Sleep Deprivation Alters Rat Ventral Prostate Morphology, Leading to Glandular Atrophy: A Microscopic Study Contrasted with the Hormonal Assays

PubMed Central

Venâncio, Daniel P.; Andersen, Monica L.; Vilamaior, Patricia S. L.; Santos, Fernanda C.; Zager, Adriano; Tufik, Sérgio; Taboga, Sebastião R.; De Mello, Marco T.

2012-01-01

We investigated the effect of 96 h paradoxical sleep deprivation (PSD) and 21-day sleep restriction (SR) on prostate morphology using stereological assays in male rats. After euthanasia, the rat ventral prostate was removed, weighed, and prepared for conventional light microscopy. Microscopic analysis of the prostate reveals that morphology of this gland was altered after 96 h of PSD and 21 days of SR, with the most important alterations occurring in the epithelium and stroma in the course of both procedures compared with the control group. Both 96 h PSD and 21-day SR rats showed lower serum testosterone and higher corticosterone levels than control rats. The significance of our result referring to the sleep deprivation was responsible for deep morphological alterations in ventral prostate tissue, like to castration microscopic modifications. This result is due to the marked alterations in hormonal status caused by PSD and SR. PMID:22927719

Chronic prostatic infection and inflammation by Propionibacterium acnes in a rat prostate infection model.

PubMed

Olsson, Jan; Drott, Johanna Bergh; Laurantzon, Lovisa; Laurantzon, Oscar; Bergh, Anders; Elgh, Fredrik

2012-01-01

Chronic inflammation in the prostate, seen as infiltration of inflammatory cells into the prostate gland in histological samples, affects approximately half the male population without indication of prostate disease, and is almost ubiquitous in patients diagnosed with benign prostate hyperplasia and cancer. Several studies have demonstrated the gram-positive bacterium Propionibacterium acnes to be frequently present in prostate tissue from men suffering from prostate disease. P. acnes has been shown to be associated with histological inflammation in human prostatectomy specimens, and also to induce strong inflammatory response in prostate-derived tissue culture models. The present paper describes a rat model for assessment of the pathogenic potential of P. acnes in prostate. Prostate glands of Sprague Dawley rats (n = 98) were exposed via an abdominal incision and live P. acnes or, in control rats, saline were injected into the ventral and dorso-lateral lobes. Rats were sacrificed 5 days, 3 weeks, 3 months and 6 months post infection, and prostate tissue was analyzed for bacterial content and histological inflammation. Rat sera were assessed for levels of CRP and anti-P. acnes IgG. Live P. acnes could be recovered from the dorso-lateral lobes up to 3 months post infection, while the ventral lobes were cleared from bacteria at that time. In samples up to 3 months post infection, the dorso-lateral lobes exhibited intense focal inflammation. CRP and IgG levels were elevated throughout the span of the experiment, and reached maximum levels 3 weeks and 3 months post infection, respectively. We show that P. acnes have the potential to cause chronic infection in previously healthy prostate, and that the infection has potential to cause chronic histological inflammation in the infected tissue. The high prevalence of P. acnes in human prostate tissue calls for resolution of pathogenic details. The present rat model suggests that complications such as chronic

Chronic Prostatic Infection and Inflammation by Propionibacterium acnes in a Rat Prostate Infection Model

PubMed Central

Olsson, Jan; Drott, Johanna Bergh; Laurantzon, Lovisa; Laurantzon, Oscar; Bergh, Anders; Elgh, Fredrik

2012-01-01

Chronic inflammation in the prostate, seen as infiltration of inflammatory cells into the prostate gland in histological samples, affects approximately half the male population without indication of prostate disease, and is almost ubiquitous in patients diagnosed with benign prostate hyperplasia and cancer. Several studies have demonstrated the Gram-positive bacterium Propionibacterium acnes to be frequently present in prostate tissue from men suffering from prostate disease. P. acnes has been shown to be associated with histological inflammation in human prostatectomy specimens, and also to induce strong inflammatory response in prostate-derived tissue culture models. The present paper describes a rat model for assessment of the pathogenic potential of P. acnes in prostate. Prostate glands of Sprague Dawley rats (n = 98) were exposed via an abdominal incision and live P. acnes or, in control rats, saline were injected into the ventral and dorso-lateral lobes. Rats were sacrificed 5 days, 3 weeks, 3 months and 6 months post infection, and prostate tissue was analyzed for bacterial content and histological inflammation. Rat sera were assessed for levels of CRP and anti-P. acnes IgG. Live P. acnes could be recovered from the dorso-lateral lobes up to 3 months post infection, while the ventral lobes were cleared from bacteria at that time. In samples up to 3 months post infection, the dorso-lateral lobes exhibited intense focal inflammation. CRP and IgG levels were elevated throughout the span of the experiment, and reached maximum levels 3 weeks and 3 months post infection, respectively. We show that P. acnes have the potential to cause chronic infection in previously healthy prostate, and that the infection has potential to cause chronic histological inflammation in the infected tissue. The high prevalence of P. acnes in human prostate tissue calls for resolution of pathogenic details. The present rat model suggests that complications such as chronic

Urinary MicroRNAs of Prostate Cancer: Virus-Encoded hsv1-miRH18 and hsv2-miR-H9-5p Could Be Valuable Diagnostic Markers.

PubMed

Yun, Seok Joong; Jeong, Pildu; Kang, Ho Won; Kim, Ye-Hwan; Kim, Eun-Ah; Yan, Chunri; Choi, Young-Ki; Kim, Dongho; Kim, Jung Min; Kim, Seon-Kyu; Kim, Seon-Young; Kim, Sang Tae; Kim, Won Tae; Lee, Ok-Jun; Koh, Gou-Young; Moon, Sung-Kwon; Kim, Isaac Yi; Kim, Jayoung; Choi, Yung-Hyun; Kim, Wun-Jae

2015-06-01

MicroRNAs (miRNAs) in biological fluids are potential biomarkers for the diagnosis and assessment of urological diseases such as benign prostatic hyperplasia (BPH) and prostate cancer (PCa). The aim of the study was to identify and validate urinary cell-free miRNAs that can segregate patients with PCa from those with BPH. In total, 1,052 urine, 150 serum, and 150 prostate tissue samples from patients with PCa or BPH were used in the study. A urine-based miRNA microarray analysis suggested the presence of differentially expressed urinary miRNAs in patients with PCa, and these were further validated in three independent PCa cohorts, using a quantitative reverse transcriptionpolymerase chain reaction analysis. The expression levels of hsa-miR-615-3p, hsv1-miR-H18, hsv2-miR-H9-5p, and hsa-miR-4316 were significantly higher in urine samples of patients with PCa than in those of BPH controls. In particular, herpes simplex virus (hsv)-derived hsv1-miR-H18 and hsv2-miR-H9-5p showed better diagnostic performance than did the serum prostate-specific antigen (PSA) test for patients in the PSA gray zone. Furthermore, a combination of urinary hsv2-miR-H9-5p with serum PSA showed high sensitivity and specificity, providing a potential clinical benefit by reducing unnecessary biopsies. Our findings showed that hsv-encoded hsv1-miR-H18 and hsv2-miR-H9-5p are significantly associated with PCa and can facilitate early diagnosis of PCa for patients within the serum PSA gray zone.

Urinary MicroRNAs of Prostate Cancer: Virus-Encoded hsv1-miRH18 and hsv2-miR-H9-5p Could Be Valuable Diagnostic Markers

PubMed Central

Yun, Seok Joong; Jeong, Pildu; Kang, Ho Won; Kim, Ye-Hwan; Kim, Eun-Ah; Yan, Chunri; Choi, Young-Ki; Kim, Dongho; Kim, Jung Min; Kim, Seon-Kyu; Kim, Seon-Young; Kim, Sang Tae; Kim, Won Tae; Lee, Ok-Jun; Koh, Gou-Young; Moon, Sung-Kwon; Kim, Isaac Yi; Kim, Jayoung; Choi, Yung-Hyun; Kim, Wun-Jae

2015-01-01

Purpose: MicroRNAs (miRNAs) in biological fluids are potential biomarkers for the diagnosis and assessment of urological diseases such as benign prostatic hyperplasia (BPH) and prostate cancer (PCa). The aim of the study was to identify and validate urinary cell-free miRNAs that can segregate patients with PCa from those with BPH. Methods: In total, 1,052 urine, 150 serum, and 150 prostate tissue samples from patients with PCa or BPH were used in the study. A urine-based miRNA microarray analysis suggested the presence of differentially expressed urinary miRNAs in patients with PCa, and these were further validated in three independent PCa cohorts, using a quantitative reverse transcriptionpolymerase chain reaction analysis. Results: The expression levels of hsa-miR-615-3p, hsv1-miR-H18, hsv2-miR-H9-5p, and hsa-miR-4316 were significantly higher in urine samples of patients with PCa than in those of BPH controls. In particular, herpes simplex virus (hsv)-derived hsv1-miR-H18 and hsv2-miR-H9-5p showed better diagnostic performance than did the serum prostate-specific antigen (PSA) test for patients in the PSA gray zone. Furthermore, a combination of urinary hsv2-miR-H9-5p with serum PSA showed high sensitivity and specificity, providing a potential clinical benefit by reducing unnecessary biopsies. Conclusions: Our findings showed that hsv-encoded hsv1-miR-H18 and hsv2-miR-H9-5p are significantly associated with PCa and can facilitate early diagnosis of PCa for patients within the serum PSA gray zone. PMID:26126436

A dual yet opposite growth-regulating function of miR-204 and its target XRN1 in prostate adenocarcinoma cells and neuroendocrine-like prostate cancer cells

PubMed Central

Ding, Miao; Lin, Biaoyang; Li, Tao; Liu, Yuanyuan; Li, Yuhua; Zhou, Xiaoyu; Miao, Maohua; Gu, Jinfa; Pan, Hongjie; Yang, Fen; Li, Tianqi; Liu, Xin Yuan; Li, Runsheng

2015-01-01

Androgen deprivation therapy in prostate cancer (PCa) causes neuroendocrine differentiation (NED) of prostatic adenocarcinomas (PAC) cells, leading to recurrence of PCa. Androgen-responsive genes involved in PCa progression including NED remain largely unknown. Here we demonstrated the importance of androgen receptor (AR)-microRNA-204 (miR-204)-XRN1 axis in PCa cell lines and the rat ventral prostate. Androgens downregulate miR-204, resulting in induction of XRN1 (5′-3′ exoribonuclease 1), which we identified as a miR-204 target. miR-204 acts as a tumor suppressor in two PAC cell lines (LNCaP and 22Rv1) and as an oncomiR in two neuroendocrine-like prostate cancer (NEPC) cell lines (PC-3 and CL1). Importantly, overexpression of miR-204 and knockdown of XRN1 inhibited AR expression in PCa cells. Repression of miR-34a, a known AR-targeting miRNA, contributes AR expression by XRN1. Thus we revealed the AR-miR-204-XRN1-miR-34a positive feedback loop and a dual function of miR-204/XRN1 axis in prostate cancer. PMID:25797256

Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate tumors; dependence upon host tissue hemodynamics and vascular reactivity

PubMed Central

Garcia, Emmanuel; Becker, Veronika G. C.; McCullough, Danielle J.; Stabley, John N.; Gittemeier, Elizabeth M.; Opoku-Acheampong, Alexander B.; Sieman, Dietmar W.

2016-01-01

Given the critical role of tumor O2 delivery in patient prognosis and the rise in preclinical exercise oncology studies, we investigated tumor and host tissue blood flow at rest and during exercise as well as vascular reactivity using a rat prostate cancer model grown in two transplantation sites. In male COP/CrCrl rats, blood flow (via radiolabeled microspheres) to prostate tumors [R3327-MatLyLu cells injected in the left flank (ectopic) or ventral prostate (orthotopic)] and host tissue was measured at rest and during a bout of mild-intensity exercise. α-Adrenergic vasoconstriction to norepinephrine (NE: 10−9 to 10−4 M) was determined in arterioles perforating the tumors and host tissue. To determine host tissue exercise hyperemia in healthy tissue, a sham-operated group was included. Blood flow was lower at rest and during exercise in ectopic tumors and host tissue (subcutaneous adipose) vs. the orthotopic tumor and host tissue (prostate). During exercise, blood flow to the ectopic tumor significantly decreased by 25 ± 5% (SE), whereas flow to the orthotopic tumor increased by 181 ± 30%. Maximal vasoconstriction to NE was not different between arterioles from either tumor location. However, there was a significantly higher peak vasoconstriction to NE in subcutaneous adipose arterioles (92 ± 7%) vs. prostate arterioles (55 ± 7%). Establishment of the tumor did not alter host tissue blood flow from either location at rest or during exercise. These data demonstrate that blood flow in tumors is dependent on host tissue hemodynamics and that the location of the tumor may critically affect how exercise impacts the tumor microenvironment and treatment outcomes. PMID:27125846

Blood flow responses to mild-intensity exercise in ectopic vs. orthotopic prostate tumors; dependence upon host tissue hemodynamics and vascular reactivity.

PubMed

Garcia, Emmanuel; Becker, Veronika G C; McCullough, Danielle J; Stabley, John N; Gittemeier, Elizabeth M; Opoku-Acheampong, Alexander B; Sieman, Dietmar W; Behnke, Bradley J

2016-07-01

Given the critical role of tumor O2 delivery in patient prognosis and the rise in preclinical exercise oncology studies, we investigated tumor and host tissue blood flow at rest and during exercise as well as vascular reactivity using a rat prostate cancer model grown in two transplantation sites. In male COP/CrCrl rats, blood flow (via radiolabeled microspheres) to prostate tumors [R3327-MatLyLu cells injected in the left flank (ectopic) or ventral prostate (orthotopic)] and host tissue was measured at rest and during a bout of mild-intensity exercise. α-Adrenergic vasoconstriction to norepinephrine (NE: 10(-9) to 10(-4) M) was determined in arterioles perforating the tumors and host tissue. To determine host tissue exercise hyperemia in healthy tissue, a sham-operated group was included. Blood flow was lower at rest and during exercise in ectopic tumors and host tissue (subcutaneous adipose) vs. the orthotopic tumor and host tissue (prostate). During exercise, blood flow to the ectopic tumor significantly decreased by 25 ± 5% (SE), whereas flow to the orthotopic tumor increased by 181 ± 30%. Maximal vasoconstriction to NE was not different between arterioles from either tumor location. However, there was a significantly higher peak vasoconstriction to NE in subcutaneous adipose arterioles (92 ± 7%) vs. prostate arterioles (55 ± 7%). Establishment of the tumor did not alter host tissue blood flow from either location at rest or during exercise. These data demonstrate that blood flow in tumors is dependent on host tissue hemodynamics and that the location of the tumor may critically affect how exercise impacts the tumor microenvironment and treatment outcomes. Copyright © 2016 the American Physiological Society.

Suppression of rat and human androgen biosynthetic enzymes by apigenin: Possible use for the treatment of prostate cancer.

PubMed

Wang, Xiudi; Wang, Guimin; Li, Xiaoheng; Liu, Jianpeng; Hong, Tingting; Zhu, Qiqi; Huang, Ping; Ge, Ren-Shan

2016-06-01

Apigenin is a natural flavone. It has recently been used as a chemopreventive agent. It may also have some beneficial effects to treat prostate cancer by inhibiting androgen production. The objective of the present study was to investigate the effects of apigenin on the steroidogenesis of rat immature Leydig cells and some human testosterone biosynthetic enzyme activities. Rat immature Leydig cells were incubated for 3h with 100μM apigenin without (basal) or with 1ng/ml luteinizing hormone (LH), 10mM 8-bromoadenosine 3',5'-cyclic monophosphate (8BR), and 20μM of the following steroid substrates: 22R-hydroxychloesterol (22R), pregnenolone (P5), progesterone (P4), and androstenedione (D4). The medium levels of 5α-androstane-3α, 17β-diol (DIOL), the primary androgen produced by rat immature Leydig cells, were measured. Apigenin significantly inhibited basal, 8BR, 22R, PREG, P4, and D4 stimulated DIOL production in rat immature Leydig cells. Further study showed that apigenin inhibited rat 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase/17, 20-lyase, and 17β-hydroxysteroid dehydrogenase 3 with IC50 values of 11.41±0.7, 8.98±0.10, and 9.37±0.07μM, respectively. Apigenin inhibited human 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase 3 with IC50 values of 2.17±0.04 and 1.31±0.09μM, respectively. Apigenin is a potent inhibitor of rat and human steroidogenic enzymes, being possible use for the treatment of prostate cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

Corn silk extract improves benign prostatic hyperplasia in experimental rat model.

PubMed

Kim, So Ra; Ha, Ae Wha; Choi, Hyun Ji; Kim, Sun Lim; Kang, Hyeon Jung; Kim, Myung Hwan; Kim, Woo Kyoung

2017-10-01

This study was conducted to investigate the effect of a corn silk extract on improving benign prostatic hyperplasia (BPH). The experimental animals, 6-week-old male Wistar rats, were divided into sham-operated control (Sham) and experimental groups. The experimental group, which underwent orchiectomy and received subcutaneous injection of 10 mg/kg of testosterone propionate to induce BPH, was divided into a Testo Only group that received only testosterone, a Testo+Fina group that received testosterone and 5 mg/kg finasteride, a Testo+CSE10 group that received testosterone and 10 mg/kg of corn silk extract, and a Testo+CSE100 group that received testosterone and 100 mg/kg of corn silk extract. Prostate weight and concentrations of dihydrotestosterone (DHT), 5α-reductase 2 (5α-R2), and prostate specific antigen (PSA) in serum or prostate tissue were determined. The mRNA expressions of 5α-R2 and proliferating cell nuclear antigen (PCNA) in prostate tissue were also measured. Compared to the Sham group, prostate weight was significantly higher in the Testo Only group and decreased significantly in the Testo+Fina, Testo+CSE10, and Testo+CSE100 groups ( P < 0.05), results that were consistent with those for serum DHT concentrations. The concentrations of 5α-R2 in serum and prostate as well as the mRNA expression of 5α-R2 in prostate were significantly lower in the Testo+Fina, Testo+CSE10, and Testo+CSE100 groups than that in the Testo Only group ( P < 0.05). Similarly, the concentrations of PSA in serum and prostate were significantly lower in the Testo+Fina, Testo+CSE10, and Testo+CSE100 groups ( P < 0.05) than in the Testo Only group. The mRNA expression of PCNA in prostate dose-independently decreased in the Testo+CSE-treated groups ( P < 0.05). BPH was induced through injection of testosterone, and corn silk extract treatment improved BPH symptoms by inhibiting the mRNA expression of 5α-R2 and decreasing the amount of 5α-R2, DHT, and PSA in serum and prostate

Corn silk extract improves benign prostatic hyperplasia in experimental rat model

PubMed Central

Kim, So Ra; Ha, Ae Wha; Choi, Hyun Ji; Kim, Sun Lim; Kang, Hyeon Jung; Kim, Myung Hwan

2017-01-01

BACKGROUND/OBJECTIVES This study was conducted to investigate the effect of a corn silk extract on improving benign prostatic hyperplasia (BPH). MATERIALS/METHODS The experimental animals, 6-week-old male Wistar rats, were divided into sham-operated control (Sham) and experimental groups. The experimental group, which underwent orchiectomy and received subcutaneous injection of 10 mg/kg of testosterone propionate to induce BPH, was divided into a Testo Only group that received only testosterone, a Testo+Fina group that received testosterone and 5 mg/kg finasteride, a Testo+CSE10 group that received testosterone and 10 mg/kg of corn silk extract, and a Testo+CSE100 group that received testosterone and 100 mg/kg of corn silk extract. Prostate weight and concentrations of dihydrotestosterone (DHT), 5α-reductase 2 (5α-R2), and prostate specific antigen (PSA) in serum or prostate tissue were determined. The mRNA expressions of 5α-R2 and proliferating cell nuclear antigen (PCNA) in prostate tissue were also measured. RESULTS Compared to the Sham group, prostate weight was significantly higher in the Testo Only group and decreased significantly in the Testo+Fina, Testo+CSE10, and Testo+CSE100 groups (P < 0.05), results that were consistent with those for serum DHT concentrations. The concentrations of 5α-R2 in serum and prostate as well as the mRNA expression of 5α-R2 in prostate were significantly lower in the Testo+Fina, Testo+CSE10, and Testo+CSE100 groups than that in the Testo Only group (P < 0.05). Similarly, the concentrations of PSA in serum and prostate were significantly lower in the Testo+Fina, Testo+CSE10, and Testo+CSE100 groups (P < 0.05) than in the Testo Only group. The mRNA expression of PCNA in prostate dose-independently decreased in the Testo+CSE-treated groups (P < 0.05). CONCLUSIONS BPH was induced through injection of testosterone, and corn silk extract treatment improved BPH symptoms by inhibiting the mRNA expression of 5α-R2 and decreasing

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

PubMed

Vaz, Cátia V; Maia, Cláudio J; Marques, Ricardo; Gomes, Inês M; Correia, Sara; Alves, Marco G; Cavaco, José E; Oliveira, Pedro F; Socorro, Sílvia

2014-09-01

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. © 2014 Wiley Periodicals, Inc.

