonizes ADR-induced responses and produces antioxidant effects. The objective of this study was to investigate whether D-004 produce antioxidant effects in rats with phenylephrine (PHE)-induced urodynamic changes.MethodsRats were randomized into eight groups (ten rats/group): a negative vehicle control and seven groups injected with PHE: a positive control, three treated with D-004 (200, 400 and 800 mg/kg) and three others with tamsulosin (0.4 mg/kg), grape seed extract (GSE) (250 mg/kg) and vitamin E (VE) (250 mg/kg), respectively.ResultsEffects on urinary total volume (UTV), volume voided per micturition (VM), malondialdehyde (MDA) and carbonyl groups (CG) concentrations in prostate and bladder homogenates were study outcomes. While VM and UTV lowered significantly in the positive control as compared to the negative control group, the opposite occurred with prostate and bladder MDA and CG values. D-004 (200-800 mg/kg) increased significantly both VM and UTV, lowered significantly MDA in prostate and bladder homogenates, and reduced GC levels only in the prostate. Tamsulosin increased significantly VM and UTV, but unchanged oxidative variables. GSE and VE unchanged the UTV, whereas VE, not GSE, modestly but significantly attenuated the PHE-induced decrease of VM.ConclusionsSingle oral administration of D-004 (200-800 mg/kg) was the only treatment that ameliorated the urodynamic changes and reduced increased oxidative variables in the prostate of rats with PHE-induced prostate hyperplasia.

Photon and carbon ion irradiation of a rat prostate carcinoma: does a higher fraction number increase the metastatic rate?

In a recent published study, we investigated the response of an experimental prostate carcinoma (R3327-AT1) after irradiation with 1, 2 or 6 fractions of carbon ions or photons, respectively. The original intention of this study was to measure the dose-dependent local control probability as well as the related relative biological effectiveness of carbon ions. However, we now report an increased metastatic rate when the number of fractions was increased from 2 to 6. In a total of 246 animals, the actuarial metastatic rates for 1, 2 and 6 fractions were 5.1 ± 3.5%, 5.7 ± 4.0% and 15.3 ± 7.1% for photons and 9.8 ± 7.5%, 4.0 ± 3.9% and 20.3 ± 6.5% for carbon ions, respectively. The increase was significant only for carbon ions (6 vs. 2 fractions,P = 0.03). Although the original experiment was not designed to investigate metastatic rates, this observation may be of general interest to researchers studying radiation-modulated metastatic activity.

Testosterone therapy differently regulates the anti- and pro-inflammatory cytokines in the plasma and prostate of rats submitted to chronic ethanol consumption (UChB).

Ethanol consumption damages the prostate, and testosterone is known by anti-inflammatory role. The cytokines were investigated in the plasma and ventral prostate of UChB rats submitted or not to testosterone therapy by ELISA and Western blot, respectively. Additionally, inflammatory foci and mast cells were identified in the ventral prostate slides stained by hematoxylin and eosin and toluidine blue, respectively. Inflammatory foci were found in the ethanol-treated animals and absent after testosterone therapy. Plasma levels of IL-6 and IL-10 were not changed while TNFα and TFG-β1 were increased in the animals submitted testosterone therapy. Regarding to ventral prostate, IL-6 did not alter, while IL-10, TNFα, and TFG-β1 were increased after testosterone therapy. Ethanol increases NFR2 in addition to high number of intact and degranulated mast cell which were reduced after testosterone therapy. So, ethanol and testosterone differentially modulates the cytokines in the plasma and prostate.

Evaluation of potential endocrine activity of 2,4-dichlorophenoxyacetic acid using in vitro assays

The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) was evaluated in five in vitro screening assays to assess the potential for interaction with the androgen, estrogen and steroidogenesis pathways in the endocrine system. The assays were conducted to meet the requirements of the in vitro component of Tier 1 of the United States Environmental Protection Agency’s Endocrine Disruptor Screening Program (EDSP), and included assays for estrogen receptor (ER) binding (rat uterine cytosol ER binding assay), ER-mediated transcriptional activation (HeLa-9903-ERα transactivation assay), androgen receptor (AR) binding (rat prostate cytosol AR binding assay), aromatase enzymatic activity inhibition (recombinant human CYP19 aromatase inhibition assay), and interference with steroidogenesis (H295R steroidogenesis assay). Results from these five assays demonstrated that 2,4-D does not have the potential to interact in vitro with the estrogen, androgen, or steroidogenesis pathways. These in vitro data are consistent with a corresponding lack of endocrine effects observed in apical in vivo animal studies, and thus provide important supporting data valuable in a comprehensive weight of evidence evaluation indicating a low potential of 2,4-D to interact with the endocrine system.