Prostatic relaxation induced by agmatine is decreased in spontaneously hypertensive rats.

PubMed

Lee, Liang-Ming; Tsai, Tsung-Chin; Chung, Hsien-Hui; Tong, Yat-Ching; Cheng, Juei-Tang

2012-09-01

What's known on the subject? and What does the study add? Neurotransmitters are known to control prostate contractility. Agmatine is one of them and induces relaxation through imidazoline receptors. The paper shows that the action of agmatine is reduced in hypertensive rats, and that this change is related to the decrease of ATP-sensitive potassium channels in the prostate. The findings can increase our understanding of the possible underlying mechanism for the development of clinical benign prostatic hyperplasia. To compare agmatine-induced prostatic relaxation in hypertensive and control rats. To investigate the responsible mechanism(s) and the role of the ATP-sensitive potassium channel. Prostate strips were isolated from male spontaneously hypertensive (SH) rats and normal Wistar-Kyoto (WKY) rats for measurement of isometric tension. The strips were precontracted with 1 µmol/L phenylephrine or 50 mmol/L KCl. Dose-dependent relaxation of the prostatic strips was studied by cumulative administration of agmatine, 1 to 100 µmol/L, into the organ bath. Effects of specific antagonists on agmatine-induced relaxation were studied. Western blotting analysis was used to measure the gene expression of the ATP-sensitive potassium channel in the rat prostate. Prostatic relaxation induced by agmatine was markedly reduced in SH rats compared with WKY rats. The relaxation caused by agmatine was abolished by BU224, a selective imidazoline I(2)-receptor antagonist, but was not modified by efaroxan at a dose sufficient to block imidazoline I(1)-receptors. The relaxation induced by diazoxide at a concentration sufficient to activate ATP-sensitive potassium channels was markedly reduced in the SH rat prostate. Expressions of ATP-sensitive potassium channel sulphonylurea receptor and inwardly rectifying potassium channel (Kir) 6.2 subunits were both decreased in the prostate of SH rats. The decrease of agmatine-induced prostatic relaxation in SH rats is related to the change in

N-acetylcysteine Ameliorates Prostatitis via miR-141 Regulating Keap1/Nrf2 Signaling.

PubMed

Wang, Liang-Liang; Huang, Yu-Hua; Yan, Chun-Yin; Wei, Xue-Dong; Hou, Jian-Quan; Pu, Jin-Xian; Lv, Jin-Xing

2016-04-01

Chronic prostatitis was the most common type of prostatitis and oxidative stress was reported to be highly elevated in prostatitis patients. In this study, we determined the effect of N-acetylcysteine (NAC) on prostatitis and the molecular mechanism involved in it. Male Sprague-Dawley rats were divided into three groups: control group (group A, n = 20), carrageenan-induced chronic nonbacterial prostatitis (CNP) model group (group B, n = 20), and carrageenan-induced CNP model group with NAC injection (group C, n = 20). Eye score, locomotion score, inflammatory cell count, cyclooxygenase 2 (COX2) expression, and Evans blue were compared in these three groups. The expression of miR-141 was determined by quantitative real-time PCR (qRT-PCR). Moreover, protein expressions of Kelch-like ECH-associated protein-1 (Keap1) and nuclear factor erythroid-2 related factor 2 (Nrf2) and its target genes were examined by Western blot. Luciferase reporter assay was performed in RWPE-1 cells transfected miR-141 mimic or inhibitor and the plasmid carrying 3'-UTR of Keap1. The value of eye score, locomotion score, inflammatory cell count, and Evans blue were significantly decreased in group C, as well as the expression of COX2, when comparing to that of group B. These results indicated that NAC relieved the carrageenan-induced CNP. Further, we found that NAC increased the expression of miR-141 and activated the Keap1/Nrf2 signaling. Luciferase reporter assay revealed that miR-141 mimic could suppress the activity of Keap1 and stimulate the downstream target genes of Nrf2. In addition, miR-141 inhibitor could reduce the effect of NAC on prostatitis. NAC ameliorates the carrageenan-induced prostatitis and prostate inflammation pain through miR-141 regulating Keap1/Nrf2 signaling.

Penetration and pharmacokinetics of non-steroidal anti-inflammatory drugs in rat prostate tissue.

PubMed

Yellepeddi, Venkata K; Radhakrishnan, Jayashree; Radhakrishnan, Rajan

2018-02-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) involves inflammation of the prostate and affects the quality of life of men of all ages. It is well reported in clinical studies that the treatment for CP/CPPS using nonsteroidal anti-inflammatory drugs (NSAIDs) produced favorable outcomes. However, currently, there are no guidelines on choice of the NSAIDs for the treatment of CP/CPPS. Therefore, in the current research study, we evaluated the prostate tissue penetration of four NSAIDs in rats to provide guidance on choice of NSAIDs for the treatment of CP/CPPS. Male Sprague-Dawley rats were administered orally with four NSAIDs viz. celecoxib, diclofenac, ibuprofen, and naproxen at 500 mg/kg dose. The animals were then sacrificed at various time points, and their prostate tissues were harvested. The NSAIDs were then extracted from the prostate tissues using liquid extraction technique, and their concentration in prostate tissue was quantified using high-performance liquid chromatography (HPLC). The prostate tissue penetration and related pharmacokinetic parameters were evaluated by non-compartmental analysis. The HPLC method for quantifying NSAIDs in prostate tissue resulted in single, sharp peaks without any interference and all validation parameters were within limits. Celecoxib showed the highest area under the curve (AUC) [146.50 ± 2.75 μg/mL*h] of all NSAID's. A two-factor analysis of variance (ANOVA) with replication indicated an overall statistically significant difference in the pharmacokinetic parameters for celecoxib, diclofenac, ibuprofen, and naproxen. This study for the first time reported the relative prostate tissue penetration of four NSAIDs. The pharmacokinetic data indicated that celecoxib has the highest penetration and retention in rat prostate tissues. Therefore, celecoxib may be considered as a better choice for the treatment CP/CPPS involving NSAIDs. © 2017 Wiley Periodicals, Inc.

Effect of obese and lean Zucker rat sera on human and rat prostate cancer cells: implications in obesity-related prostate tumor biology.

PubMed

Lamarre, Neil S; Ruggieri, Michael R; Braverman, Alan S; Gerstein, Matthew I; Mydlo, Jack H

2007-01-01

Several reports have demonstrated the effects of obesity on prostate cancer. Also several reports have linked expression of vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (FGF-2) to prostate cancer aggressiveness. The objective of this study was to determine whether a difference exists between lean and obese Zucker rat sera on proliferation prostate cancer cell lines, as well as to examine the differences in FGF-2 and VEGF concentrations. Ten-week-old female obese and lean Zucker rat sera were subjected to charcoal stripping and tested for the proliferation of human LNCaP and rat AT3B-1 prostate cancer cells. An acetonitrile extract of the charcoal used to strip the sera was also tested for mitogenicity. VEGF and FGF-2 concentrations were determined by enzyme-linked immunosorbent assay. Both unstripped and charcoal-stripped obese rat sera had a greater mitogenic effect than did the lean sera on the LNCaP cell line. Charcoal stripping of both obese and lean sera reduced the mitogenic effect on the AT3B-1 cell line. The acetonitrile extract of the charcoal used to strip the sera was unable to recover this proliferative effect. The concentration of VEGF was greater in the obese serum than in the lean serum, and charcoal stripping reduced the concentrations of both FGF-2 and VEGF. The finding of greater VEGF in obese rat sera, as well as greater mitogenic responses on human prostate cancer cells in vitro, suggests this as one of the many possible mechanisms involved in obesity-related prostate cancer biology.

Red maca (Lepidium meyenii) reduced prostate size in rats

PubMed Central

Gonzales, Gustavo F; Miranda, Sara; Nieto, Jessica; Fernández, Gilma; Yucra, Sandra; Rubio, Julio; Yi, Pedro; Gasco, Manuel

2005-01-01

Background Epidemiological studies have found that consumption of cruciferous vegetables is associated with a reduced risk of prostate cancer. This effect seems to be due to aromatic glucosinolate content. Glucosinolates are known for have both antiproliferative and proapoptotic actions. Maca is a cruciferous cultivated in the highlands of Peru. The absolute content of glucosinolates in Maca hypocotyls is relatively higher than that reported in other cruciferous crops. Therefore, Maca may have proapoptotic and anti-proliferative effects in the prostate. Methods Male rats treated with or without aqueous extracts of three ecotypes of Maca (Yellow, Black and Red) were analyzed to determine the effect on ventral prostate weight, epithelial height and duct luminal area. Effects on serum testosterone (T) and estradiol (E2) levels were also assessed. Besides, the effect of Red Maca on prostate was analyzed in rats treated with testosterone enanthate (TE). Results Red Maca but neither Yellow nor Black Maca reduced significantly ventral prostate size in rats. Serum T or E2 levels were not affected by any of the ecotypes of Maca assessed. Red Maca also prevented the prostate weight increase induced by TE treatment. Red Maca administered for 42 days reduced ventral prostatic epithelial height. TE increased ventral prostatic epithelial height and duct luminal area. These increases by TE were reduced after treatment with Red Maca for 42 days. Histology pictures in rats treated with Red Maca plus TE were similar to controls. Phytochemical screening showed that aqueous extract of Red Maca has alkaloids, steroids, tannins, saponins, and cardiotonic glycosides. The IR spectra of the three ecotypes of Maca in 3800-650 cm (-1) region had 7 peaks representing 7 functional chemical groups. Highest peak values were observed for Red Maca, intermediate values for Yellow Maca and low values for Black Maca. These functional groups correspond among others to benzyl glucosinolate. Conclusions

Characterization of SV-40 Tag rats as a model to study prostate cancer

PubMed Central

2009-01-01

Background Prostate cancer is the second most frequently diagnosed cancer in men. Animal models that closely mimic clinical disease in humans are invaluable tools in the fight against prostate cancer. Recently, a Simian Virus-40 T-antigen (SV-40 Tag) targeted probasin promoter rat model was developed. This model, however, has not been extensively characterized; hence we have investigated the ontogeny of prostate cancer and determined the role of sex steroid receptor and insulin-like growth factor-1 (IGF-1) signaling proteins in the novel SV-40 Tag rat. Methods The SV-40 Tag rat was histopathologically characterized for time to tumor development, incidence and multiplicity and in the ventral, dorsal, lateral and anterior lobes of the prostate. Immunoassay techniques were employed to measure cell proliferation, apoptosis, and sex steroid receptor and growth factor signaling-related proteins. Steroid hormone concentrations were measured via coated well enzyme linked immunosorbent assay (ELISA) kits. Results Prostatic intraepithelial neoplasia (PIN) and well-differentiated prostate cancer developed as early as 2 and 10 weeks of age, respectively in the ventral prostate (VP) followed by in the dorsolateral (DLP). At 8 weeks of age, testosterone and dihydrotestosterone (DHT) concentrations in SV-40 Tag rats were increased when compared to non-transgenic rats. High cell proliferation and apoptotic indices were found in VP and DLP of transgenic rats. Furthermore, we observed increased protein expression of androgen receptor, IGF-1, IGF-1 receptor, and extracellular signal-regulated kinases in the prostates of SV-40 Tag rats. Conclusion The rapid development of PIN and prostate cancer in conjunction with the large prostate size makes the SV-40 Tag rat a useful model for studying prostate cancer. This study provides evidence of the role of sex steroid and growth factor proteins in prostate cancer development and defines appropriate windows of opportunity for preclinical

[Bushen Huoxue Fang promotes the apoptosis of epithelial cells in the prostatic ductal system of rats with benign prostatic hyperplasia].

PubMed

Sun, Jie; Li, Qiu-Fen; Tian, Dai-Zhi; Jiang, Shao-Bo; Wu, Xian-De; Qiu, Shun-An; Ren, Xiao-Gang; Li, Yu-Bing

2014-09-01

To investigate the effects of Bushen Huoxue Fang (BSHX) on the apoptosis of epithelial cells in the prostatic ductal system of rats with benign prostatic hyperplasia (BPH) and its possible action mechanism. One hundred 3- month-old male Wistar rats were randomly divided into four groups of equal number (control, castrated, BPH model, and BSHX). BPH models were made by subcutaneous injection of testosterone following castration; the rats in the BSHX group were treated intragastrically with BSHX at 2.34 g/ml after modeling, while those in the other two groups with equal volume of saline, all for 37 days. On the 38th day, all the rats were sacrificed and their prostates harvested for detection of the distribution of TGF-beta1 and alpha-actin and the count of positive cells in the prostatic ductal system by immunohistochemical staining. The apoptosis rate of epithelial cells in the prostatic ductal system was determined by TUNEL assay. The expression of TGF-beta1 was significantly increased in the rats of the BSHX group as compared with the BPH models in both the proximal prostatic duct ([15.28 +/- 4.30]% vs [36.42 +/- 8.10]%, P < 0.01) and the distal prostatic duct ([4.42 +/- 2.07]% vs [8.71 +/- 2.28 ]%, P < 0.05), while the expression of alpha-actin in the proximal duct was remarkably higher in the BSHX-treated rats than in the models ([28.14 +/- 7.43]% vs [18.28 +/- 4.07]%, P < 0.01), but lower than in the control animals ([33.57 +/- 6.85]%, P < 0.05). Compared with the control group, the BPH models and BSHX-treated rats both exhibited markedly decreased apoptosis of epithelial cells in the proximal prostatic duct ([39.42 +/- 9.20]% vs [3.86 +/- 1.34]%, P < 0.01, and [31.14 +/- 5.64]%, P < 0.01) and distal prostatic duct ([17.60 +/- 4.86]% vs [3.07 +/- 1.14]%, P < 0.01, and [12.37 +/- 2.25]%, P < 0.05). The apoptosis rate of epithelial cells in the prostatic ductal system was significantly higher in the BSHX-treated rats than in the BPH models (P < 0.01). By

Inflammation and Atrophy Precede Prostate Neoplasia in PhIP Induced Rat Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Borowsky, A D; Dingley, K; Ubick, E

2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) has been implicated as a major mutagenic heterocyclic amine in the human diet and is carcinogenic in the rat prostate. In order to validate PhIP induced rat prostate neoplasia as a model of human prostate cancer progression, we sought to study the earliest histologic and morphologic changes in the prostate and to follow the progressive changes over time. We fed 67 male Fischer F344 5 week old rats with PhIP (400 PPM) or control diets for 20 weeks, and then sacrificed animals for histomorphologic examination at age 25 weeks, 45 weeks, and 65 weeks. Animals treated with PhIPmore » showed significantly more inflammation (P=.002 (25wk), >.001(45wk), .016(65wk)) and atrophy (P=.003(25wk), >.001(45wk), .006 (65wk)) in their prostate glands relative to controls. Prostatic intraepithelial neoplasia (PIN) occurred only in PhIP treated rats. PIN lesions arose in areas of glandular atrophy, most often in the ventral prostate. Atypical cells in areas of atrophy show loss of glutathione S-transferase pi immunostaining preceding development of PIN. None of the animals in this study developed invasive carcinomas differing from previous reports. Overall, these findings suggest that the pathogenesis of prostatic neoplasia in the PhIP treated rat prostate proceeds from inflammation to post-inflammatory proliferative atrophy to PIN.« less

Androgen-sensitive spermine-binding protein of rat ventral prostate. Purification of the protein and characterization of the hormonal effect.

PubMed Central

Mezzetti, G; Loor, R; Liao, S

1979-01-01

The rat ventral prostate contains a cytosol protein that can non-covalently bind spermine much more tightly than spermidine or other natural diamines. The protein has been purified to homogeneity, as judged by electrophoresis in urea- and sodium dodecyl sulphate-containing polyacrylamide gels. The protein, with or without spermine bound to it, sediments at 3 S in a sucrose gradient with or without 0.4 M-KCl. The molecular weight of the protein is about 30 000. Each molecule of the binding protein can bind one molecule of spermine. In the prostate of rats injected with cycloheximide, the protein appears to have a half-life of about 3.5 h. The spermine-binding activity of an acidic fraction obtained by DEAE-cellulose chromatography of the prostate cytosol proteins is reduced by about 40--60% within 20--40 h after castration. This effect is reversed very rapidly within 15--30 min by intraperitoneal injection of 5 alpha-dihydrotestosterone. The hormonal effect is androgen-specific and is not mimicked by dexamethasone or oestradiol-17 beta. The androgen effect was reduced significantly when rats were injected with cycloheximide or actinomycin D, suggesting that the acidic protein may be one of the earliest proteins induced by androgen in the rat ventral prostate. Images Fig. 1. PMID:534539

Protective effect of zinc on N-methyl-N-nitrosourea and testosterone-induced prostatic intraepithelial neoplasia in the dorsolateral prostate of Sprague Dawley rats.

PubMed

Banudevi, Sivanantham; Elumalai, Perumal; Sharmila, Govindaraj; Arunkumar, Ramachandran; Senthilkumar, Kalimuthu; Arunakaran, Jagadeesan

2011-09-01

Previous studies have suggested that zinc exerts anticarcinogenic and antiproliferative effects against prostate cancer both in vitro and in rat ventral prostate. Zinc accumulation diminishes early in the course of prostate malignancy and it inhibits the growth of several carcinoma cells through induction of cell cycle arrest and apoptosis. In this study, we have investigated the influence of zinc on N-methyl-N-nitrosourea (MNU) and testosterone (T)-induced prostatic intraepithelial neoplasia in the dorsolateral prostate of Sprague Dawley (SD) rats. The results indicate that zinc plays an important role in prostate carcinogenesis. Increased tumor incidence was accompanied by a decrease in prostatic acid phosphatase activity, citrate, zinc, glutathione-S-transferase, reduced glutathione, p53, B-cell lymphoma protein (Bcl-2)-associated X protein and caspase-3 levels in MNU + T-treated rats. On the contrary, significantly increased phase I drug metabolizing enzyme activities, lipid peroxide, hydrogen peroxide, proliferating cell nuclear antigen, Bcl-2 and Bcl-X(L) protein levels were observed in the dorsolateral prostate of MNU + T-treated rats. Simultaneous zinc supplementation significantly reversed these effects in MNU + T-treated rats. Signs of dysplasia, a characteristic of prostatic intraepithelial neoplasia, were evident in the dorsolateral prostatic tissue sections by MNU + T administration. However, zinc supplementation has reversed these effects in the dorsolateral prostatic histoarchitecture. These results suggest that zinc may act as an essential trace element against MNU and testosterone-induced prostatic preneoplastic progression in SD rats.

Identification of secretaglobin Scgb2a1 as a target for developmental reprogramming by BPA in the rat prostate.

PubMed

Wong, Rebecca Lee Yean; Wang, Quan; Treviño, Lindsey S; Bosland, Maarten C; Chen, Jing; Medvedovic, Mario; Prins, Gail S; Kannan, Kurunthachalam; Ho, Shuk-Mei; Walker, Cheryl Lyn

2015-01-01

Secretoglobins are a superfamily of secreted proteins thought to participate in inflammation, tissue repair, and tumorigenesis. Secretoglobin family 2A member 1 (Scgb2a1) is a component of prostatein, a major androgen-binding protein secreted by the rat prostate. Using a rat model for developmental reprogramming of susceptibility to prostate carcinogenesis, we identified, by RNA-seq, that Scgb2a1 is significantly upregulated (>100-fold) in the prostate of adult rats neonatally exposed to bisphenol A (BPA), with increased gene expression confirmed by quantitative RT-PCR and chromatin immunoprecipitation for histone H3 lysine 9 acetylation. Bisulfite analysis of both CpG islands located within 10 kb of the Scgb2a1 promoter identified significant hypomethylation of the CpG island upstream of the transcription start site of this gene in the reprogrammed prostate. These data suggest that expression of Scgb2a1 in the adult prostate could be epigenetically reprogrammed by BPA exposure during prostate development, with potential implications for cancer risk and response to chemotherapeutics associated with prostatein binding.

20 CFR 332.7 - Consideration of evidence.

Code of Federal Regulations, 2010 CFR

2010-04-01

... INSURANCE ACT MILEAGE OR WORK RESTRICTIONS AND STAND-BY OR LAY-OVER RULES § 332.7 Consideration of evidence... as to lay-over or stand-by status as may be necessary for the determination of his claim. An employee's statement in connection with his claim that he was not out of service because of a lay-over or...