Effects of Motherwort Total Alkaloids on Prostatitis Model of Rats

Abstract Objective:To study the effects of Motherwort total alkaloids on prostatitis model of rats. Methods:Give different doses of Motherwort total alkaloids to the prostatitis model of rats, measured in rat prostate prostatitis model index, prostatic fluid white blood cell count, IL-2, IL-8. Results: Compared with the model group, the Motherwort total alkaloid dose group can significantly reduce the prostate index of model rats (P&lt;0.05), the Motherwort total alkaloid of high,medium and low dose group could significantly decrease the levels of white blood cell in prostate fluid model in rats (P&lt;0.01), IL-2 and IL-8 level in prostate inflammation model in prostate homogenate (P &lt; 0.01).Conclusion:The high, medium dose groups of the motherwort total alkaloids has inhibitory effect on prostatitis.

L-Selenomethionine Does Not Protect Against Testosterone Plus 17β-Estradiol-Induced Oxidative Stress and Preneoplastic Lesions in the Prostate of NBL Rats

Previous animal studies examining dietary selenium effects on prostatic carcinogenesis did not show preventive benefit, including 1 study in a rat model involving testosterone (T) and estradiol (E2)-induced prostatic oxidative stress. Here, we examined modulation of T + E2-induced prostatic oxidative stress, dysplasia, and inflammation by L-selenomethionine at 1.5 or 3.0 mg selenium/kg in NIH-07 diet in Noble (Nbl)/Crl rats treated with T + E2 for 16 wk. Hormone treatment increased immunohistochemical staining for 8-hydroxydeoxyguanosine (8-OHdG) in the prostatic sites of T + E2-induced preneoplasia (P < 0.05), but selenomethionine did not attenuate 8-OHdG staining and dysplasia in the lateral prostate. Glutathione-peroxidase activity (P < 0.05) and mRNA expression were induced by T + E2 (P < 0.0001) but not changed by selenomethionine. Selenomethionine did not cause significant responses in expression and activity of glutathione-peroxidase and MnSOD, except for a reduction of MnSOD protein expression in the lateral prostate (P < 0.01). The absence of reduction of oxidative stress and dysplasia and the minimal effects on antioxidant enzymes caused by selenomethionine are consistent with the null effects observed in selenium supplementation animal studies and clinical trials. Significant (P < 0.01) opposite apoptosis/cell proliferation balance responses to selenomethionine and to T + E2 occurred in the lateral and dorsal prostate, explaining why T + E2 induces lesions selectively in the lateral lobe of NBL rats.

Protective effects of different antioxidants against cadmium induced oxidative damage in rat testis and prostate tissues

The present study was performed to determine the effects of different antioxidants on testicular histopathology and oxidative damage induced by cadmium (Cd) in rat testis and prostate. Twenty five rats were equally divided into five groups (n = 5/group). The control group was injected subcutaneously with saline while the Cd alone treated group received a subcutaneous injection of 0.2 mg/kg CdCl2. Other groups were treated with sulphoraphane (25 µg/rat), vitamin E (75 mg/kg), and Ficus Religiosa plant extract (100 mg/kg) orally along with subcutaneous injections of 0.2 mg/kg CdCl2 for fifteen days. Oxidative damage in the testicular and prostate tissues were assessed by the estimation of catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), and glutathione reductase (GSR) activity. Lipid peroxidation (TBARS), protein estimation, and histomorphology were also assessed. Cadmium exposure caused a significant decrease in antioxidant enzymes like CAT, POD, SOD, GSR, protein concentrations, and a marked increase in TBARS activity in rat testis and prostate. Histological examination of adult male rat testes showed a disruption in the arrangement of seminiferous tubules along with a reduction in the number of germ cells, Leydig cells, tunica albuginea thickness, diameter of seminiferous tubules, and height of germinal epithelium. Co-treatment with vitamin E, sulphoraphane, and Ficus religiosa were found to be effective in reversing Cd induced toxicity, representing potential therapeutic options to protect the reproductive tissues from the detrimental effects of Cd toxicity.

Epithelial-to-mesenchymal transition and estrogen receptor α mediated epithelial dedifferentiation mark the development of benign prostatic hyperplasia.