Isoflavones isolated from red clover (Trifolium pratense) inhibit smooth muscle contraction of the isolated rat prostate gland.

PubMed

Brandli, A; Simpson, J S; Ventura, S

2010-09-01

This study investigated whether red clover contains any bioactive constituents which may affect contractility of rat prostatic smooth muscle in an attempt to determine whether its medicinal use in the treatment of benign prostatic hyperplasia is supported by pharmacological effects. A commercially available red clover extract was chemically fractionated and various isoflavones (genistein, formononetin and biochanin A) were isolated from these fractions and their effects on contractility were examined on preparations of the isolated rat prostate gland. Contractile effects of the isolated fractions were compared with commercially available isoflavones (genistein, formononetin and biochanin A). Pharmacological tools were used to investigate the mechanism of action modifying smooth muscle contraction. Crude red clover extract (Trinovin) inhibited electrical field stimulation induced contractions of the rat prostate across a range of frequencies with an IC(50) of approximately 68 microg/ml. Contractions of the rat prostate elicited by exogenous administration of acetylcholine, noradrenaline or adenosine 5'-triphosphate (ATP) were also inhibited. Chromatographic separation, and final purification by high performance liquid chromatography (HPLC) permitted the isolation of the isoflavones: daidzein, calycosin, formononetin, prunetin, pratensin, biochanin A and genistein. Genistein, formononetin and biochanin A (100 microM) from either commercial sources or isolated from red clover extract inhibited electrical field stimulation induced contractions of the isolated rat prostate. It is concluded that isoflavones contained in red clover are able to inhibit prostatic smooth muscle contractions in addition to their antiproliferative effects. However, the high concentrations required to observe these smooth muscle relaxant effects mean that a therapeutic benefit from this mechanism is unlikely at doses used clinically. Crown Copyright 2010. Published by Elsevier GmbH. All rights

Saw palmetto is an indirectly acting sympathomimetic in the rat-isolated prostate gland.

PubMed

Cao, Nga; Haynes, John M; Ventura, Sabatino

2006-02-01

To investigate whether saw palmetto that inhibits alpha1-adrenoceptor binding in vitro affects contractility of the rat prostate gland. The effects of a commercially available saw palmetto extract were examined on the contractility of rat-isolated prostate glands. The extract was tested in the presence and absence of phentolamine, prazosin, yohimbine, propranolol, hexamethonium, cocaine, desipramine, nifedipine, guanethidine, atropine, and alpha,beta-methylene ATP to evaluate the mechanism of action. Isolated preparations of rat vas deferens and bladder were used for comparison. Unexpectedly, saw palmetto extract caused contractions of the rat prostate gland that could be attenuated by prazosin, phentolamine, nifedipine, guanethidine, cocaine, and desipramine but not by any of the other pharmacological tools. Similar contractile effects were observed in rat-isolated vas deferens preparations but not in rat-isolated bladder preparations. In the rat prostate gland, saw palmetto extract causes indirect alpha1-adrenoceptor-mediated contractions via the release of noradrenaline from sympathetic neurons. Copyright 2005 Wiley-Liss, Inc.

Photoacoustic imaging to assess pixel-based sO2 distributions in experimental prostate tumors.

PubMed

Bendinger, Alina L; Glowa, Christin; Peter, Jörg; Karger, Christian P

2018-03-01

A protocol for photoacoustic imaging (PAI) has been developed to assess pixel-based oxygen saturation (sO2) distributions of experimental tumor models. The protocol was applied to evaluate the dependence of PAI results on measurement settings, reproducibility of PAI, and for the characterization of the oxygenation status of experimental prostate tumor sublines (Dunning R3327-H, -HI, -AT1) implanted subcutaneously in male Copenhagen rats. The three-dimensional (3-D) PA data employing two wavelengths were used to estimate sO2 distributions. If the PA signal was sufficiently strong, the distributions were independent from signal gain, threshold, and positioning of animals. Reproducibility of sO2 distributions with respect to shape and median values was demonstrated over several days. The three tumor sublines were characterized by the shapes of their sO2 distributions and their temporal response after external changes of the oxygen supply (100% O2 or air breathing and clamping of tumor-supplying artery). The established protocol showed to be suitable for detecting temporal changes in tumor oxygenation as well as differences in oxygenation between tumor sublines. PA results were in accordance with histology for hypoxia, perfusion, and vasculature. The presented protocol for the assessment of pixel-based sO2 distributions provides more detailed information as compared to conventional region-of-interest-based analysis of PAI, especially with respect to the detection of temporal changes and tumor heterogeneity. (2018) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).

Photoacoustic imaging to assess pixel-based sO2 distributions in experimental prostate tumors

NASA Astrophysics Data System (ADS)

Bendinger, Alina L.; Glowa, Christin; Peter, Jörg; Karger, Christian P.

2018-03-01

A protocol for photoacoustic imaging (PAI) has been developed to assess pixel-based oxygen saturation (sO2) distributions of experimental tumor models. The protocol was applied to evaluate the dependence of PAI results on measurement settings, reproducibility of PAI, and for the characterization of the oxygenation status of experimental prostate tumor sublines (Dunning R3327-H, -HI, -AT1) implanted subcutaneously in male Copenhagen rats. The three-dimensional (3-D) PA data employing two wavelengths were used to estimate sO2 distributions. If the PA signal was sufficiently strong, the distributions were independent from signal gain, threshold, and positioning of animals. Reproducibility of sO2 distributions with respect to shape and median values was demonstrated over several days. The three tumor sublines were characterized by the shapes of their sO2 distributions and their temporal response after external changes of the oxygen supply (100% O2 or air breathing and clamping of tumor-supplying artery). The established protocol showed to be suitable for detecting temporal changes in tumor oxygenation as well as differences in oxygenation between tumor sublines. PA results were in accordance with histology for hypoxia, perfusion, and vasculature. The presented protocol for the assessment of pixel-based sO2 distributions provides more detailed information as compared to conventional region-of-interest-based analysis of PAI, especially with respect to the detection of temporal changes and tumor heterogeneity.

Effects of Estrogen Receptor β Stimulation in a Rat Model of Non-Bacterial Prostatic Inflammation

PubMed Central

Mizoguchi, Shinsuke; Mori, Kenichi; Wang, Zhou; Liu, Teresa; Funahashi, Yasuhito; Sato, Fuminori; DeFranco, Donald B.; Yoshimura, Naoki; Mimata, Hiromitsu

2017-01-01

BACKGROUND There is increasing evidence showing that chronic non-bacterial prostatic inflammation is involved in the pathogenesis of benign prostatic hyperplasia (BPH) and male lower urinary tract symptoms (LUTS). It has also been reported that estrogen receptor β (ERβ) could have an immunoprotective role in prostatic tissue. Therefore, we investigated the effect of ERβ-activation on not only prostatic inflammation, but also bladder overactive conditions in a rat model with nonbacterial prostatic inflammation. METHODS Male Sprague-Dawley rats (8 weeks, n = 15) were divided into three groups: sham-saline group (n = 5), formalin-vehicle group (n = 5), and formalin-treatment group (n = 5). The sham-saline group had sham operation and 50 μl normal saline injected into each ventral lobe of the prostate. The formalin-vehicle group had 50 μl 5% formalin injection into bilateral ventral lobes of the prostate. The formalin-treatment group was treated with 3α-Adiol (a selective ERβ agonist precursor) at a dose of 3 mg/kg daily from 2 days before induction of prostatic inflammation, whereas formalin-vehicle rats received vehicle (olive oil). In each group, conscious cystometry was performed on day 28 after intraprostatic formalin injection or sham treatment. After cystometry, the bladder and prostate were harvested for evaluation of mRNA expression and histological analysis. RESULTS In cystometric investigation, the mean number of non-voiding contractions was significantly greater and voiding intervals were significantly shorter in formalin-vehicle rats than those in sham-saline rats (P < 0.05). In RT-qPCR analysis, mRNA expression of NGF, P2X2, and TRPA1 receptors was significantly increased in the bladder mucosa, and mRNA expression of TNF-α, iNOS and COX2 in the ventral lobes of prostate was significantly increased in formalin-vehicle rats compared with sham-saline rats (P < 0.05). In addition, relative mRNA expression ratio of ERβ to ERα (ERβ/ERα) in the

The Anti-Inflammatory Effects of a Yin Zhi Huang Soup in an Experimental Autoimmune Prostatitis Rat Model.

PubMed

Deng, Longsheng; Zhang, Xikui; Zhu, Weikun; Lu, Taikun; Chen, Jinchun; Zou, Qiang; Zheng, Qizhong; Chen, Junying; Jiang, Changming; Jin, Guanyu

2017-01-01

The present study aimed to investigate the therapeutic effects of the Chinese herbal medicine Yin Zhi Huang soup (YZS) in an experimental autoimmune prostatitis (EAP) rat model. In total, 48 rats were randomly divided into the following four groups ( n = 12/group): saline group, pathological model group, Qianlietai group, and YZS group. We determined the average wet weight of the prostate tissue, the ratio of the wet weight of the prostate tissue to body weight, tumor necrosis factor-alpha (TNF- α ) levels in the blood serum, the expression of inducible nitric oxide synthase (iNOS) in the rats' prostate tissues, and the pathological changes in the prostate tissue using light microscopy. YZS reduced the rats' prostate wet weight, the ratio of the prostate wet weight to body weight, and TNF- α levels in the blood serum and inhibited the expression of iNOS in the rats' prostate tissues ( P < 0.05). Following YZS treatment, the pathological changes in the rats' prostates were improved compared with those in the model group ( P < 0.05). Furthermore, YZS treatment reduced inflammatory changes in the prostate tissue. It also significantly suppressed proinflammatory cytokines, such as TNF- α , and chemokines, such as iNOS, in the rat model of EAP.

The Anti-Inflammatory Effects of a Yin Zhi Huang Soup in an Experimental Autoimmune Prostatitis Rat Model

PubMed Central

Zhang, Xikui; Zhu, Weikun; Lu, Taikun; Chen, Jinchun; Zou, Qiang; Zheng, Qizhong; Chen, Junying; Jiang, Changming; Jin, Guanyu

2017-01-01

The present study aimed to investigate the therapeutic effects of the Chinese herbal medicine Yin Zhi Huang soup (YZS) in an experimental autoimmune prostatitis (EAP) rat model. In total, 48 rats were randomly divided into the following four groups (n = 12/group): saline group, pathological model group, Qianlietai group, and YZS group. We determined the average wet weight of the prostate tissue, the ratio of the wet weight of the prostate tissue to body weight, tumor necrosis factor-alpha (TNF-α) levels in the blood serum, the expression of inducible nitric oxide synthase (iNOS) in the rats' prostate tissues, and the pathological changes in the prostate tissue using light microscopy. YZS reduced the rats' prostate wet weight, the ratio of the prostate wet weight to body weight, and TNF-α levels in the blood serum and inhibited the expression of iNOS in the rats' prostate tissues (P < 0.05). Following YZS treatment, the pathological changes in the rats' prostates were improved compared with those in the model group (P < 0.05). Furthermore, YZS treatment reduced inflammatory changes in the prostate tissue. It also significantly suppressed proinflammatory cytokines, such as TNF-α, and chemokines, such as iNOS, in the rat model of EAP. PMID:29430255

Studies of rhodamine-123: effect on rat prostate cancer and human prostate cancer cells in vitro.

PubMed

Arcadi, J A; Narayan, K S; Techy, G; Ng, C P; Saroufeem, R M; Jones, L W

1995-06-01

The effect of the lipophilic, cationic dye, Rhodamine-123 (Rh-123), on prostate cancer in rats, and on three tumor cell lines in vitro is reported here. The general toxicity of Rh-123 in mice has been found to be minimal. Lobund-Wistar (L-W) rats with the autochthonous prostate cancer of Pollard were treated for six doses with Rh-123 at a dose of 15 mg/kg subcutaneously every other day. Microscopic examination of the tumors revealed cellular and acinar destruction. The effectiveness of Rh-123 as a cytotoxic agent was tested by clonogenic and viability assays in vitro with three human prostate cancer cell lines. Severe (60-95%) growth inhibition was observed following Rh-123 exposure for 2-5 days at doses as low as 1.6 micrograms/ml in all three prostate cancer cell lines.

Caffeic acid phenethyl ester guards against benign prostate hypertrophy in rats: Role of IGF-1R/protein kinase-B (Akt)/β-catenin signaling.

PubMed

Omar, Hany A; Tolba, Mai F

2018-06-01

Benign prostate hypertrophy (BPH) is among the most common diseases with a huge impact on the quality of life of elderly men. There is a current need for the development of well-tolerated and effective preventive strategies to improve the clinical outcome. Caffeic acid phenethyl ester (CAPE) is an important active ingredient isolated from honey-bee propolis with potent anti-proliferative, anti-inflammatory and antioxidant effects. These properties promote CAPE as a promising candidate to be tested as an alternative therapy for BPH, which is still uninvestigated. Herein, we tested the ability of CAPE to guard against testosterone-induced BPH and investigated the involvement of IGF1-R/Akt/β-catenin signaling as a protective mechanism in testosterone-induced BPH rat model. Treatment with CAPE reduced testosterone-induced increase in the prostate index and histopathological alterations. In addition, co-treatment with CAPE significantly suppressed insulin-like growth factor-1 receptor (IGF-1R)/Akt/β-catenin/cyclinD1 axis as well as tumor necrosis factor-α level and nuclear factor (NF)-kB activity. Furthermore, the treatment with CAPE replenished the antioxidant defense systems, superoxide dismutase (SOD) and reduced glutathione (GSH) with subsequent reduction in prostate tissue lipid peroxides. This study highlights the potential merit of CAPE-enriched propolis formulations to protect elderly men against the development of BPH. © 2018 IUBMB Life, 70(6):519-528, 2018. © 2018 International Union of Biochemistry and Molecular Biology.

miR-888 is an expressed prostatic secretions-derived microRNA that promotes prostate cell growth and migration

PubMed Central

Lewis, Holly; Lance, Raymond; Troyer, Dean; Beydoun, Hind; Hadley, Melissa; Orians, Joseph; Benzine, Tiffany; Madric, Kenya; Semmes, O John; Drake, Richard; Esquela-Kerscher, Aurora

2014-01-01

microRNAs (miRNAs) are a growing class of small non-coding RNAs that exhibit widespread dysregulation in prostate cancer. We profiled miRNA expression in syngeneic human prostate cancer cell lines that differed in their metastatic potential in order to determine their role in aggressive prostate cancer. miR-888 was the most differentially expressed miRNA observed in human metastatic PC3-ML cells relative to non-invasive PC3-N cells, and its levels were higher in primary prostate tumors from cancer patients, particularly those with seminal vesicle invasion. We also examined a novel miRNA-based biomarker source called expressed prostatic secretions in urine (EPS urine) for miR-888 expression and found that its levels were preferentially elevated in prostate cancer patients with high-grade disease. These expression studies indicated a correlation for miR-888 in disease progression. We next tested how miR-888 regulated cancer-related pathways in vitro using human prostate cancer cell lines. Overexpression of miR-888 increased proliferation and migration, and conversely inhibition of miR-888 activity blocked these processes. miR-888 also increased colony formation in PC3-N and LNCaP cells, supporting an oncogenic role for this miRNA in the prostate. Our data indicates that miR-888 functions to promote prostate cancer progression and can suppress protein levels of the tumor suppressor genes RBL1 and SMAD4. This miRNA holds promise as a diagnostic tool using an innovative prostatic fluid source as well as a therapeutic target for aggressive prostate cancer. PMID:24200968

Quantitative Proteomic Profiling of Prostate Cancer Reveals a Role for miR-128 in Prostate Cancer*

PubMed Central

Khan, Amjad P.; Poisson, Laila M.; Bhat, Vadiraja B.; Fermin, Damian; Zhao, Rong; Kalyana-Sundaram, Shanker; Michailidis, George; Nesvizhskii, Alexey I.; Omenn, Gilbert S.; Chinnaiyan, Arul M.; Sreekumar, Arun

2010-01-01

Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of biomarkers of cancer invasion and disease aggressiveness. Although alterations in gene expression have been extensively quantified during neoplastic progression, complementary analyses of proteomic changes have been limited. Here we interrogate the proteomic alterations in a cohort of 15 prostate-derived tissues that included five each from adjacent benign prostate, clinically localized prostate cancer, and metastatic disease from distant sites. The experimental strategy couples isobaric tags for relative and absolute quantitation with multidimensional liquid phase peptide fractionation followed by tandem mass spectrometry. Over 1000 proteins were quantified across the specimens and delineated into clinically localized and metastatic prostate cancer-specific signatures. Included in these class-specific profiles were both proteins that were known to be dysregulated during prostate cancer progression and new ones defined by this study. Enrichment analysis of the prostate cancer-specific proteomic signature, to gain insight into the functional consequences of these alterations, revealed involvement of miR-128-a/b regulation during prostate cancer progression. This finding was validated using real time PCR analysis for microRNA transcript levels in an independent set of 15 clinical specimens. miR-128 levels were elevated in benign prostate epithelial cell lines compared with invasive prostate cancer cells. Knockdown of miR-128 induced invasion in benign prostate epithelial cells, whereas its overexpression attenuated invasion in prostate cancer cells. Taken together, our profiles of the proteomic alterations of prostate cancer progression revealed miR-128 as a potentially important negative regulator of prostate cancer cell invasion. PMID:19955085

The effects of high doses of nandrolone decanoate and exercise on prostate microvasculature of adult and older rats.

PubMed

de Melo Neto, João Simão; de Campos Gomes, Fabiana; Pinheiro, Patrícia Fernanda Felipe; Pereira, Sérgio; Scarano, Wellerson Rodrigo; Fávaro, Wagner José; Domeniconi, Raquel Fantin

2015-01-15

The present study aimed to investigate the effects of the interaction between the abusive use of nandrolone decanoate (ND) and physical activity on the prostate structure of adult and older rats. We evaluated whether the use of ND, associated or not with physical exercise during the post-pubertal stage, interferes with the morphophysiology of the prostate. Fifty-six male Sprague-Dawley rats were divided into eight groups. The animals were treated for eight weeks and divided into sedentary and trained groups, with or without ND use. Four groups were sacrificed 48 h after the end of the eight week experiment (adult groups), and four other groups were sacrificed at 300 days of age (older groups). The prostate was collected and processed for stereological and histopathological analysis and for the expression of AQP1 and VEGF by the Western blotting technique. Both ND and physical activity altered the ventral prostate structure of the rats; the AQP1 and VEGF expression increased in young animals subjected to physical exercise. Thus, it was concluded that the use of ND, associated or not with exercise during the post-pubertal stage, interferes with the morphophysiology of the prostate. Copyright © 2014 Elsevier Inc. All rights reserved.

Characteristics of recombinantly expressed rat and human histamine H3 receptors.

PubMed

Wulff, Birgitte S; Hastrup, Sven; Rimvall, Karin

2002-10-18

Human and rat histamine H(3) receptors were recombinantly expressed and characterized using receptor binding and a functional cAMP assay. Seven of nine agonists had similar affinities and potencies at the rat and human histamine H(3) receptor. S-alpha-methylhistamine had a significantly higher affinity and potency at the human than rat receptor, and for 4-[(1R*,2R*)-2-(5,5-dimethyl-1-hexynyl)cyclopropyl]-1H-imidazole (Perceptin) the preference was the reverse. Only two of six antagonists had similar affinities and potencies at the human and the rat histamine H(3) receptor. Ciproxifan, thioperamide and (1R*,2R*)-trans-2-imidazol-4 ylcyclopropyl) (cyclohexylmethoxy) carboxamide (GT2394) had significantly higher affinities and potencies at the rat than at the human histamine H(3) receptor, while for N-(4-chlorobenzyl)-N-(7-pyrrolodin-1-ylheptyl)guanidine (JB98064) the preference was the reverse. All antagonists also showed potent inverse agonism properties. Iodoproxyfan, Perceptin, proxyfan and GR175737, compounds previously described as histamine H(3) receptor antagonists, acted as full or partial agonists at both the rat and the human histamine H(3) receptor. Copyright 2002 Elsevier Science B.V.

Interaction of tomato lycopene and ketosamine against rat prostate tumorigenesis.

PubMed

Mossine, Valeri V; Chopra, Pankaj; Mawhinney, Thomas P

2008-06-01

Prior investigations on the beneficial effect of dietary processed tomato products and lycopene on prostate cancer risk suggested that lycopene may require the presence of other constituents to exert its chemopreventive potential. We investigated whether ketosamines, a group of carbohydrate derivatives present in dehydrated tomato products, may interact with lycopene against prostate tumorigenesis. One ketosamine, FruHis, strongly synergized with lycopene against proliferation of the highly metastatic rat prostate adenocarcinoma MAT-LyLu cell line in vitro. The FruHis/lycopene combination significantly inhibited in vivo tumor formation by MAT-LyLu cells in syngeneic Copenhagen rats. Energy-balanced diets, supplemented with tomato paste, tomato powder, or tomato paste plus FruHis, were fed to Wistar-Unilever rats (n = 20 per group) treated with N-nitroso-N-methylurea and testosterone to induce prostate carcinogenesis. Survival from carcinogenesis was lowest in the control group (median survival time, 40 weeks) and highest in the group fed the tomato paste/FruHis diet (51 weeks; P = 0.004, versus control). The proportions of dying rats with macroscopic prostate tumors in the control, tomato paste, tomato powder, and tomato paste/FruHis groups were 63% (12 of 19), 39% (5 of 13), 43% (6 of 14), and 18% (2 of 11), respectively. FruHis completely blocked DNA oxidative degradation at >250 micromol/L in vitro, whereas neither ascorbate nor phenolic antioxidants from tomato were effective protectors in this assay. FruHis, therefore, may exert tumor-preventive effect through its antioxidant activity and interaction with lycopene.

14 CFR 33.27 - Turbine, compressor, fan, and turbosupercharger rotors.

Code of Federal Regulations, 2011 CFR

2011-01-01

... TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: AIRCRAFT ENGINES Design and Construction; General § 33.27... service. (c) The most critically stressed rotor component (except blades) of each turbine, compressor, and... 14 Aeronautics and Space 1 2011-01-01 2011-01-01 false Turbine, compressor, fan, and...

14 CFR 33.27 - Turbine, compressor, fan, and turbosupercharger rotors.

Code of Federal Regulations, 2010 CFR

2010-01-01

... TRANSPORTATION AIRCRAFT AIRWORTHINESS STANDARDS: AIRCRAFT ENGINES Design and Construction; General § 33.27... service. (c) The most critically stressed rotor component (except blades) of each turbine, compressor, and... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Turbine, compressor, fan, and...

Effect of Benincasa hispida fruits on testosterone-induced prostatic hypertrophy in albino rats

PubMed Central

Nandecha, Chetan; Nahata, Alok; Dixit, Vinod Kumar

2010-01-01

Background: Benincasa hispida Cogn. has been used traditionally in India for the management of urinary disorders. The fruit of B hispida is used as a diuretic and the seeds have been reported to possess antiangiogenic effects in prostate cells. Objective: The aim of the present study was to examine the effect of petroleum ether extract, ethanolic extract, and B hispida seed oil on hyperplasia of the prostate induced by the subcutaneous administration of testosterone in rats. Methods: In vitro studies were performed to determine the 5α-reductase inhibitory potential of the extracts. The results of those studies paved the way for the pharmacologic screening of the extracts to assess their potential against testosterone-induced hyperplasia in rats. Nine groups containing 10 rats per group were created for this study. Hyperplasia was induced by administration of testosterone (3 mg/kg SC) for 14 days in all the groups except the vehicle-treated group. Simultaneous administration of petroleum ether extract (100 or 200 mg/kg PO), ethanolic extract (100 or 200 mg/kg PO), and B hispida seed oil (20 or 40 mg/kg PO) was conducted. A standard 5α-reductase inhibitor (ie, finasteride) was used as a positive control. The weight of the rats was recorded on day 0 (ie, day 1 of the study) and on day 14, and the influence of testosterone and test extracts on the weight of the rats was determined. On day 14, rats were euthanized; prostates were dissected out, and weighed. The rats' prostate/body weight (P/BW) ratio was then determined. Histologic examinations were performed on prostates from each group. Results: The petroleum ether extract as well as B hispida seed oil exhibited inhibition of 5α-reductase activity in in vitro studies. Ethanolic extract did not exhibit significant inhibitory potential in vitro. Further in vivo study found that testosterone treatment significantly increased the rats' P/BW ratio in all the groups except the vehicle-treated rats, and this increase in

Pharmacological characterization and chemical fractionation of a liposterolic extract of saw palmetto (Serenoa repens): effects on rat prostate contractility.

PubMed

Chua, Thiam; Eise, Nicole T; Simpson, Jamie S; Ventura, Sabatino

2014-03-14

Saw palmetto (Serenoa repens) was first used medicinally by native American Indians to treat urological disorders. Nowadays, saw palmetto extracts are widely used in Europe and North America to treat the urinary symptoms associated with benign prostatic hyperplasia even though its mechanisms of action are poorly understood. This study aimed to characterize the bioactive constituents of a lipid extract of saw palmetto that are able to affect contractility of the rat prostate gland. The mechanism of action will also be investigated. A commercially available lipid extract of saw palmetto was subjected to fractionation using normal phase column chromatography. Composition of fractions was assessed by proton nuclear magnetic resonance spectroscopy ((1)H NMR) and mass spectrometry (MS). Contractile activities of these fractions were evaluated pharmacologically using isolated preparations of rat prostate gland and compared to the activity of the crude extract. Saw palmetto extract inhibited contractions of the rat prostate gland which were consistent with smooth muscle relaxant activity. Only the ethyl acetate fraction resulting from chromatography inhibited contractions of isolated rat prostates similarly to the inhibition produced by the crude lipid extract. Comparison with authentic samples and analysis of NMR data revealed that this bioactivity was due to the fatty acid components present in the ethyl acetate fraction. Bioassay using various pharmacological tools identified multiple contractile mechanisms which were affected by the bioactive constituents. A fatty acid component of saw palmetto extract causes inhibition of prostatic smooth muscle contractions via a non-specific mechanism. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Preventive effects of ACTICOA powder, a cocoa polyphenolic extract, on experimentally induced prostate hyperplasia in Wistar-Unilever rats.

PubMed

Bisson, Jean-François; Hidalgo, Sophie; Rozan, Pascale; Messaoudi, Michaël

2007-12-01

Plant extracts are useful in the management of benign prostatic hyperplasia (BPH). This study investigates whether ACTICOA (Barry Callebaut France, Louviers, France) powder (AP), a cocoa polyphenolic extract, could prevent prostate hyperplasia induced by testosterone propionate (TP) in rats. Male Wistar-Unilever rats were randomly divided in four groups of 12 rats: one negative control group receiving subcutaneous injections of corn oil and treated with vehicle and three groups injected subcutaneously with TP and treated with the vehicle (positive control) or AP at 24 (AP24) and 48 (AP48) mg/kg/day. Treatments were given orally and started 2 weeks before the induction of prostate hyperplasia. The influence of TP and AP on body weights and food and water consumption of rats was examined. On day 36, rats were sacrificed, and the prostates were removed, cleaned, and weighed. The prostate size ratio (prostate weight/rat body weight) was then calculated. TP significantly influenced the body weight gain of the rats and their food and water consumption, while AP at both doses tested reduced significantly these differences. TP significantly increased prostate size ratio (P < .001), and this induced increase was significantly inhibited in AP-treated rats in comparison with positive controls (P < .001) in a dose-dependent manner. We conclude that AP can prevent TP-induced prostate hyperplasia and therefore may be beneficial in the management of BPH.

Onion and garlic extracts as potential antidotes for cadmium-induced biochemical alterations in prostate glands of rats.

PubMed

Ola-Mudathir, F K; Suru, S M

2015-11-01

Cadmium (Cd) has been implicated in increased prostate gland malignancy risk in both wildlife and humans. This study examines the chemoprotective roles of onion and garlic extracts on Cd-induced biochemical alterations in the prostate glands of rats. Adult male Wistar rats were randomly divided into nine groups: control group received double distilled water; Cd group received Cd alone (1.5 mg/100 g bwt per day); extract-treated groups were pre-treated with varied doses of onion and/or garlic extract (0.5 ml and 1.0 ml/100 g bwt per day) for 1 week and then co-treated with Cd (1.5 mg/100 g bwt per day) for additional 3 weeks. Oxidant/antioxidant status and acid phosphatase (ACPtotal and ACPprostatic ) activity were examined in prostate glands. Cd intoxication caused a marked (P < 0.001) increase in lipid peroxidation (LPO) and glutathione S-transferase (GST) levels, whereas glutathione (GSH), superoxide dismutase and catalase levels were markedly (P < 0.001) decreased. We also observed significant (P < 0.001) decrease in ACPtotal and ACPprostatic activities in prostate glands and a concomitant significant (P < 0.001) increase in the plasma. However, treatment of Cd-intoxicated rats with onion and/or garlic extract significantly minimised these alterations. The onion extract offered a dose-dependent protection. Our findings suggest a chemoprotective capability for onion and garlic extracts against Cd-induced biochemical alteration in the prostate glands. © 2014 Blackwell Verlag GmbH.

Preventive Effects of Fermented Brown Rice and Rice Bran against Prostate Carcinogenesis in TRAP Rats.

PubMed

Kuno, Toshiya; Nagano, Aya; Mori, Yukiko; Kato, Hiroyuki; Nagayasu, Yuko; Naiki-Ito, Aya; Suzuki, Shugo; Mori, Hideki; Takahashi, Satoru

2016-07-11

Fermented brown rice and rice bran with Aspergillus oryzae (FBRA) is considered to have the potential to prevent chemically-induced carcinogenesis in multiple organs of rodents. In the present study, we evaluated the possible chemopreventive effects of FBRA against prostate tumorigenesis. Six-week-old male rats of the transgenic rat for adenocarcinoma of prostate (TRAP) strain were fed diets containing 5% or 10% FBRA for 15 weeks. Animals were sacrificed at 21 weeks of age, and the ventral and lateral prostate were removed for histopathological evaluation and immunoblot analyses. FBRA decreased the incidence of adenocarcinoma in the lateral prostate and suppressed the progression of prostate carcinogenesis. Treatment with FBRA induced apoptosis and inhibited cell proliferation in histologically high-grade prostatic intraepithelial neoplasias. Phospho-AMP-activated kinase α (Thr172) was up-regulated in the prostate of rats fed the diet supplemented with FBRA. These results indicate that FBRA controls tumor growth by activating pathways responsive to energy deprivation and suggest that FBRA has translational potential for the prevention of human prostate cancer.

Graminex Pollen: Phenolic Pattern, Colorimetric Analysis and Protective Effects in Immortalized Prostate Cells (PC3) and Rat Prostate Challenged with LPS.

PubMed

Locatelli, Marcello; Macchione, Nicola; Ferrante, Claudio; Chiavaroli, Annalisa; Recinella, Lucia; Carradori, Simone; Zengin, Gokhan; Cesa, Stefania; Leporini, Lidia; Leone, Sheila; Brunetti, Luigi; Menghini, Luigi; Orlando, Giustino

2018-05-11

Prostatitis, a general term describing prostate inflammation, is a common disease that could be sustained by bacterial or non-bacterial infectious agents. The efficacy of herbal extracts with antioxidant and anti-inflammatory effects for blunting the burden of inflammation and oxidative stress, with possible improvements in clinical symptoms, is under investigation. Pollen extracts have been previously reported as promising agents in managing clinical symptoms related to prostatitis. The aim of the present work was to evaluate the protective effects of Graminex pollen (Graminex TM , Deshler, OH, USA), a commercially available product based on standardized pollen extracts, in rat prostate specimens, ex vivo. In this context, we studied the putative mechanism of action of pollen on multiple inflammatory pathways, including the reduction of prostaglandin E₂ (PGE₂), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and malondialdehyde (MDA), whose activities were significantly increased by inflammatory stimuli. We characterized by means of chromatographic and colorimetric studies the composition of Graminex pollen to better correlate the activity of pollen on immortalized prostate cells (PC3), and in rat prostate specimens challenged with Escherichia coli lipopolysaccharide (LPS). We found that Graminex pollen was able to reduce radical oxygen species (ROS) production by PC3 cells and MDA, NFκB mRNA, and PGE₂ levels, in rat prostate specimens. According to our experimental evidence, Graminex pollen appears to be a promising natural product for the management of the inflammatory components in the prostate.

Chemoprevention of hormone-dependent prostate cancer in the Wistar-Unilever rat.

PubMed

McCormick, D L; Rao, K V

1999-01-01

The high incidence and long latent period of prostate cancer make it an ideal target for chemoprevention. We have evaluated a series of agents for chemopreventive efficacy using a model in which hormone-dependent prostate cancers are induced in the Wistar-Unilever (WU) rat by sequential treatment with antiandrogen (cyproterone acetate), androgen (testosterone propionate), and direct-acting chemical carcinogen (N-methyl-N-nitrosourea), followed by chronic androgen stimulation (testosterone). This regimen reproducibly induces prostate cancers in high incidence, with no gross toxicity and a low incidence of neoplasia in the seminal vesicle and other non-target tissues. Dehydroepiandrosterone (DHEA) and 9-cis-retinoic acid (9-cis-RA) are the most active agents identified to date. DHEA inhibits prostate cancer induction both when chronic administration is begun prior to carcinogen exposure, and when administration is delayed until preneoplastic prostate lesions are present. 9-cis-RA is the most potent inhibitor of prostate carcinogenesis identified; a study to determine the efficacy of delayed administration of 9-cis-RA is in progress. Liarozole fumarate confers modest protection against prostate carcinogenesis, while N-(4-hydroxyphenyl)retinamide (fenretinide), alpha-difluoromethylornithine, oltipraz, DL-alpha-tocopherol acetate (vitamin E), and L-selenomethionine are inactive. Chemoprevention efficacy evaluations in the WU rat will support the identification of agents that merit study for prostate cancer chemoprevention in humans.

Therapeutic effect of ACTICOA powder, a cocoa polyphenolic extract, on experimentally induced prostate hyperplasia in Wistar-Unilever rats.

PubMed

Bisson, Jean-François; Hidalgo, Sophie; Rozan, Pascale; Messaoudi, Michaël

2007-12-01

Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of the prostate that results in obstructive lower urinary tract symptoms. Plant extracts are frequently used to treat BPH rather than therapeutics that can cause severe side effects. ACTICOA() (Ba0rry Callebaut France, Louviers, France) powder (AP) is a cocoa polyphenolic extract, and we have shown in a previous study that oral treatment with AP prevented prostate hyperplasia. This study investigated whether AP could improve established prostate hyperplasia using the same testosterone propionate (TP)-induced prostate hyperplasia model in rats. Male Wistar-Unilever rats were randomly divided in four groups of 12 rats: one group injected with corn oil and orally treated with the vehicle (negative control) and three groups injected subcutaneously with TP and orally treated with the vehicle (positive control) or AP at 24 (AP24) and 48 (AP48) mg/kg/day. Treatments started 1 week after the start of the induction of prostate hyperplasia and lasted for 2 weeks. The influence of TP and AP on body weights, food and water consumptions, plasma polyphenolic concentration, and serum dihydrotestoterone (DHT) level of rats was examined. At completion of the study, rats were sacrificed, and the prostates were removed, cleaned, and weighed. The prostate size ratio (prostate weight/rat body weight) was then calculated. TP significantly influenced the body weight gain of the rats and their food and water consumptions, while AP reduced significantly these differences in a dose-dependent manner. AP significantly reduced serum DHT level and prostate size ratio in comparison with positive controls also dose-dependently. In conclusion, AP orally administered was effective for reducing established prostate hyperplasia, especially at the dose of 48 mg/kg/day.

Therapeutic effect of melittin on a rat model of chronic prostatitis induced by Complete Freund's Adjuvant.

PubMed

Lin, Li; Zhu, Bao-Ping; Cai, Liang

2017-06-01

The present study was aimed to establish a model of chronic prostatitis in rat with the use of intraprostatic injection of Complete Freund's Adjuvant, and to examine the anti-inflammatory and analgesic effects of melittin on the newly-developed chronic prostatic pain model. Adult male Sprague-Dawley rats were injected with Complete Freund's Adjuvant (CFA) into the prostate. Twelve days after model rats of the treatment group were injected melittin into the prostate, while those of the control group received sterile saline injection. The nociceptive effects of CFA were evaluated by using a behavior approach (i.e. mechanical pain threshold measurement) on the day of CFA injection and 6, 12, and 18days after CFA injection. After the in-live study was done, the prostate was collected for histological examination of inflammatory cell infiltration. Levels of cyclooxygenase (COX)-2 in prostate and glial fibrillary acidic protein (GFAP) in spinal cord were determined using immunohistochemistry. Rats of the sham control group received intraprostatic injection of sterile saline and were studied using the same methods RESULTS: Intraprostatic CFA injection induced local allodynia that lasted over at least 2 weeks. The pain behavior of rat was associated with increases in inflammatory cell infiltration into the prostate. Levels of COX-2 in prostate and GFAP in spinal cord were also elevated. Treatment with melittin significantly raised pain threshold, decreased inflammatory infiltrates, and suppressed COX-2 and GFAP expression. Intraprostatic injection of CFA induced neurogenic prostatitis and prostatic pain. The established model will be useful to the study of CP/CPPS pathogenesis. Melittin demonstrated profound anti-inflammatory and analgesic effects on the chronic prostatic pain model, suggesting melittin may hold promise as a novel therapeutic for treatment of CP/CPPS. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Investigation of the effect of traditional Chinese medicine on pain and inflammation in chronic nonbacterial prostatitis in rats.

PubMed

Liu, Y-J; Song, G-H; Liu, G T

2016-08-01

According to traditional Chinese medicine, the symptoms of chronic nonbacterial prostatitis/chronic pelvic pain syndrome (CNP/CPPS) may be treated using a cocktail of herbs that stimulate blood circulation ('activating blood circulation formula'). We investigated the effect of three doses of this formula on a rat model of CNP/CPPS. Male Wistar rats were injected with a saline extract of male sex accessory glands on days 0 and 30 to induce prostatitis and then treated daily by gavage between days 32 and 60. Treatment with low, medium and high doses of activating blood circulation formula resulted in an almost total rescue of paw withdrawal threshold at day 60, and treatment with the highest dose also significantly decreased prostate inflammation (assessed histopathologically). We further observed elevated serum prostaglandin E2 levels in the CNP/CPPS model which decreased upon high-dose treatment, and increased Cox-2 expression in the prostate and spinal cord dorsal horn which was rescued in both tissues in the high-dose group and in the prostate in the medium-dose group. These results shed light on a possible mechanism by which activating blood circulation therapy may alleviate pain in a rat model of CNP/CPPS by downregulating Cox-2 expression in the spinal cord, thereby raising the pain threshold. Further research will be needed to fully characterise the mechanism by which activating blood circulation therapy produces this therapeutic effect. © 2016 Blackwell Verlag GmbH.

Molecular classification of benign prostatic hyperplasia: A gene expression profiling study in a rat model.