Epithelial-to-mesenchymal transition (EMT) has been reported involved in the pathogenesis of fibrotic disorders and associated with stemness characteristics. Recent studies demonstrated that human benign prostatic hyperplasia (BPH) development involves accumulation of mesenchymal-like cells derived from the prostatic epithelium. However, the inductive factors of EMT in the adult prostate and the cause-and-effect relationship between EMT and stemness characteristics are not yet resolved. EMT expression patterns were immunohistochemically identified in the human epithelia of normal/BPH prostate tissue and in a rat BPH model induced by estrogen/androgen (E2/T, ratio 1:100) alone or in the presence of the ER antagonist raloxifene. Gene expression profiles were analyzed in micro-dissected prostatic epithelia of rat stimulated by E2/T for 3 days. Two main morphological features both accompanied with EMT were observed in the epithelia of human BPH. Luminal cells undergoing EMT dedifferentiated from a cytokeratin (CK) CK18(+) /CK8(+) /CK19(+) to a CK18(-) /CK8(+) /CK19(-) phenotype and CK14 expression increased in basal epithelial cells. ERα expression was closely related to these dedifferentiated cells and the expression of EMT markers. A similar pattern of EMT events was observed in the E2/T induced rat model of BPH in comparison to the prostates of untreated rats, which could be prevented by raloxifene. Epithelial and mesenchymal phenotype switching is an important mechanism in the etiology of BPH. ERα mediated enhanced estrogenic effect is a crucial inductive factor of epithelial dedifferentiation giving rise to activation of an EMT program in prostate epithelium.

Adrenomedullin increases the short‐circuit current in the rat prostate: Receptors, chloride channels, the effects of cAMP and calcium ions and implications on fluid secretion

In this study, we have investigated the effects of adrenomedullin on chloride and fluid secretion in the rat prostate. The presence of adrenomedullin (ADM) in rat prostate was confirmed using immunostaining, and the molecular species was determined using gel filtration chromatography coupled with an enzyme-linked assay for ADM. The effects of ADM on fluid secretion were studied by short-circuit current technique in a whole mount preparation of the prostate in an Ussing chamber. The results indicated that the ADM level was higher in the ventral than the dorso-lateral prostate and the major molecular species was the active peptide. ADM increased the short-circuit current through both the cAMP- and calcium-activated chloride channels in the ventral lobe, but only through the calcium-activated channels in the dorso-lateral lobe. These stimulatory effects were blocked by the calcitonin gene-related peptide (CGRP) receptor antagonist, hCGRP8-37. We conclude that ADM may regulate prostatic fluid secretion through the chloride channels, which may affect the composition of the seminal plasma bathing the spermatozoa and hence fertility.

B‐success supplement (abnigerian herbal remedy): Reproductive implications on on male albino rats (LB631)

We investigated the effects of B‐Success herbal supplement ( A Nigerian Herbal Remedy ) on the accessory sex organs of male Albino Rats. Twenty eight weight matched male Albino Rats were given 0.00, 315, 630, 945 mg/kg of B‐success herbal agent for a period of 90 days. The Rats had free access to deionized water and were fed with rat pellets for the entire period of study. The feed and fluid consumption of the animals were measured on daily basis while the body weight was measured weekly. Animals were anaesthetized after 90 days, bled and sacrificed. Epididymis, seminal vesicle and prostate were excised and weighed. The result showed significant (P蠄 0.05) decrease in both absolute and relative weights of seminal vesicle, prostate and epididymis in all the treated animals when compared with the control. The epididymal acid and alkaline phosphatase contents and semen count decreased significantly (p蠄 0.05) in all the treated animals when compared with the control. The DNA and protein contents of seminal vesicle (SV), prostate (P) and epididymis (E) of albino rats treated with the B‐success herbal supplement decreased significantly (p蠄 0.05) in all the treated animals when compared with the control. B‐success herbal supplement may have toxic effect on the accessory sex organs of male albino rats Key words: B‐success herbal supplement, seminal vesicle (SV), prostate (P) and epididymis (E), male albino rats.

Androgen withdrawal fails to induce detectable tissue hypoxia in the rat prostate

It has been reported that significant hypoxia may occur in the rat prostate following androgen deprivation (AD). It is well known that hypoxia substantially reduces radiation sensitivity of cells both in vitro and in vivo. Given that contemporary management of men with intermediate and high-risk prostate cancer includes the use of neoadjuvant androgen suppression and radiation, AD-induced hypoxia in the prostate could result in suboptimal therapeutic results. Given this concern, we fully investigate possible AD-induced hypoxia in the ventral prostate (VP) of adult rats by two independent methods. Tissue pO2 levels in the VP of adult Spraque-Dawley rats were evaluated prior to and at various time points following castration by two independent techniques. First, an Oxylab tissue oxygen monitor with a 240 μm probe was used for quantitative monitoring of global VP oxygenation. Second, fluorescence immunohistochemistry using the hypoxia marker EF5, known to be metabolically activated by hypoxic cells, was used to evaluate cell-to-cell variation in hypoxia at various days post-castration. Neither the oxygen probe nor EF5 method demonstrate any substantive change in pO2 levels in the rat VP at any time point post-castration. We find no evidence that the rat VP becomes hypoxic at any point following castration using an animal model that closely mimics the human prostate. These data are in contrast to previous reports suggesting prostatic hypoxia occurs following AD and provide assurance that our present therapeutic strategy of neoadjuvant AD followed by radiation is not compromised by AD-induced tissue hypoxia.