PubMed

Hata, Junya; Satoh, Yuichi; Akaihata, Hidenori; Hiraki, Hiroyuki; Ogawa, Soichiro; Haga, Nobuhiro; Ishibashi, Kei; Aikawa, Ken; Kojima, Yoshiyuki

2016-07-01

To characterize the molecular features of benign prostatic hyperplasia by carrying out a gene expression profiling analysis in a rat model. Fetal urogenital sinus isolated from 20-day-old male rat embryo was implanted into a pubertal male rat ventral prostate. The implanted urogenital sinus grew time-dependently, and the pathological findings at 3 weeks after implantation showed epithelial hyperplasia as well as stromal hyperplasia. Whole-genome oligonucleotide microarray analysis utilizing approximately 30 000 oligonucleotide probes was carried out using prostate specimens during the prostate growth process (3 weeks after implantation). Microarray analyses showed 926 upregulated (>2-fold change, P < 0.01) and 3217 downregulated genes (<0.5-fold change, P < 0.01) in benign prostatic hyperplasia specimens compared with normal prostate. Gene ontology analyses of upregulated genes showed predominant genetic themes of involvement in development (162 genes, P = 2.01 × 10(-4) ), response to stimulus (163 genes, P = 7.37 × 10(-13) ) and growth (32 genes, P = 1.93 × 10(-5) ). When we used both normal prostate and non-transplanted urogenital sinuses as controls to identify benign prostatic hyperplasia-specific genes, 507 and 406 genes were upregulated and downregulated, respectively. Functional network and pathway analyses showed that genes associated with apoptosis modulation by heat shock protein 70, interleukin-1, interleukin-2 and interleukin-5 signaling pathways, KIT signaling pathway, and secretin-like G-protein-coupled receptors, class B, were relatively activated during the growth process in the benign prostatic hyperplasia specimens. In contrast, genes associated with cholesterol biosynthesis were relatively inactivated. Our microarray analyses of the benign prostatic hyperplasia model rat might aid in clarifying the molecular mechanism of benign prostatic hyperplasia progression, and identifying molecular targets for benign prostatic hyperplasia treatment. �

Effect of Tripterygium Wilfordii Polyglycoside on Experimental Prostatitis Caused by Ureaplasma Urealyticum in Rats

PubMed Central

Shan, Pingnan; Lu, Zhiyong; Ye, Lihong; Fang, Yaqin; Tan, Suhong; Xuan, Guohong; Ru, Jincheng; Mao, Liming

2016-01-01

Background Prostatitis is a common and refractory urological disease with complicated etiology. Ureaplasma urealyticum (UU) has a close relationship with human urinary tract infection that can induce nonbacterial prostatitis. Tripterygium wilfordii polyglycoside (TWP) is a non-steroidal immune inhibitor that causes significant immune suppression and anti-inflammatory effects. Its role in prostatitis caused by UU has not yet been established. The aim of this study was to investigate the effect of TWP on UU-infected prostatitis in a rat model. Material/Methods UU-infected prostatitis SD model rats were randomly divided into 2 groups: the prostatitis group (model group) and the TWP treatment group (treatment group). At 7 days after treatment, prostate weight, leucocyte count, lecithin corpuscles, UU infection rate, and UU microbe count were compared between the 2 groups. Serum inflammatory cytokines TNF-α was determined by ELISA, and ICAM-1 and NF-κB expression were detected. Results UU infection rate was 80% after modeling. The rat prostate weight and leucocyte count in the model group increased significantly, while lecithin corpuscles decreased. Compared with controls, inflammatory factor TNF-α, ICAM-1, and NF-κB expression were obviously higher (P<0.05). TWP markedly reduced prostate weight and leucocyte count, increased lecithin corpuscles, and decreased UU microbe count and TNF-α, ICAM-1, and NF-κB expression (P<0.05). Conclusions TWP can inhibit expression of inflammatory factors and may be useful in treating UU-infected prostatitis through reducing UU infection rate. PMID:27743513

Effect of Tripterygium Wilfordii Polyglycoside on Experimental Prostatitis Caused by Ureaplasma Urealyticum in Rats.

PubMed

Shan, Pingnan; Lu, Zhiyong; Ye, Lihong; Fang, Yaqin; Tan, Suhong; Xuan, Guohong; Ru, Jincheng; Mao, Liming

2016-10-15

BACKGROUND Prostatitis is a common and refractory urological disease with complicated etiology. Ureaplasma urealyticum (UU) has a close relationship with human urinary tract infection that can induce nonbacterial prostatitis. Tripterygium wilfordii polyglycoside (TWP) is a non-steroidal immune inhibitor that causes significant immune suppression and anti-inflammatory effects. Its role in prostatitis caused by UU has not yet been established. The aim of this study was to investigate the effect of TWP on UU-infected prostatitis in a rat model. MATERIAL AND METHODS UU-infected prostatitis SD model rats were randomly divided into 2 groups: the prostatitis group (model group) and the TWP treatment group (treatment group). At 7 days after treatment, prostate weight, leucocyte count, lecithin corpuscles, UU infection rate, and UU microbe count were compared between the 2 groups. Serum inflammatory cytokines TNF-α was determined by ELISA, and ICAM-1 and NF-κB expression were detected. RESULTS UU infection rate was 80% after modeling. The rat prostate weight and leucocyte count in the model group increased significantly, while lecithin corpuscles decreased. Compared with controls, inflammatory factor TNF-α, ICAM-1, and NF-κB expression were obviously higher (P<0.05). TWP markedly reduced prostate weight and leucocyte count, increased lecithin corpuscles, and decreased UU microbe count and TNF-α, ICAM-1, and NF-κB expression (P<0.05). CONCLUSIONS TWP can inhibit expression of inflammatory factors and may be useful in treating UU-infected prostatitis through reducing UU infection rate.

Regulation of 5alpha-reductase isoforms by oxytocin in the rat ventral prostate.

PubMed

Assinder, S J; Johnson, C; King, K; Nicholson, H D

2004-12-01

Oxytocin (OT) is present in the male reproductive tract, where it is known to modulate contractility, cell growth, and steroidogenesis. Little is known about how OT regulates these processes. This study describes the localization of OT receptor in the rat ventral prostate and investigates if OT regulates gene expression and/or activity of 5alpha-reductase isoforms I and II. The ventral prostates of adult male Wistar rats were collected following daily sc administration of saline (control), OT, a specific OT antagonist or both OT plus antagonist for 3 d. Expression of the OT receptor was identified in the ventral prostate by RT-PCR and Western blot, and confirmed to be a single active binding site by radioreceptor assay. Immunohistochemistry localized the receptor to the epithelium of prostatic acini and to the stromal tissue. Real-time RT-PCR determined that OT treatment significantly reduced expression of 5alpha-reductase I but significantly increased 5alpha-reductase II expression in the ventral prostate. Activity of both isoforms of 5alpha-reductase was significantly increased by OT, resulting in increased concentration of prostatic dihydrotestosterone. In conclusion, OT is involved in regulating conversion of testosterone to the biologically active dihydrotestosterone in the rat ventral prostate. It does so by differential regulation of 5alpha-reductase isoforms I and II.

Proton MRS detects metabolic changes in hormone sensitive and resistant human prostate cancer models CWR22 and CWR22r.

PubMed

Le, H Carl; Lupu, Mihaela; Kotedia, Khushali; Rosen, Neal; Solit, David; Koutcher, Jason A

2009-11-01

17-Allylamino, 17-demethoxygeldanamycin (17-AAG), an effective inhibitor of the heat shock protein hsp90, preferentially inhibiting tumor hsp90 compared to hsp90 from normal cells, has shown promising results against several cancers, including hormone-resistant prostate cancer. Levels of several oncogenic proteins critical to tumor growth and progression, such as androgen receptor and HER2/neu, were reduced 4 h post 17-allylamino, 17-demethoxygeldanamycin treatment. Posttreatment metabolic changes have also been observed in several tumor cell lines. In this study, total choline distributions in hormone sensitive CWR22 and hormone resistant CWR22r prostate cancer xenograft tumors in mice were measured before and at 4 h and 48 h after a single-bolus 17-allylamino, 17-demethoxygeldanamycin treatment at 100 mg/kg, using proton MR spectroscopy. Our results show that tumor total choline levels declined 4 h after the treatment for CWR22 (P = 0.001) and 48 h post treatment for CWR22r (P = 0.003). Metabolic changes, in particular of total choline intensity detected by proton magnetic resonance spectroscopic imaging (MRSI), are consistent with the observed immunohistochemistry changes, tumor growth inhibition for CWR22r (P = 0.01 at 14 days post treatment), and a constant prostate specific antigen level versus increasing prostate specific antigen for control CWR22 (P = 0.01). Metabolic changes in total choline by proton MRSI can be used as an early biomarker of response for advanced-stage prostate cancer in targeted therapy such as 17-allylamino, 17-demethoxygeldanamycin. (c) 2009 Wiley-Liss, Inc.

Chemoprevention of rat prostate carcinogenesis by soy isoflavones and by Bowman-Birk inhibitor.

PubMed

McCormick, David L; Johnson, William D; Bosland, Maarten C; Lubet, Ronald A; Steele, Vernon E

2007-01-01

Epidemiology studies suggest that soy consumption confers protection against human prostate cancer. To identify the soy component(s) that may be responsible for this chemopreventive activity, studies were conducted to determine the influence of a soy isoflavone mixture (PTI G-2535; 45% genistein, 22% daidzein, 2% glycitein) and a soy-derived protease inhibitor (Bowman-Birk Inhibitor Concentrate; BBIC) on prostate carcinogenesis in rats. Prostate cancers were induced in male Wistar-Unilever rats by a sequential regimen of cyproterone acetate and testosterone propionate, followed by a single intravenous injection of N-methyl-N-nitrosourea (MNU) and chronic androgen stimulation. In separate studies, PTI G-2535 and BBIC were administered continuously at 0 (control), 200, or 2000 mg/kg diet, beginning 1 wk post-MNU. PTI G-2535 and BBIC both conferred modest, but statistically significant and dose-related protection against carcinogenesis in the dorsolateral+anterior prostate. These data demonstrate that both the isoflavone and protein (protease inhibitor) components of soy can inhibit prostate carcinogenesis in the rat. However, the modest individual activities of soy isoflavones and BBIC suggest that while both components may contribute to the chemopreventive activity of soy, combination administration (or exposure to whole soy) may be more effective in prostate cancer prevention than is administration of either component alone.

miR-618 Inhibits Prostate Cancer Migration and Invasion by Targeting FOXP2.

PubMed

Song, Xian-Lu; Tang, Yao; Lei, Xiang-Hui; Zhao, Shan-Chao; Wu, Zi-Qing

2017-01-01

miRNAs play critical role in the development and progression of prostate cancer. Here we studied the role of miR-618 in prostate cancer migration and invasion. miR-618 was downregulated in metastatic androgen-independent prostate cancer (AIPC), patients with low miR-618 had poor outcome. Overexpression of miR-618 inhibited migration and invasion and induced mesenchymal to epithelial transition (MET). Conversely, knockdown of miR-618 promoted migration and invasion and induced epithelial to mesenchymal transition (EMT). FOXP2 was the direct target of miR-618, and promoted TGF-β expression, inhibition of TGF-β reversed the effect of miR-618 knockdown. We further analyzed the correlation between miR-618 expression and FOXP2 in human prostate cancer tissues, and found there was a negative correlation between miR-618 expression and FOXP2 levels. In conclusion, we found miR-618 inhibited prostate cancer migration and invasion by targeting FOXP2 and inhibiting TGF-β.

P110β Inhibition Reduces Histone H3K4 Di-Methylation in Prostate Cancer.

PubMed

Pang, Jun; Yang, Yue-Wu; Huang, Yiling; Yang, Jun; Zhang, Hao; Chen, Ruibao; Dong, Liang; Huang, Yan; Wang, Dongying; Liu, Jihong; Li, Benyi

2017-02-01

Epigenetic alteration plays a major role in the development and progression of human cancers, including prostate cancer. Histones are the key factors in modulating gene accessibility to transcription factors and post-translational modification of the histone N-terminal tail including methylation is associated with either transcriptional activation (H3K4me2) or repression (H3K9me3). Furthermore, phosphoinositide 3-kinase (PI3 K) signaling and the androgen receptor (AR) are the key determinants in prostate cancer development and progression. We recently showed that prostate-targeted nano-micelles loaded with PI3 K/p110beta specific inhibitor TGX221 blocked prostate cancer growth in vitro and in vivo. Our objective of this study was to determine the role of PI3 K signaling in histone methylation in prostate cancer, with emphasis on histone H3K4 methylation. PI3 K non-specific inhibitor LY294002 and p110beta-specific inhibitor TGX221 were used to block PI3 K/p110beta signaling. The global levels of H3K4 and H3K9 methylation in prostate cancer cells and tissue specimens were evaluated by Western blot assay and immunohistochemical staining. A synthetic androgen R1881 was used to stimulate AR activity in prostate cancer cells. A castration-resistant prostate cancer (CRPC) specific human tissue microarray (TMA) was used to assess the global levels of H3K4me2 methylation by immunostaining approach. Our data revealed that H3K4me2 levels were significantly elevated after androgen stimulation. With RNA silencing and pharmacology approaches, we further defined that inhibition of PI3 K/p110beta activity through gene-specific knocking down and small chemical inhibitor TGX221 abolished androgen-stimulated H3K4me2 methylation. Consistently, prostate cancer-targeted delivery of TGX221 in vivo dramatically reduced the global levels of H3K4me2 as assessed by immunohistochemical staining on tissue section of mouse xenografts from CRPC cell lines 22RV1 and C4-2. Finally

Protective effect of Acticoa powder, a cocoa polyphenolic extract, on prostate carcinogenesis in Wistar-Unilever rats.

PubMed

Bisson, Jean-François; Guardia-Llorens, Maria-Alba; Hidalgo, Sophie; Rozan, Pascale; Messaoudi, Michaël

2008-02-01

The effects of Acticoa powder on prostate carcinogenesis were investigated using the N-methylnitrosourea and testosterone propionate prostate tumor model. Sixty male Wistar-Unilever rats were randomly divided in four groups of 15 rats: one control group not induced but treated with vehicle (not induced+vehicle) and three chemo-induced groups. Two weeks before prostate tumor induction and then throughout the experiment, chemo-induced rats were orally treated with Acticoa powder at 24 (chemo-induced+Acticoa powder24) or 48 (chemo-induced+Acticoa powder48) mg/kg or with vehicle (chemo-induced+vehicle), daily from Monday to Friday. Survival, body weight, food and water consumption were recorded throughout the experiment. Six rats per group were randomly killed 9 months after the prostate tumor induction for histopathological analysis of prostates. A reduction in the incidence of prostate tumors was observed for the chemo-induced+Acticoa powder48-treated group in comparison with the chemo-induced+vehicle-treated group and no tumors were observed in the chemo-induced+Acticoa powder24-treated group as in the not induced+vehicle-treated group after 9 months. The nine remaining rats per group were maintained in a long-term survival study. The life span of the chemo-induced+Acticoa powder24-treated group was significantly increased in comparison with the chemo-induced+Acticoa powder48 and the chemo-induced+vehicle-treated groups, close to the one of the not induced+vehicle-treated group. A significant reduction in the incidence of prostate tumors was also observed for the chemo-induced+Acticoa powder24 and chemo-induced+Acticoa powder48-treated groups in comparison with the chemo-induced+vehicle-treated group. In conclusion, Acticoa powder at 24 mg/kg protected rats from prostate carcinogenesis when chronically given before the initiation and promotion phases of induction.

Inhibition of 5α-Reductase in Rat Prostate Reveals Differential Regulation of Androgen-Response Gene Expression by Testosterone and Dihydrotestosterone

PubMed Central

Dadras, Soheil S.; Cai, Xiaoyan; Abasolo, Ibane; Wang, Zhou

2001-01-01

The growth and development of some of the male sex accessory organs such as the prostate requires the conversion of testosterone to dihydrotestosterone (DHT) by 5α-reductase. To provide insights into the role of testosterone versus DHT in the prostate, we studied the impact of finasteride, a potent and specific inhibitor of 5α-reductase, on the expression of prostatic androgen-response genes in testis-intact rats and in 7-day castrated rats. Finasteride inhibition of the conversion of testosterone to DHT was confirmed by measuring serum and intraprostatic androgens. As expected, finasteride treatment caused a reduction in the wet weight of the prostate in the testis-intact rats and inhibited the testosterone-stimulated prostatic regrowth in the 7-day castrated rats. Although finasteride treatment had little or no effect on the expression of the surveyed androgen-response genes in testis-intact rats, its administration enhanced the expression of many androgen-response genes during the testosterone-stimulated regrowth of the regressed prostate in castrated rats. These observations suggest that testosterone is more potent than DHT in stimulating the expression of many androgen-response genes in the regressed prostate. The expression of androgen-response genes is mainly prostate specific and thus is likely to be associated with androgen-dependent prostatic differentiation. Therefore, testosterone is more potent than DHT in inducing differentiation and weaker in stimulating proliferation during prostate regrowth. The fact that testosterone is a strong inducer of prostatic differentiation has potential clinical implications. PMID:11444528

Biosynthesis of putrescine in the prostate gland of the rat

PubMed Central

Pegg, A. E.; Williams-Ashman, H. G.

1968-01-01

In the rat ventral prostate gland the biosynthesis of putrescine, a precursor of spermidine and spermine, is shown to occur by the direct decarboxylation of l-ornithine. Some properties of a soluble pyridoxal phosphate-dependent l-ornithine decarboxylase are described. The findings are discussed in relation to other enzymic reactions involved in the biosynthesis of polyamines by the prostate gland. PMID:5667265

Inhibition of growth of experimental prostate cancer with sustained delivery systems (microcapsules and microgranules) of the luteinizing hormone-releasing hormone antagonist SB-75.

PubMed Central

Korkut, E; Bokser, L; Comaru-Schally, A M; Groot, K; Schally, A V

1991-01-01

Inhibitory effects of the sustained delivery systems (microcapsules and microgranules) of a potent antagonist of luteinizing hormone-releasing hormone N-Ac-[3-(2-naphthyl)-D-alanine1, 4-chloro-D-phenylalanine2, 3-(3-pyridyl)-D-alanine3, D-citrulline6, D-alanine10]LH-RH (SB-75) on the growth of experimental prostate cancers were investigated. In the first experiment, three doses of a microcapsule preparation releasing 23.8, 47.6, and 71.4 micrograms of antagonist SB-75 per day were compared with microcapsules of agonist [D-Trp6]LH-RH liberating 25 micrograms/day in rats bearing Dunning R3327H transplantable prostate carcinoma. During 8 weeks of treatment, tumor growth was decreased by [D-Trp6]LH-RH and all three doses of SB-75 as compared to untreated controls. The highest dose of SB-75 (71.4 micrograms/day) caused a greater inhibition of prostate cancer growth than [D-Trp6]LH-RH as based on measurement of tumor volume and percentage change in tumor volume. Doses of 23.8 and 47.6 micrograms of SB-75 per day induced a partial and submaximal decrease, respectively, in tumor weight and volume. Tumor doubling time was the longest (50 days) with the high dose of SB-75 vs. 15 days for controls. The body weights were unchanged. The weights of testes, seminal vesicles, and ventral prostate were greatly reduced in all three groups that received SB-75, and testosterone levels were decreased to nondetectable values in the case of the two higher doses of SB-75. LH levels were also diminished. Similar results were obtained in the second experiment, in which the animals were treated for a period of 8 weeks with microgranules of SB-75. Therapy with microgranules of SB-75 significantly decreased tumor growth as measured by the final tumor volume, the percentage change from the initial tumor volume, and the reduction in tumor weight. The results indicate that antagonist SB-75, released from sustained delivery systems, can produce a state of chemical castration and effectively

Inhibition of growth of experimental prostate cancer with sustained delivery systems (microcapsules and microgranules) of the luteinizing hormone-releasing hormone antagonist SB-75.

PubMed

Korkut, E; Bokser, L; Comaru-Schally, A M; Groot, K; Schally, A V

1991-02-01

Inhibitory effects of the sustained delivery systems (microcapsules and microgranules) of a potent antagonist of luteinizing hormone-releasing hormone N-Ac-[3-(2-naphthyl)-D-alanine1, 4-chloro-D-phenylalanine2, 3-(3-pyridyl)-D-alanine3, D-citrulline6, D-alanine10]LH-RH (SB-75) on the growth of experimental prostate cancers were investigated. In the first experiment, three doses of a microcapsule preparation releasing 23.8, 47.6, and 71.4 micrograms of antagonist SB-75 per day were compared with microcapsules of agonist [D-Trp6]LH-RH liberating 25 micrograms/day in rats bearing Dunning R3327H transplantable prostate carcinoma. During 8 weeks of treatment, tumor growth was decreased by [D-Trp6]LH-RH and all three doses of SB-75 as compared to untreated controls. The highest dose of SB-75 (71.4 micrograms/day) caused a greater inhibition of prostate cancer growth than [D-Trp6]LH-RH as based on measurement of tumor volume and percentage change in tumor volume. Doses of 23.8 and 47.6 micrograms of SB-75 per day induced a partial and submaximal decrease, respectively, in tumor weight and volume. Tumor doubling time was the longest (50 days) with the high dose of SB-75 vs. 15 days for controls. The body weights were unchanged. The weights of testes, seminal vesicles, and ventral prostate were greatly reduced in all three groups that received SB-75, and testosterone levels were decreased to nondetectable values in the case of the two higher doses of SB-75. LH levels were also diminished. Similar results were obtained in the second experiment, in which the animals were treated for a period of 8 weeks with microgranules of SB-75. Therapy with microgranules of SB-75 significantly decreased tumor growth as measured by the final tumor volume, the percentage change from the initial tumor volume, and the reduction in tumor weight. The results indicate that antagonist SB-75, released from sustained delivery systems, can produce a state of chemical castration and effectively

Histopathological classification criteria of rat model of chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Wang, Xianjin; Zhong, Shan; Xu, Tianyuan; Xia, Leilei; Zhang, Xiaohua; Zhu, Zhaowei; Zhang, Minguang; Shen, Zhoujun

2015-02-01

A variety of murine models of experimental prostatitis that mimic the phenotype of human chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) have been developed. However, there is still a lack of explicit diagnosis criteria about those animal model. Our study is to establish histopathological classification criteria, which will be conducive to evaluate the animal models. We firstly established a rat model of experimental autoimmune prostatitis that is considered a valid model for CP/CPPS. For modelling, male Sprague-Dawley rats were immunized with autologous prostate tissue homogenate supernatant emulsified with complete Freund's adjuvant by subcutaneous injection into abdominal flank and simultaneously immunized with pertussis-diphtheria-tetanus vaccine by intraperitoneal injection. Three immunizations were administered semimonthly. At the 45th day, animals were killed, and prostate tissues were examined for morphology. Histologically, the prostate tissues were characterized by lymphoproliferation, atrophy of acini, and chronic inflammatory cells infiltration in the stromal connective tissue around the acini or ducts. Finally, we built histopathological classification criteria incorporating inflammation locations (mesenchyme, glands, periglandular tissues), ranges (focal, multifocal, diffuse), and grades (grade I-IV). To verify the effectiveness and practicability of the histopathological classification criteria, we conducted the treatment study with one of the alpha blockers, tamsulosin. The histopathological classification criteria of rat model of CP/CPPS will serve for further research of the pathogenesis and treatment strategies of the disease.

Aggressive rat prostate tumors reprogram the benign parts of the prostate and regional lymph nodes prior to metastasis

PubMed Central

Thysell, Elin; Halin Bergström, Sofia; Bergh, Anders

2017-01-01

In order to grow and spread tumors need to interact with adjacent tissues. We therefore hypothesized that small but aggressive prostate cancers influence the rest of the prostate and regional lymph nodes differently than tumors that are more indolent. Poorly metastatic (Dunning AT1) or highly metastatic (Dunning MLL) rat prostate tumor cells were injected into the ventral prostate lobe of immunocompetent rats. After 10 days—when the tumors occupied about 30% of the prostate lobe and lymph node metastases were undetectable—the global gene expression in tumors, benign parts of the prostate, and regional iliac lymph nodes were examined to define tumor-induced changes related to preparation for future metastasis. The tumors induced profound effects on the gene expression profiles in the benign parts of the prostate and these were strikingly different in the two tumor models. Gene ontology enrichment analysis suggested that tumors with high metastatic capacity were more successful than less metastatic tumors in inducing tumor-promoting changes and suppressing anti-tumor immune responses in the entire prostate. Some of these differences such as altered angiogenesis, nerve density, accumulation of T-cells and macrophages were verified by immunohistochemistry. Gene expression alterations in the regional lymph nodes suggested decreased quantity and activation of immune cells in MLL-lymph nodes that were also verified by immunostaining. In summary, even when small highly metastatic prostate tumors can affect the entire tumor-bearing organ and pre-metastatic lymph nodes differently than less metastatic tumors. When the kinetics of these extratumoral influences (by us named TINT = tumor instructed normal tissue) are more precisely defined they could potentially be used as markers of disease aggressiveness and become therapeutic targets. PMID:28472073

[Effects of soy bean isoflavone on inhibition of benign prostatic hyperplasia and the expressions of NO and NOS of rats].

PubMed

Yang, Aiqing; Ren, Guofeng; Tang, Ling; Jiang, Weiwei

2009-03-01

To explore the inhibitive effect of soybean isoflavone on the prostatic hyperplasia on the expressions of nitric oxid and nitric oxide synthase in the prostatic hyperplasia rats. Subcutaneously injected testosterone propionate were to induce prostate hyperplasia in rats. The changes of prostate wet weight, prostatic index, liver index, the changes of some biochemical indexes in rat prostate tissue in the control and the treatment, the low, moderate, high dose groups of soybean isoflavone groups were observed. The prostate wet weight and prostatic index in all dose groups were merely lower than those in the treatment and the moderate groups were lowest in all dose group. There were no significant differences in liver index, urea nitrogen, glutamic-pyruvic transaminase of each group. Acid phosphatase, prostatic acid phosphatase and lactate dehydrogenase in all dose groups were merely lower than those in the treatment group. Nitric oxide and nitric oxide synthase in all dose groups were merely higher than those in the treatment group. Soybean isoflavone could inhibit prostate hyperplasia and increase the expressions of nitric oxide and nitric oxide synthase in rats.

Role of the TGFBeta1 in the Prevention of Prostate Cancer

DTIC Science & Technology

2002-04-01

benzothiophene analog with bone efficacy comple- prostate. In Lepor H, Lawson R (eds): Prostate Diseases. Phil - mentary to PTH (1-34). Endocrinology...R., Brachman, D. G.. Beckett , M. A., Virudachalam, S., Yandell. D. W., and Weichselbaum, R. R. Two prostate carcinoma 1. Landis, S. H., Murray, T

A study of the prostate, androgens and sexual activity of male rats

PubMed Central

Hernandez, Maria Elena; Soto-Cid, Abraham; Aranda-Abreu, Gonzalo E; Díaz, Rosaura; Rojas, Fausto; Garcia, Luis I; Toledo, Rebeca; Manzo, Jorge

2007-01-01

Background The prostate is a sexual gland that produces important substances for the potency of sperm to fertilize eggs within the female reproductive tract, and is under complex endocrine control. Taking advantage of the peculiar behavioral pattern of copulating male rats, we developed experimental paradigms to determine the influence of sexual behavior on the level of serum testosterone, prostate androgen receptors, and mRNA for androgen receptors in male rats displaying up to four consecutive ejaculations. Methods The effect of four consecutive ejaculations was investigated by determining levels of (i) testosterone in serum by solid phase RIA, (ii) androgen receptors at the ventral prostate with Western Blots, and (iii) androgen receptors-mRNA with RT-PCR. Data were analyzed with a one-way ANOVA followed by a post hoc application of Dunnett's test if required. Results The constant execution of sexual behavior did not produce any change in the weight of the ventral prostate. Serum testosterone increased after the second ejaculation, and remained elevated even after four ejaculations. The androgen receptor at the ventral prostate was higher after the first to third ejaculations, but returned suddenly to baseline levels after the fourth ejaculation. The level of mRNA increased after the first ejaculation, continued to increase after the second, and reached the highest peak after the third ejaculation; however, it returned suddenly to baseline levels after the fourth ejaculation. Conclusion Four consecutive ejaculations by sexually experienced male rats had important effects on the physiological responses of the ventral prostate. Fast responses were induced as a result of sexual behavior that involved an increase and decrease in androgen receptors after one and four ejaculations, respectively. However, a progressive response was observed in the elevation of mRNA for androgen receptors, which also showed a fast decrease after four ejaculations. All of these changes

Effect of two different extracts of red maca in male rats with testosterone-induced prostatic hyperplasia.

PubMed

Gonzales, Gustavo F; Vasquez, Vanessa; Rodriguez, Daniella; Maldonado, Carmen; Mormontoy, Juliet; Portella, Jimmy; Pajuelo, Monica; Villegas, León; Gasco, Manuel

2007-03-01

To determine the effect of two different extracts of red maca in male rats. Prostatic hyperplasia was induced in male rats with testosterone enanthate (TE). The study comprised six groups: one control group (group 1), one group treated with TE (group 2), two groups treated with TE and aqueous extract of red maca (groups 3 and 4), one group treated with hydroalcoholic extract of red maca (group 5) and one group treated with finasteride (0.1 mg, group 6). Differences in the aqueous extract dependent on the length of time of boiling, whether for 2 or 3 hours, for groups 3 and 4 was assessed. Extracts of red maca contained 0.1 mg of benzylglucosinolate. Thereafter, a dose-response effect of different doses of benzylglucosinolates (0.02-0.08 mg) in red maca extracts was assessed. Prostate weight was similar in rats treated with freeze-dried aqueous extract of red maca prepared after 2 and 3 hours of boiling. Freeze-dried aqueous extract of red maca, hydroalcoholic extract of red maca and finasteride reduced prostate weight in rats with prostatic hyperplasia. No difference was observed between the data obtained from aqueous extract or hydroalcoholic extract of red maca. A dose dependent reduction of prostate weight was observed with the increase of the dose of benzylglucosinolates in red maca extracts. The present study showed that hydroalcoholic or aqueous extract of red maca containing 0.1 mg of benzylglucosinolate can reduce prostate size in male rats in which prostatic hyperplasia had been induced by TE.

Evaluation of the protective effect of pentoxifylline on carrageenan-induced chronic non-bacterial prostatitis in rats.

PubMed

Hajighorbani, Mahboobeh; Ahmadi-Hamedani, Mahmood; Shahab, Elaheh; Hayati, Farzad; Kafshdoozan, Khatereh; Keramati, Keivan; Amini, Amin Hossein

2017-06-01

Chronic non-bacterial prostatitis (CNP) is the most common type of prostatitis and oxidative stress (OS) was shown to be highly elevated in prostatitis patients. This study aimed to investigate the protective effect of pentoxifylline (PTX) on CNP induced by carrageenan in rats. Male adult Wistar rats (n = 30) were divided into control, CNP and three treatment groups (n = 6) including CNP + cernilton and CNP + PTX groups. CNP was induced by single intraprostatic injection of 1% carrageenan (100 µl). Rats in treatment groups received orally cernilton 100 mg/kg and PTX at 50 and 100 mg/kg 1 week after CNP induction for 21 days. Prostatic index (PI), prostatic specific antigen (PSA), tumor-necrosis factor alpha (TNF-α), serum lipid peroxidation (MDA), blood urea nitrogen, creatinine and histopathological changes were compared between groups. There were significant increase of PI, serum levels of PSA, TNF-α and MDA in CNP group at 29 day. In treatment groups, significant reduction in PI, serum levels of PSA, TNF-α, MDA and creatinine was observed especially in rats treated with dose of 50 mg/kg of PTX. In CNP group, histopathological changes of the prostate such as leucocyte infiltration, large involutions and projection into the lumen and reducing the volume of the lumen were observed as well. Whereas PTX, especially at dose of 50 mg/kg, could improve the above-mentioned changes remarkably in CNP treated rats. For the first time, our findings indicated that PTX improved CNP induced by carrageenan in rats.

miR-15a/miR-16 cluster inhibits invasion of prostate cancer cells by suppressing TGF-β signaling pathway.

PubMed

Jin, Wei; Chen, Fangjie; Wang, Kefeng; Song, Yan; Fei, Xiang; Wu, Bin

2018-05-23

To determine whether and how miR15a/16 regulate TGF-β signaling pathways during the progression of prostate cancer. We used bioinformatics prediction, reporter gene assay, real-time PCR, Matrigel invasion assay and Western blot to dissect the molecular mechanism of how miR-15a/miR-16 may cause metastasis in prostate tumor. MiR-15a/16 targeted and inhibited the expression of endogenous Smad3 and ACVR2A proteins. The overexpression of miR15a/16 down-regulated p-smad3 expression, affected the expression of both MMP2 and E-cadherin, and down-regulated the expression of the EMT-mediated factors Snail and Twist in LNCaP prostate cancer cells. The overexpression of miR15a/16 decreased the invasion of LNCaP cells. MiR-15a/miR-16 cluster could reverse the invasion of activin A-mediated prostate cancer cells. After the inhibition of the activin/smad signaling pathway, the inhibitory effect of invasion in prostate cancer cells by miR-15a/miR-16 cluster disappeared. Our data indicated that miR15a/16 inhibited the components of TGF-β signaling pathways in LNCaP cell line, which might relate to the progression and metastasis of prostate cancer. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Population Pharmacokinetic Modeling of the Unbound Levofloxacin Concentrations in Rat Plasma and Prostate Tissue Measured by Microdialysis

PubMed Central

Hurtado, Felipe K.; Weber, Benjamin; Derendorf, Hartmut; Hochhaus, Guenther

2014-01-01

Levofloxacin is a broad-spectrum fluoroquinolone used in the treatment of both acute and chronic bacterial prostatitis. Currently, the treatment of bacterial prostatitis is still difficult, especially due to the poor distribution of many antimicrobials into the prostate, thus preventing the drug to reach effective interstitial concentrations at the infection site. Newer fluoroquinolones show a greater penetration into the prostate. In the present study, we compared the unbound levofloxacin prostate concentrations measured by microdialysis to those in plasma after a 7-mg/kg intravenous bolus dose to Wistar rats. Plasma and dialysate samples were analyzed using a validated high-pressure liquid chromatography-fluorescence method. Both noncompartmental analysis (NCA) and population-based compartmental modeling (NONMEM 6) were performed. Unbound prostate tissue concentrations represented 78% of unbound plasma levels over a period of 12 h by comparing the extent of exposure (unbound AUC0–∞) of 6.4 and 4.8 h·μg/ml in plasma and tissue, respectively. A three-compartment model with simultaneous passive diffusion and saturable distribution kinetics from the prostate to the central compartment gave the best results in terms of curve fitting, precision of parameter estimates, and model stability. The following parameter values were estimated by the population model: V1 (0.38 liter; where V1 represents the volume of the central compartment), CL (0.22 liter/h), k12 (2.27 h−1), k21 (1.44 h−1), k13 (0.69 h−1), Vmax (7.19 μg/h), kM (0.35 μg/ml), V3/fuprostate (0.05 liter; where fuprostate represents the fraction unbound in the prostate), and k31 (3.67 h−1). The interindividual variability values for V1, CL, Vmax, and kM were 21, 37, 42, and 76%, respectively. Our results suggest that levofloxacin is likely to be substrate for efflux transporters in the prostate. PMID:24217697

Comparison of Saw Palmetto (extract and whole berry) and Cernitin on prostate growth in rats.

PubMed

Talpur, Nadeem; Echard, Bobby; Bagchi, Debasis; Bagchi, Manashi; Preuss, Harry G

2003-08-01

Pharmaceuticals such as finasteride and alpha blockers are used to treat symptoms of benign prostatic hyperplasia (BPH) and are known to cause severe adverse reactions. Accordingly, a search for safer, natural products has been undertaken. Two natural agents (nutraceuticals) have come under recent scrutiny; because natural products, in general, often have evidence of long-term safety. The present study compares the in vivo effects on androgen-induced prostatic enlargement in rats of two nutraceuticals--the widely recognized Saw Palmetto (Serenoa repens) and the less well-known Cernitin (defined pollen extract). Non-castrated rats, had a mean prostate weight of 124 mg +/- 8.8 (S.E.M.) compared to the 24.5 mg +/- 1.9 (S.E.M.) of the castrated rat followed under the same regimen (p < 0.01). When castrated rats were given testosterone, the mass increased significantly to 250.0 mg +/- 31.7 (S.E.M.) (p < 0.01). In the five remaining groups, castrated rats receiving testosterone were given finasteride, an extract of Saw Palmetto, crushed whole berry derived from Saw Palmetto fruit, a water soluble and fat soluble extract of Cernitin or a combination of the Saw Palmetto extract and Cernitin. All treatments decreased the size of the prostate to roughly the same size as in the non-castrated rats, a size that was significantly smaller than castrated rats treated with testosterone in the same manner (p < 0.01). A second study examining non-castrated rats treated with very high doses of testosterone showed similar results. In both studies, the nutraceuticals generally decreased body weight. In conclusion, these studies show the ability of Saw Palmetto (whole berry and extract) and Cernitin to influence prostatic hyperplasia via effects on androgen metabolism.

Genistein and resveratrol, alone and in combination, suppress prostate cancer in SV-40 tag rats.

PubMed

Harper, Curt E; Cook, Leah M; Patel, Brijesh B; Wang, Jun; Eltoum, Isam A; Arabshahi, Ali; Shirai, Tomoyuki; Lamartiniere, Coral A

2009-11-01

Chemoprevention utilizing dietary agents is an effective means to slow the development of prostate cancer. We evaluated the potential additive and synergistic effects of genistein and resveratrol for suppressing prostate cancer in the Simian Virus-40 T-antigen (SV-40 Tag) targeted probasin promoter rat model, a transgenic model of spontaneously developing prostate cancer. Rats were fed genistein or resveratrol (250 mg/kg AIN-76A diet) alone and in combination, and a low-dose combination (83 mg genistein + 83 mg resveratrol/kg diet). Histopathology and mechanisms of action studies were conducted at 30 and 12 weeks of age, respectively. Genistein, resveratrol, and the high-dose combination treatments suppressed prostate cancer. The low-dose combination did not elicit protection against prostate cancer and was most likely below the effective dose for causing significant histopathological changes. Total genistein and resveratrol concentrations in the blood reached 2,160 and 211 nM, respectively in rats exposed to the single treatments. Polyphenol treatments decreased cell proliferation and insulin-like growth factor-1 (IGF-1) protein expression in the prostate. In addition, genistein as a single agent induced apoptosis and decreased steroid receptor coactivator-3 (SRC-3) in the ventral prostate (VP). Genistein and resveratrol, alone and in combination, suppress prostate cancer development in the SV-40 Tag model. Regulation of SRC-3 and growth factor signaling proteins are consistent with these nutritional polyphenols reducing cell proliferation and increasing apoptosis in the prostate.

HPLC–electrospray mass spectrometric assay for the determination of (R,R)-fenoterol in rat plasma

PubMed Central

Siluk, Danuta; Kim, Hee Seung; Cole, Tyler; Wainer, Irving W.

2008-01-01

A fast and specific liquid chromatography–mass spectrometry method for the determination of (R,R)-fenoterol ((R,R)-Fen) in rat plasma has been developed and validated. (R,R)-Fen was extracted from 125 µl of plasma using solid phase extraction and analyzed on Atlantis HILIC Silica 3 µm column. The mobile phase was composed of acetonitrile:ammonium acetate (pH 4.1; 20 mM) (85:15, v/v), at a flow rate of 0.2 ml/min. The lower limit of detection (LLOD) was 2 ng/ml . The procedure was validated and applied to the analysis of plasma samples from rats previously administered (R,R)-Fen in an intravenous bolus. PMID:18617349

HPLC-electrospray mass spectrometric assay for the determination of (R,R)-fenoterol in rat plasma.

PubMed

Siluk, Danuta; Kim, Hee Seung; Cole, Tyler; Wainer, Irving W

2008-11-04

A fast and specific liquid chromatography-mass spectrometry method for the determination of (R,R)-fenoterol ((R,R)-Fen) in rat plasma has been developed and validated. (R,R)-Fen was extracted from 125 microl of plasma using solid phase extraction and analyzed on Atlantis HILIC Silica 3 microm column. The mobile phase was composed of acetonitrile:ammonium acetate (pH 4.1; 20mM) (85:15, v/v), at a flow rate of 0.2 ml/min. The lower limit of detection (LLOD) was 2 ng/ml . The procedure was validated and applied to the analysis of plasma samples from rats previously administered (R,R)-Fen in an intravenous bolus.

Early diagnostic role of PSA combined miR-155 detection in prostate cancer.

PubMed

Guo, T; Wang, X-X; Fu, H; Tang, Y-C; Meng, B-Q; Chen, C-H

2018-03-01

As a kind of malignant tumor in the male genitourinary system, prostate cancer exhibits significantly increased occurrence. Prostate-specific antigen (PSA) expression can be seen in the prostate cancer, prostatitis, and other diseases, therefore, lack of diagnostic specificity. The miR-155 expression is abnormally increased in the tumors. Therefore, this study aims to explore the clinical significance of PSA combined miR-155 detection in the early diagnosis of prostate cancer. A total of 86 patients diagnosed with prostate cancer were enrolled in this study. PSA and miR-155 gene expression in tumor tissue were detected by using Real-time PCR. The serum levels of PSA were measured by using enzyme-linked immunosorbent assay (ELISA). The correlation of PSA and miR-155 expression with age, body mass index (BMI), tumor volume, tumor-node-metastasis (TNM) stage, lymph node metastasis (LNM), and other clinicopathological features were analyzed, respectively. Serum PSA expression and PSA gene in tumor tissue were significantly higher compared to that in adjacent tissues (p<0.05). PSA gene and protein increased significantly with the clinical stage of TNM and decreased following the increase of grade (p<0.05). The miR-155 level was significantly elevated in the tumor tissue compared with para-carcinoma tissue (p<0.05). PSA and miR-155 expressions were positively correlated with TNM stage, tumor volume, and LNM, and negatively correlated with grade (p<0.05). PSA and miR-155 were closely related to the clinicopathological features of prostate cancer. Combined detection is helpful for the early diagnosis of prostate cancer.

Perinatal exposure to mixtures of anti-androgenic chemicals causes proliferative lesions in rat prostate.