The bioavailability of different zinc compounds used as human dietary supplements in rat prostate: a comparative study

The normal human prostate accumulates the highest levels of zinc (Zn) of any soft tissue in the body. The pool of zinc available to the body is known to significantly decrease with age. It is suggested that dietary Zn supplementation protects against oxidative damage and reduces the risk of cancer. Zinc sulfate and zinc gluconate were the most frequently mentioned in per os administration in studies on Zn supplementation. The major aim of the study was to compare the bioavailability of different Zn compounds (sulfate, gluconate and citrate) in the prostate after their daily administration to male rats at three different doses (3.0; 15.0; and 50.0 mg Zn/kg b.w.) for 30 days. The results show that bioavailability in the prostate differs significantly between individual zinc preparations. A significantly elevated Zn concentration in the dorso-lateral lobe of the prostate, compared to controls, was found in the rats supplemented with two compounds only: zinc gluconate and zinc citrate. However, after administration of zinc gluconate, this effect occurred even at the lowest dose. The lowest zinc bioavailability in the prostate was found in the rats administered zinc sulfate: no significant Zn increase was seen in particular zones of the prostate. To sum up, the use of zinc gluconate is worth considering as a possible means of zinc supplementation in men.

Exendin-4 shows no effects on the prostatic index in high-fat-diet-fed rat with benign prostatic hyperplasia by improving insulin resistance

Benign prostatic hyperplasia (BPH) is a prevalent disease globally, and accumulating evidence has indicated an association between BPH, insulin resistance (IR) and diabetes. Exendin-4 is widely used in clinics, which could enhance the proliferation of pancreatic β cells. The ability of exendin-4 to promote tumorigenesis has been of concern, and whether exendin-4 would enhance the propagation of BPH is not fully understood. We aimed to determine whether glucagon-like peptide-1 receptors (GLP-1Rs) were expressed in rat prostate and to determine the effect of exendin-4 on prostate of BPH. Male Wistar rats were used and assigned to six groups: normal diet (ND), high-fat diet (HFD), HFD + exendin-4, HFD + BPH, HFD + BPH + exendin-4 and HFD + BPH + rosiglitazone group. After castration, steroids were injected subcutaneously for 4 weeks to induce BPH. Rats were kept on high-fat diet to induce IR. Treatment groups were treated with exendin-4 and rosiglitazone. Prostatic index and HOMA-IR index were used to evaluate the prostatic hyperplasia status and the degree of IR respectively. The expression of GLP-1R was indicated not only by immunohistochemistry, but also by Western blot analysis. The expression of GLP-1R was significantly higher, and HOMA-IR index and body weight significantly decreased after administration of exendin-4. However, no significant differences in the prostatic index were observed between exendin-4 treatment groups and non-exendin-4 treatment groups. Prostatic index was not influenced by exendin-4 maybe by improving IR and weight loss.

Clusterin: a key player in cancer chemoresistance and its inhibition

Clusterin is a heterodimeric disulfide-linked glycoprotein (449 amino acids) isolated in the rat prostate after castration. It is widely distributed in different tissues and highly conserved in species. There are two isoforms (1 and 2) with antagonistic actions regarding apoptosis. Clusterin is implicated in a number of biological processes, including lipid transport, membrane recycling, cell adhesion, programmed cell death, and complement cascade, representing a truly multifunctional protein. Isoform 2 is overexpressed under cellular stress conditions and protects cells from apoptosis by impeding Bax actions on the mitochondrial membrane and exerts other protumor activities, like phosphatidylinositol 3-kinase/protein kinase B pathway activation, modulation of extracellular signal-regulated kinase 1/2 signaling and matrix metallopeptidase-9 expression, increased angiogenesis, modulation of the nuclear factor kappa B pathway, among others. Its overexpression should be considered as a nonspecific cellular response to a wide variety of tissue insults like cytotoxic chemotherapy, radiation, excess of free oxygen radicals, androgen or estrogen deprivation, etc. A review of the recent literature strongly suggests potential roles for custirsen in particular, and proapoptosis treatments in general, as novel modalities in cancer management. Inhibition of clusterin is known to increase the cytotoxic effects of chemotherapeutic agents, and custirsen, a second-generation antisense oligonucleotide that blocks clusterin, is being tested in a Phase III clinical trial after successful results were achieved in Phase II studies. A major issue in cancer evolution that remains unanswered is whether clusterin represents a driving force of tumorigenesis or a late phenomenon after chemotherapy. This review presents preclinical data that encourages trials in various types of cancer other than advanced castration-resistance prostate cancer and discusses briefly the appropriate timing for clusterin inhibition in the clinical context.