PubMed

Boberg, Julie; Johansson, Hanna K L; Hadrup, Niels; Dreisig, Karin; Berthelsen, Line; Almstrup, Kristian; Vinggaard, Anne Marie; Hass, Ulla

2015-02-01

Elevated levels of endogenous or exogenous estrogens during fetal life can induce permanent disturbances in prostate growth and predispose to precancerous lesions. Recent studies have indicated that also early anti-androgen exposure may affect prostate cancer risk. We examined the influence of perinatal exposure to mixtures of anti-androgenic and estrogenic chemicals on prostate development. Wistar rats were exposed from gestation day 7 to postnatal day 22 to a mixture of 8 anti-androgenic compounds (AAMix), a mixture of four estrogenic compounds (EMix), or paracetamol or a mixture of all 13 compounds (TotalMix) in mixture ratios reflecting human exposure levels. Ventral prostate weights were reduced by the TotalMix and AAMix in pre-pubertal rats. Histological changes in prostate appeared with increasing age and indicated a shift from the normal age-dependent epithelial atrophy towards hyperplasia. These lesions showed similarities to pre-cancerous lesions in humans. Increased proliferation was observed already in pre-puberty and it was hypothesized that this could be associated with reduced ERβ signaling, but no clear conclusions could be made from gene expression studies on ERβ-related pathways. The influences of the estrogenic chemicals and paracetamol on prostate morphology were minor, but in young adulthood the estrogen mixture reduced ventral prostate mRNA levels of Igf1 and paracetamol reduced the mRNA level ofPbpc3. Mixtures of endocrine disrupters relevant for human exposure was found to elicit persistent effects on the rat prostate following perinatal exposure, suggesting that human perinatal exposure to environmental chemicals may increase the risk of prostate cancer later in life. © 2014 Wiley Periodicals, Inc.

[Influence of Kudou Shencha decotion on INF-gamma, ICAM-1, MCP-1 levels of prostate tissue homogenate in immunity prostatitis model rats].

PubMed

Xia, Li-Ying; Liu, Wei-Jia; Li, Ming-Xi; Ge, Wen-Jin; Gao, Xue-Min; Zhang, Jian-Jun

2014-05-01

To investigate the influence of Kudou Shencha decotion on INF-y, ICAM-1, MCP-1 levels of prostate tissue homogenate in immunity prostatitis model rats. Forty Wistar male rats were divided into 5 groups randomly: Kudou Shencha decotion group with high dosage and low dosage, Qianleitai group, the model control group and normal group. The rat model of chronic nonbacterial prostatitis was established by multiple hypodermical injection of the suspension of prostatic protein purification with Freund's completed adjuvant. The level of intercellular adhesion molecule (ICAM-1), interferon gamma (INF-gamma) and monocyte chemotactic protein-1 (MCP-1) were measured by enzyme linked immunosorbent assay (ELISA). The content of ICAM-1 and MCP-1 in the model group was higher than that of the normal group (P < 0.05), the content of ICAM-1 was obviously decreased in Kudou Shencha decotion group with high dosage (P <0.05), the contents of MCP-1 were all obviously decreased in Kudou Shencha decotion groups and Qianlietai group. Compared with the model group, the contents of INF-gamma in all treatment groups were decreased insignificantly. Kudou Shencha decotion has the action of lowering the level of ICAM-1 and MCP-1, which may be one of the mechanisms of Kudou Shencha decotion in the therapy of chronic prostatitis.

[Bone marrow mesenchymal stem cells suppress E coli-induced bacterial prostatitis in rats].

PubMed

Han, Guang-wei; Liu, Cheng-cheng; Gao, Wen-hong; Cui, Dong; Yi, Shan-hong

2015-04-01

To investigate the inhibitory effect of bone marrow mesenchymal stem cells (BMSCs) on E coliinduced prostatitis in rats. BMSCs were isolated, cultured and amplified by the attached choice method. Fifty SD rats were randomized into five groups of equal number: normal control, acute bacterial prostatitis (ABP) , chronic bacterial prostatitis (CBP), ABP + BMSCs, and CBP + BMSCs, and the animals in the latter four groups were injected with E. coli into both sides of the prostate under ultrasound guidance for 1 - 14 days to induce ABP and for 4 - 12 weeks to induce CBP. The control rats were injected with the same amount of PBS. Two weeks after injection of BMSCs into the prostates, pathomorphological changes in the prostate were observed under the light microscope and the mRNA and protein levels of IL-1β and TNF-α determined by RT-PCR and ELISA, respectively, followed by statistical analysis with SPSS 18.0. Histopathological evaluation showed typical pathological inflammatory changes in the prostates of the rats in the ABP and CBP groups, including glandular structural changes, interstitial edema, inflammatory cell infiltration, and fibrous hyperplasia, which were all remarkably relieved after treated with BMSCs. The mRNA and protein levels of IL-β ([0.829 ± 0.121] and [271.75 ± 90.59] pg/ml) and TNF-α ([0.913 ± 0. 094] and [105.78 ± 19. 05] pg/ml) in the ABP and those of IL-1β ([0. 975 ± 0. 114] and [265. 31 ± 71. 34] pg/ml) and TNF-α ([0. 886 ± 0. 084] and [107. 45 ± 26. 11 ] pg/ml) in the CBP groups were significantly higher than those in the control rats ([0. 342 ± 0.087] and [45.76 17. 99] pg/ml, P <0. 05); ([0.247 ± 0.054] and ([19.42 ± 7. 75] pg/ml, P <0. 01) as well as than those in the ABP + BMSCs ([0. 433 ± 0. 072] and [51. 34 ± 22. 13] pg/ml, P < 0. 05 ) ; ( [0. 313 ± 0. 076] and [28. 38 ± 8. 78] pg/ml, P < 0. 01) and the CBP + BMSCs group ([0.396 ± 0.064] and [56.37 ± 21.22] pg/ml, P <0.05); ([0.417 ± 0.068] and [29.21 ± 10.22] pg

Anti-inflammatory and antimicrobial effects of garlic and synergistic effect between garlic and ciprofloxacin in a chronic bacterial prostatitis rat model.

PubMed

Sohn, Dong Wan; Han, Chang Hee; Jung, Yun Seok; Kim, Sung In; Kim, Sae Woong; Cho, Yong-Hyun

2009-09-01

Chronic bacterial prostatitis (CBP), which is characterised by recurrent urinary tract infection (UTI) and persistence of pathogenic bacteria and evidence of inflammation in the prostatic secretions, is one of the most common causes of relapsing UTI in men. In this study, we evaluated the antimicrobial and anti-inflammatory effects of garlic as well as the synergistic effect of garlic with ciprofloxacin on the treatment of CBP in an animal model. An experimental CBP model was induced in 60 adult male Sprague-Dawley rats by instillation of 0.2 mL of bacterial suspension (Escherichia coli Z17, O2:K1:H-) containing 1 x 10(8) colony-forming units/mL into the prostatic urethra. Microbiologically and histologically proven CBP was demonstrated in 68.3% (41/60) of the rats after 4 weeks of bacterial instillation. The 41 rats demonstrating CBP were randomly divided into four treatment groups: control; garlic; ciprofloxacin; and garlic plus ciprofloxacin. After 3 weeks of treatment, microbiological cultures of the urine and prostate samples as well as histological findings of the prostate were analysed. Microbiological cultures and histological findings of the prostate samples demonstrated reduced bacterial growth and improved inflammatory responses in all three experimental groups compared with the control group. The garlic group showed a statistically significant decrease in bacterial growth and improvement in prostatic inflammation compared with the control group. The garlic plus ciprofloxacin group showed a statistically significant decrease in bacterial growth and improvement in prostatic inflammation compared with the ciprofloxacin group. These results suggest that garlic may have anti-inflammatory and antimicrobial effects as well as a synergistic effect with ciprofloxacin. We therefore suggest that the combination of garlic and ciprofloxacin may be effective in treating CBP with a higher success rate.

Temperature-controlled optical stimulation of the rat prostate cavernous nerves

NASA Astrophysics Data System (ADS)

Tozburun, Serhat; Hutchens, Thomas C.; McClain, Michael A.; Lagoda, Gwen A.; Burnett, Arthur L.; Fried, Nathaniel M.

2013-06-01

Optical nerve stimulation (ONS) may be useful as a diagnostic tool for intraoperative identification and preservation of the prostate cavernous nerves (CN), responsible for erectile function, during prostate cancer surgery. Successful ONS requires elevating the nerve temperature to within a narrow range (˜42 to 47°C) for nerve activation without thermal damage to the nerve. This preliminary study explores a prototype temperature-controlled optical nerve stimulation (TC-ONS) system for maintaining a constant (±1°C) nerve temperature during short-term ONS of the rat prostate CNs. A 150-mW, 1455-nm diode laser was operated in continuous-wave mode, with and without temperature control, during stimulation of the rat CNs for 15 to 30 s through a fiber optic probe with a 1-mm-diameter spot. A microcontroller opened and closed an in-line mechanical shutter in response to an infrared sensor, with a predetermined temperature set point. With TC-ONS, higher laser power settings were used to rapidly and safely elevate the CNs to a temperature necessary for a fast intracavernous pressure response, while also preventing excessive temperatures that would otherwise cause thermal damage to the nerve. With further development, TC-ONS may provide a rapid, stable, and safe method for intraoperative identification and preservation of the prostate CNs.

Ameliorative effects of stinging nettle (Urtica dioica) on testosterone-induced prostatic hyperplasia in rats.

PubMed

Nahata, A; Dixit, V K

2012-05-01

The present study investigated the effects of stinging nettle (Urtica dioica L.) (UD) on benign prostatic hyperplasia (BPH) induced by testosterone. In vitro studies were conducted to assess the 5α-reductase inhibitory potential of UD. Two biochemical markers viz., β-sitosterol and scopoletin, were isolated and characterised in the extracts utilising High-performance thin layer chromatographic, FTIR, NMR and overlain UV spectral studies. Hyperplasia was induced in rats by subcutaneous administration of testosterone (3 mg kg(-1) s.c.) for 28 days in all the groups except the vehicle-treated group. Simultaneous administration of petroleum ether and ethanolic extracts (10, 20 and 50 mg kg(-1) p.o.) and isolated β-sitosterol (10 and 20 mg kg(-1) p.o.) was undertaken. Finasteride was used as a positive control (1 mg kg(-1) p.o.). Measurement of prostate/body weight ratio, weekly urine output and serum testosterone levels, prostate-specific antigen levels (on day 28) and histological examinations carried out on prostates from each group led us to conclude that UD can be used as an effective drug for the management of BPH. © 2011 Blackwell Verlag GmbH.

miR-128 modulates chemosensitivity and invasion of prostate cancer cells through targeting ZEB1.

PubMed

Sun, Xianglun; Li, Youkong; Yu, Jie; Pei, Hong; Luo, Pengcheng; Zhang, Jie

2015-05-01

Recent reports strongly suggest the profound role of miRNAs in cancer therapeutic response and progression, including invasion and metastasis. The sensitivity to therapy and invasion is the major obstacle for successful treatment in prostate cancer. We aimed to investigate the regulative effect of miR-128/zinc-finger E-box-binding homeobox 1 axis on prostate cancer cell chemosensitivity and invasion. The miR-128 expression pattern of prostate cancer cell lines and tissues was detected by real-time reverse transcriptase-polymerase chain reaction, while the mRNA and protein expression levels of zinc-finger E-box-binding homeobox 1 were measured by real-time reverse transcriptase-polymerase chain reaction and western blot assay, respectively. Dual-luciferase reporter gene assay was used to find the direct target of miR-128. Furthermore, prostate cancer cells were treated with miR-128 mimic or zinc-finger E-box-binding homeobox 1-siRNA, and then the cells' chemosensitivity and invasion were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and transwell assay, respectively. We found miR-128 expression obviously decreased in prostate cancer tissues compared with paired normal tissues. Restored miR-128 expression sensitized prostate cancer cells to cisplatin and inhibited the invasion. Furthermore, there was an inverse expression pattern between miR-128 and zinc-finger E-box-binding homeobox 1 in prostate cancer cells and tissues, and zinc-finger E-box-binding homeobox 1 was identified as a direct target of miR-128 in prostate cancer. Knockdown of zinc-finger E-box-binding homeobox 1 expression efficiently sensitized prostate cancer cells to cisplatin and inhibited the invasion. However, ectopic zinc-finger E-box-binding homeobox 1 expression impaired the effects of miR-128 on chemosensitivity and invasion in prostate cancer cells. miR-128 functions as a potential cancer suppressor in prostate cancer progression and rational therapeutic

Dapoxetine attenuates testosterone-induced prostatic hyperplasia in rats by the regulation of inflammatory and apoptotic proteins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sayed, Rabab H., E-mail: rabab.sayed@pharma.cu.edu

Serotonin level plays a role in suppressing the pathological findings of benign prostatic hyperplasia (BPH). Thus a new selective serotonin reuptake inhibitor, dapoxetine was used to test its ability to ameliorate the pathological changes in the rat prostate. A dose response curve was constructed between the dose of dapoxetine and prostate weight as well as relative prostate weight, then a 5 mg/kg dose was used as a representative dose for dapoxetine administration. Rats were divided into four groups; the control group that received the vehicle; the BPH-induced group received daily s.c injection of 3 mg/kg testosterone propionate dissolved in olivemore » oil for four weeks; BPH-induced group treated with finasteride 5 mg/kg/day p.o and BPH-induced group treated with dapoxetine 5 mg/kg/day p.o. Injection of testosterone increased prostate weight and relative prostate weight which were both returned back to the normal value after treatment with dapoxetine as well as finasteride. Testosterone also upregulated androgen receptor (AR) and proliferating cell nuclear antigen gene expression. Furthermore, testosterone injection elevated cyclooxygenase-II (COX II), inducible nitric oxide synthase (iNOS), B-cell lymphoma-2 (Bcl2) expression and tumor necrosis factor alpha content and reduced caspase-3 activity, Bcl-2-associated X protein (Bax) expression and Bax/Bcl2 ratio. Dapoxetine and finasteride administration reverted most of the changes made by testosterone injection. In conclusion, the current study provides an evidence for the protective effects of dapoxetine against testosterone-induced BPH in rats. This can be attributed, at least in part, to decreasing AR expression, and the anti-proliferative, anti-inflammatory and pro-apoptotic activities of dapoxetine in BPH. - Highlights: • Dapoxetine attenuates testosterone-induced prostatic hyperplasia in rats. • Dapoxetine decreased androgen receptor gene expression in rat prostate. • Dapoxetine possess anti

A Multiscale, Mechanism-Driven, Dynamic Model for the Effects of 5α-Reductase Inhibition on Prostate Maintenance

PubMed Central

Zager, Michael G.; Barton, Hugh A.

2012-01-01

A systems-level mathematical model is presented that describes the effects of inhibiting the enzyme 5α-reductase (5aR) on the ventral prostate of the adult male rat under chronic administration of the 5aR inhibitor, finasteride. 5aR is essential for androgen regulation in males, both in normal conditions and disease states. The hormone kinetics and downstream effects on reproductive organs associated with perturbing androgen regulation are complex and not necessarily intuitive. Inhibition of 5aR decreases the metabolism of testosterone (T) to the potent androgen 5α-dihydrotestosterone (DHT). This results in decreased cell proliferation, fluid production and 5aR expression as well as increased apoptosis in the ventral prostate. These regulatory changes collectively result in decreased prostate size and function, which can be beneficial to men suffering from benign prostatic hyperplasia (BPH) and could play a role in prostate cancer. There are two distinct isoforms of 5aR in male humans and rats, and thus developing a 5aR inhibitor is a challenging pursuit. Several inhibitors are on the market for treatment of BPH, including finasteride and dutasteride. In this effort, comparisons of simulated vs. experimental T and DHT levels and prostate size are depicted, demonstrating the model accurately described an approximate 77% decrease in prostate size and nearly complete depletion of prostatic DHT following 21 days of daily finasteride dosing in rats. This implies T alone is not capable of maintaining a normal prostate size. Further model analysis suggests the possibility of alternative dosing strategies resulting in similar or greater effects on prostate size, due to complex kinetics between T, DHT and gene occupancy. With appropriate scaling and parameterization for humans, this model provides a multiscale modeling platform for drug discovery teams to test and generate hypotheses about drugging strategies for indications like BPH and prostate cancer, such as compound

Changes in erectile organ structure and function in a rat model of chronic prostatitis/chronic pelvic pain syndrome.

PubMed

Wang, X-J; Xia, L-L; Xu, T-Y; Zhang, X-H; Zhu, Z-W; Zhang, M-G; Liu, Y; Xu, C; Zhong, S; Shen, Z-J

2016-04-01

There is a growing recognition of the association between chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and erectile dysfunction (ED); however, most of the reports are based on questionnaires which cannot distinguish between organic and functional ED. The purpose of this study was to determine the exact relationship between CP/CPPS and ED, and to investigate the changes in erectile organ structure and function in a rat model of CP/CPPS. We established a rat model of experimental autoimmune prostatitis (EAP), which is a valid model for CP/CPPS. Erectile function in EAP and normal rats was comparable after cavernous nerve electrostimulation. The serum testosterone and oestradiol levels, ultrastructure of the corpus cavernosum and expression of endothelial nitric oxide synthase and neuronal nitric oxide synthase in the two groups were similar; however, there was a decrease in smooth muscle-to-collagen ratio and alpha-smooth muscle actin expression and an increase in transforming growth factor-beta 1 expression was observed in EAP rats. Thus, organic ED may not exist in EAP rats. We speculate that ED complained by patients with CP/CPPS may be psychological, which could be caused by impairment in the quality of life; however, further studies are needed to fully understand the potential mechanisms underlying the penile fibrosis in EAP rats. © 2015 Blackwell Verlag GmbH.

Celastrol Induces Autophagy by Targeting AR/miR-101 in Prostate Cancer Cells

PubMed Central

Guo, Jianquan; Huang, Xuemei; Wang, Hui; Yang, Huanjie

2015-01-01

Autophagy is an evolutionarily conserved process responsible for the degradation and recycling of cytoplasmic components through autolysosomes. Targeting AR axis is a standard strategy for prostate cancer treatment; however, the role of AR in autophagic processes is still not fully understood. In the present study, we found that AR played a negative role in AR degrader celastrol-induced autophagy. Knockdown of AR in AR-positive prostate cancer cells resulted in enhanced autophagy. Ectopic expression of AR in AR-negative prostate cancer cells, or gain of function of the AR signaling in AR-positive cells, led to suppression of autophagy. Since miR-101 is an inhibitor of autophagy and its expression was decreased along with AR in the process of celastrol-induced autophagy, we hypothesize that AR inhibits autophagy through transactivation of miR-101. AR binding site was defined in the upstream of miR-101 gene by luciferase reporter and ChIP assays. MiR-101 expression correlated with AR status in prostate cancer cell lines. The inhibition of celastrol-induced autophagy by AR was compromised by blocking miR-101; while transfection of miR-101 led to inhibition of celastrol-induced autophagy in spite of AR depletion. Furthermore, mutagenesis of the AR binding site in miR-101 gene led to decreased suppression of autophagy by AR. Finally, autophagy inhibition by miR-101 mimic was found to enhance the cytotoxic effect of celastrol in prostate cancer cells. Our results demonstrate that AR inhibits autophagy via transactivation of miR-101, thus combination of miR-101 mimics with celastrol may represent a promising therapeutic approach for treating prostate cancer. PMID:26473737

Null effect of dietary restriction on prostate carcinogenesis in the Wistar-Unilever rat.

PubMed

McCormick, David L; Johnson, William D; Haryu, Todd M; Bosland, Maarten C; Lubet, Ronald A; Steele, Vernon E

2007-01-01

Chronic dietary restriction inhibits carcinogenesis in several sites in laboratory animals. To determine the effects of dietary restriction on prostate carcinogenesis, prostate cancers were induced in male Wistar-Unilever rats by a sequential regimen of cyproterone acetate (50 mg/day; 21 days); testosterone propionate (100 mg/kg/day; 3 days); N-methyl-N-nitrosourea [MNU; 30 mg/kg; single dose]; and testosterone (subcutaneous implants of 2 pellets containing 40 mg each). Dietary restriction (0% [ad libitum control], 15%, or 30%) was initiated 2 wk post-MNU, and continued until study termination at 12 mo. Dietary restriction induced a rapid suppression of body weight gain but conferred no protection against prostate carcinogenesis. 74% of carcinogen-treated ad libitum controls developed accessory sex gland cancers, versus cancer incidences of 64% and 72% in groups restricted by 15% and 30%, respectively. Similarly, 44% of dietary controls developed cancers limited to the dorsolateral/prostate, versus incidences of 45% and 53% in groups restricted by 15% and 30%. The results of the present study do not support the hypothesis that prostate carcinogenesis can be prevented by reducing caloric intake. Reducing mean body weight by up to 25% through chronic dietary restriction has no effect on the induction of prostate cancers in the Wistar-Unilever rat model.

Early-Onset Endocrine Disruptor–Induced Prostatitis in the Rat

PubMed Central

Cowin, Prue A.; Foster, Paul; Pedersen, John; Hedwards, Shelley; McPherson, Stephen J.; Risbridger, Gail P.

2008-01-01

Background Androgens are critical for specifying prostate development, with the fetal prostate sensitive to altered hormone levels and endocrine-disrupting chemicals (EDCs) that exhibit estrogenic or antiandrogenic properties. Prostatic inflammation (prostatitis) affects 9% of men of all ages, and > 90% of cases are of unknown etiology. Objectives In this study we aimed to evaluate effects of in utero exposure to the antiandrogenic EDC vinclozolin, during the period of male reproductive tract development, on neonatal, prepubertal, and postpubertal prostate gland function of male offspring. Methods Fetal rats were exposed to vinclozolin (100 mg/kg body weight) or vehicle control (2.5 mL/kg body weight) in utero from gestational day 14 (GD14) to GD19 via oral administration to pregnant dams. Tissue analysis was carried out when male offspring were 0, 4, or 8 weeks of age. Results In utero exposure to vinclozolin was insufficient to perturb prostatic development and branching, although expression of androgen receptor and mesenchymal fibroblast growth factor-10 was down-regulated. Prostate histology remained normal until puberty, but 100% of animals displayed prostatitis postpubertally (56 days of age). Prostatic inflammation was associated with phosphorylation and nuclear translocation of nuclear factor-kappa B (NFκB) and postpubertal activation of proinflammatory NFκB-dependent genes, including the chemokine interleukin-8 and the cytokine transforming growth factor-β1. Significantly, inflammation arising from vinclozolin exposure was not associated with the emergence of premalignant lesions, such as prostatic intra-epithelial neoplasia or proliferative inflammatory atrophy, and hence mimics nonbacterial early-onset prostatitis that commonly occurs in young men. Conclusions These data are the first to unequivocally implicate EDCs as a causative factor and fill an important knowledge gap on the etiology of prostatitis. PMID:18629315

The therapeutic effects of docosahexaenoic acid on oestrogen/androgen-induced benign prostatic hyperplasia in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Chao; Luo, Fei; Zhou, Ying

Benign prostatic hyperplasia (BPH) is one of the major disorders of the urinary system in elderly men. Docosahexaenoic acid (DHA) is the main component of n-3 polyunsaturated fatty acids (n-3 PUFAs) and has nerve protective, anti-inflammatory and tumour-growth inhibitory effects. Here, the therapeutic potential of DHA in treating BPH was investigated. Seal oil effectively prevented the development of prostatic hyperplasia induced by oestradiol/testosterone in a rat model by suppressing the increase of the prostatic index (PI), reducing the thickness of the peri-glandular smooth muscle layer, inhibiting the proliferation of both prostate epithelial and stromal cells, and downregulating the expression ofmore » androgen receptor (AR) and oestrogen receptor α (ERα). An in vitro study showed that DHA inhibited the growth of the human prostate stromal cell line WPMY-1 and the epithelial cell line RWPE-1 in a dose- and time-dependent manner. In both cell lines, the DHA arrested the cell cycle in the G2/M phase. In addition, DHA also reduced the expression of ERα and AR in the WPMY-1 and RWPE-1 cells. These results indicate that DHA inhibits the multiplication of prostate stromal and epithelial cells through a mechanism that may involve cell cycle arrest and the downregulation of ERα and AR expression. - Highlights: • Seal oil prevents oestradiol/testosterone (E2/T)-induced BPH in castrated rats. • Seal oil downregulates the expression of oestrogen receptor α(ERα) and androgen receptor (AR) in rat BPH tissues. • DHA inhibits the growth of human prostate stromal and epithelial cells in vitro. • DHA arrests human prostate stromal and epithelial cells in the G2/M phase and downregulates the expression of cyclin B1. • DHA inhibits the expression of ERα and AR in human prostate stromal and epithelial cells.« less

Null activity of selenium and vitamin e as cancer chemopreventive agents in the rat prostate.

PubMed

McCormick, David L; Rao, K V N; Johnson, William D; Bosland, Maarten C; Lubet, Ronald A; Steele, Vernon E

2010-03-01

To evaluate the potential efficacy of selenium and vitamin E as inhibitors of prostate carcinogenesis, four chemoprevention studies using a common protocol were done in a rat model of androgen-dependent prostate cancer. After stimulation of prostate epithelial cell proliferation by a sequential regimen of cyproterone acetate followed by testosterone propionate, male Wistar-Unilever rats received a single i.v. injection of N-methyl-N-nitrosourea (MNU) followed by chronic androgen stimulation via subcutaneous implantation of testosterone pellets. At 1 week post-MNU, groups of carcinogen-treated rats (39-44/group) were fed either a basal diet or a basal diet supplemented with l-selenomethionine (3 or 1.5 mg/kg diet; study 1), dl-alpha-tocopherol (vitamin E, 4,000 or 2,000 mg/kg diet; study 2), l-selenomethionine + vitamin E (3 + 2,000 mg/kg diet or 3 + 500 mg/kg diet; study 3), or selenized yeast (target selenium levels of 9 or 3 mg/kg diet; study 4). Each chemoprevention study was terminated at 13 months post-MNU, and prostate cancer incidence was determined by histopathologic evaluation. No statistically significant reductions in prostate cancer incidence were identified in any group receiving dietary supplementation with selenium and/or vitamin E. These data do not support the hypotheses that selenium and vitamin E are potent cancer chemopreventive agents in the prostate, and when considered with the recent clinical data reported in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), show the predictive nature of this animal model for human prostate cancer chemoprevention.

Withania coagulans Extract Induces Cell Apoptosis and Inhibits COX-2 Expression in a Rat Model of Benign Prostatic Hyperplasia

PubMed Central

Sarbishegi, Maryam; Khajavi, Ozra; Arab, Mohammad Reza

2016-01-01

Background Phytotherapy is a popular treatment option in cases of benign prostatic hyperplasia (BPH), with many different herbal products being used for the treatment of this condition. Withania coagulans (WC) is an herbal medicine that has shown anti-tumoral, anti-inflammatory, and antioxidant effects. Objectives This study examined the effect of Withania coagulans extract (WCE) on prostatic cell apoptosis and cyclooxygenase-2 (COX-2) expression in cases of benign prostatic hyperplasia (BPH) in rats. Methods Forty Wistar rats were equally divided into five groups: control, sham, BPH, BPH + WCE, and BPH + CLX (celecoxib) as a positive control group. The induction of BPH was achieved via the subcutaneous injection of 3 mg/kg of testosterone propionate (TP) daily for 28 days. The animals received WCE, celecoxib, or distilled water by oral gavage accompanied by the TP injection. After four weeks, the prostate glands of the rats were weighed to measure the prostatic index (PI). The ventral lobes of the prostates were dissected and processed with paraffin blocks in order to study the number of mast cells. A TUNEL analysis was performed to evaluate the cell apoptosis, while the expression of COX-2 was examined using immunohistochemistry. Results BPH was obvious in the ventral lobe of the prostate, and the administration of WCE markedly decreased the PI and the number of mast cells (P < 0.001) in the BPH rats. Additionally, the WCE treatment induced prostatic cell apoptosis when compared to the BPH group. Furthermore, following the WCE treatment, the expression of COX-2 in the prostatic tissues was significantly decreased when compared to the BPH groups. Conclusions According to the results of this study, WCE was effective in the treatment of BPH in rats. It may therefore have beneficial effects in the treatment of patients with BPH. PMID:27878112

PROFILING GENE EXPRESSION IN HUMAN H295R ADRENOCORTICAL CARCINOMA CELLS AND RAT TESTES TO IDENTIFY PATHWAYS OF TOXICITY FOR CONAZOLE FUNGICIDES

EPA Science Inventory

Profiling Gene Expression in Human H295R Adrenocortical Carcinoma Cells and Rat Testes to Identify Pathways of Toxicity for Conazole Fungicides
Ren1, H., Schmid1, J., Retief2, J., Turpaz2, Y.,Zhang3, X.,Jones3, P., Newsted3, J.,Giesy3, J., Wolf1, D.,Wood1, C., Bao1, W., Dix1, ...

Chemoprevention of rat prostate carcinogenesis by dietary 16alpha-fluoro-5-androsten-17-one (fluasterone), a minimally androgenic analog of dehydroepiandrosterone.

PubMed

McCormick, David L; Johnson, William D; Kozub, Nicole M; Rao, K V N; Lubet, Ronald A; Steele, Vernon E; Bosland, Maarten C

2007-02-01

Dehydroepiandrosterone (DHEA) is a potent inhibitor of prostate carcinogenesis in rats. However, concerns related to the possible androgenicity of DHEA may preclude its use for chemoprevention of human prostate cancer. Studies were performed to compare the androgenicity of DHEA and a fluorinated DHEA analog, 16alpha-fluoro-5-androsten-17-one (fluasterone), and to determine the chemopreventive activity of fluasterone in the rat prostate. Comparisons of accessory sex gland weight and histology in gonadectomized male rats demonstrated that fluasterone is less androgenic than is DHEA. Fluasterone conferred significant protection against prostate carcinogenesis induced in Wistar-Unilever rats by a sequential regimen of N-methyl-N-nitrosourea+testosterone. Chronic administration of fluasterone at levels of 2000 and 1000 mg/kg diet reduced the incidence of adenocarcinoma in the dorsolateral/anterior prostate from 64% in dietary controls to 28 and 31%, respectively. Other than a dose-related suppression of body weight gain, chronic exposure to fluasterone induced no clinical evidence of toxicity; suppression of body weight gain may be either a pharmacological effect or a minimally toxic effect of the compound. These data demonstrate that a minimally androgenic analog of DHEA protects against prostate carcinogenesis induced in rats by a chemical carcinogen + androgen. The reduced androgenicity of fluasterone may obviate toxicities associated with the androgenicity of the parent compound. On this basis, fluasterone merits consideration for evaluation in clinical trials for prostate cancer prevention. The chemopreventive activity of a non-androgenic DHEA analog suggests that at least a portion of the chemopreventive activity of DHEA in the rat prostate is unrelated to hormonal effects.

Null Activity of Selenium and Vitamin E as Cancer Chemopreventive Agents in the Rat Prostate1

PubMed Central

McCormick, David L.; Rao, K.V.N.; Johnson, William D.; Bosland, Maarten C.; Lubet, Ronald A.; Steele, Vernon E.

2009-01-01

To evaluate the potential efficacy of selenium and vitamin E as inhibitors of prostate carcinogenesis, four chemoprevention studies using a common protocol were performed in a rat model of androgen-dependent prostate cancer. After stimulation of prostate epithelial cell proliferation by a sequential regimen of cyproterone acetate followed by testosterone propionate, male Wistar-Unilever rats received a single intravenous injection of N-methyl-N-nitrosourea (MNU) followed by chronic androgen stimulation via subcutaneous implantation of testosterone pellets. At one week post-MNU, groups of carcinogen-treated rats (39–44/group) were fed either basal diet or basal diet supplemented with L-selenomethionine (3 or 1.5 mg/kg diet; Study 1); DL-α-tocopherol (Vitamin E; 4000 or 2000 mg/kg diet; Study 2); L-selenomethionine + Vitamin E (3 + 2000 mg/kg diet or 3 + 500 mg/kg diet; Study 3), or selenized yeast (target selenium levels of 9 or 3 mg/kg diet; Study 4). Each chemoprevention study was terminated at 13 months post-MNU, and prostate cancer incidence was determined by histopathologic evaluation. No statistically significant reductions in prostate cancer incidence were identified in any group receiving dietary supplementation with selenium and/or vitamin E. These data do not support the hypotheses that selenium and vitamin E are potent cancer chemopreventive agents in the prostate, and when considered with the recent clinical data reported in the SELECT trial, demonstrate the predictive nature of this animal model for human prostate cancer chemoprevention. PMID:20145190

Resveratrol Improves Cell Cycle Arrest in Chronic Prostatitis Rats, by C-kit/SCF Suppression.

PubMed

He, Yi; Zeng, Huizhi; Yu, Yang; Zhang, Jiashu; Zeng, Xiaona; Gong, Fengtao; Liu, Qi; Yang, Bo

2017-08-01

Chronic prostatitis (CP) with complex pathogenesis is difficult for treatment. c-kit has been associated with the control of cell proliferation of prostate cells. This study aims to evaluate the role of resveratrol, an activator of Sirt1, in regulating the expression of c-kit in CP and investigate the consequent effects on cell cycle. Rat model of CP was established through subcutaneous injections of diphtheria-pertussis-tetanus vaccine and subsequently treated with resveratrol. Hematoxylin and eosin staining was performed to identify the histopathological changes in prostates. Western blotting and immunohistochemical staining examined the expression level of c-kit, stem cell factor (SCF), Sirt1, and cell cycle-associated proteins. The model group exhibited severe diffuse chronic inflammation, characterized by leukocyte infiltration and papillary frond protrusion into the gland cavities, and a notable increase in prostatic epithelial height. Gland lumen diameter was also significantly smaller; the activity of c-kit/SCF in the CP rats was increased significantly compared to the control group. Meanwhile, the cell cycle proteins are dysregulated significantly in CP rats. Resveratrol treatment significantly improved these factors by Sirt1 activation. Dysregulation of cell cycle was involved in the pathological processes of CP, which was improved after resveratrol treatment by the downregulation of c-kit/SCF by activating Sirt1.

Altered neurochemical profile in the McGill-R-Thy1-APP rat model of Alzheimer's disease: a longitudinal in vivo 1 H MRS study.

PubMed

Nilsen, Linn H; Melø, Torun M; Saether, Oddbjørn; Witter, Menno P; Sonnewald, Ursula

2012-11-01

We investigated metabolite levels during the progression of pathology in McGill-R-Thy1-APP rats, a transgenic animal model of Alzheimer's disease, and in healthy age-matched controls. Rats were subjected to in vivo (1) H magnetic resonance spectroscopy (MRS) of the dorsal hippocampus at age 3, 9 and 12 months and of frontal cortex at 9 and 12 months. At 3 months, a stage in which only Aβ oligomers are present, lower glutamate, myo-inositol and total choline content were apparent in McGill-R-Thy1-APP rats. At age 9 months, lower levels of glutamate, GABA, N-acetylaspartate and total choline and elevated myo-inositol and taurine were found in dorsal hippocampus, whereas lower levels of glutamate, GABA, glutamine and N-acetylaspartate were found in frontal cortex. At age 12 months, only the taurine level was significantly different in dorsal hippocampus, whereas taurine, myo-inositol, N-acetylaspartate and total creatine levels were significantly higher in frontal cortex. McGill-R-Thy1-APP rats did not show the same changes in metabolite levels with age as displayed in the controls, and overall, prominent and complex metabolite differences were evident in this transgenic rat model of Alzheimer's disease. The findings also demonstrate that in vivo (1) H MRS is a powerful tool to investigate disease-related metabolite changes in the brain. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Potential Prognostic Markers for Human Prostate Cancer

DTIC Science & Technology

2001-03-01

thymosin 0315 gene. The gene appears to exist as a single copy in the rat genome and is comprised of 3 exons distributed over 3 kilobases. The...metastatic prostate cancer cells. Autocrine motility factor ( AMF ), a prostate tumor G low low cell secreted factor [13], also affects motility of...prostate H low low carcinoma cells. Tumor cell migration in response to HIF low low ATI low low AMF has been associated with metastatic potential. AT2 low

The prostate after administration of anabolic androgenic steroids: a morphometrical study in rats.

PubMed

Vargas, Rafael Arêas; Oliveira, Leonardo Pires; Frankenfeld, Stephan; Souza, Diogo Benchimol de; Costa, Waldemar Silva; Favorito, Luciano Alves; Sampaio, Francisco José Barcellos

2013-01-01

Many adverse effects have been associated with abuse of anabolic-androgenic steroids (AAS), including disorders of the urogenital tract. The objective of this study is to analyze the morphological modifications in the prostate ventral lobe of pubertal and adult rats chronically treated with AAS, using morphometric methods. We studied 39 male Wistar rats weighing between 400 g and 550 g. The rats were divided into four groups: (a) control rats, with 105 days of age (C105) (n = 7); (b) control rats with 65 days of age (C65) (n = 9), injected only with the vehicle (peanut oil); (c) treated rats, with 105 days of age (T105) (n = 10) and (d) treated rats with 65 days of age (T65) (n = 13). The treated rats were injected with nandrolone decanoate at a dose of 10 mg.Kg-1 body weight. The steroid hormone and the vehicle were administered by intramuscular injection once a week for eight weeks. The rats were killed at 161 days of age (C105 and T105) and 121 days of age (C65 and T65) and the ventral prostate lobe was dissected and processed for histology. The height of the acinar epithelium, the surface densities of the lumen, epithelium and stroma were observed with X400 magnification using an Olympus light microscope coupled to a Sony CCD video camera, and the images transferred to a Sony monitor KX14-CP1. The selected histological areas were then quantified using the M42 test-grid system on the digitized fields. The data were analyzed with the Graphpad software. To compare the quantitative data in both groups (controls and treated) and the outcomes, Student's t-test was used (p < 0.05 was considered significant). The weight (p < 0.001) and volume (p = 0.004) of the prostate ventral lobe showed differences between C65 and T65 groups and between C105 and T105 groups. The epithelium height showed no difference between groups C65 and T65 (p = 0.8509), but the T105 group showed an increase of 32% compared to C105 (p = 0.0089). Concerning the lumen, surface density presented no

MiR-141-3p promotes prostate cancer cell proliferation through inhibiting kruppel-like factor-9 expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Jiu-zhi; Department of Urology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, 830001; Li, Jia

Evidence has revealed that some microRNAs play a critical role in tumor proliferation. We demonstrated that miR-141-3p appears to be a novel oncogene miRNA, which promotes prostate tumorigenesis and facilitates the stemness of prostate cancer cells via suppressing a key transcription factor kruppel-like factor-9 (KLF9). KLF9 is the core effector protein that might suppress tumor growth. MiR-141-3p is upregulated in prostate cancer cells and tissues compared to non-tumorigenic prostate epithelial cells and prostate tissues. MiR-141-3p positively regulated proliferation, spheroid formation, and expression of the stemness factors OCT-4, Nanog, SOX-9, Bmil, CCND1, and CD44 in PC-3 cells. Restoration of miR-141-3p suppresses themore » expression of the transcription factor KLF9 in PC-3 and accelerates prostate tumorigenesis via targeted binding with its 3′-UTR. Downregulation of KLF9 enhances spheres formation of prostate cancer cells. Our results suggest that miR-141-3p/KLF9 may play an important role in regulating the growth of prostate cancer and is a potential target of prevention and therapy. - Highlights: • MiR-141-3p is upregulated in human prostate cancer. • MiR-141-3p induces cell proliferation and apoptosis resistance. • KLF9 is a direct and functional target of miR-141-3p.« less

Arecoline augments cellular proliferation in the prostate gland of male Wistar rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saha, Indraneel; Chatterjee, Aniruddha; Mondal, Anushree

Areca nut chewing is the fourth most popular habit in the world due to its effects as a mild stimulant, causing a feeling of euphoria and slightly heightened alertness. Areca nuts contain several alkaloids and tannins, of which arecoline is the most abundant and known to have several adverse effects in humans, specially an increased risk of oral cancer. On evaluating the effects of arecoline on the male endocrine physiology in Wistar rats, it was found that arecoline treatment led to an overall enlargement and increase in the wet weight of the prostate gland, and a two-fold increase in serummore » gonadotropin and testosterone levels. Since the prostate is a major target for testosterone, the consequences of arecoline consumption were studied specifically in the prostate gland. Arecoline treatment led to an increase in the number of rough endoplasmic reticulum and reduction of secretory vesicles, signifying a hyperactive state of the prostate. Increased expression of androgen receptors in response to arecoline allowed for enhanced effect of testosterone in the prostate of treated animals, which augmented cell proliferation, subsequently confirmed by an increase in the expression of Ki-67 protein. Cellular proliferation was also the outcome of concomitant over expression of the G{sub 1}-to-S cell cycle regulatory proteins, cyclin D1 and CDK4, both at the transcriptional and translational levels. Taken together, the findings provide the first evidence that regular use of arecoline may lead to prostatic hyperplasia and hypertrophy, and eventually to disorders associated with prostate enlargement. - Highlights: > Effect of arecoline was investigated on the endocrine physiology of male Wistar rats. > Increase observed in prostate size, wet weight, serum testosterone and gonadotropins. > Arecoline increased RER, expression of androgen receptor and cellular proliferation. > Upregulation of cyclin D1 and CDK4 seen at transcriptional and translational levels. > It may

[Circulating miR-152 helps early prediction of postoperative biochemical recurrence of prostate cancer].

PubMed

Chen, Jun-Feng; Liao, Yu-Feng; Ma, Jian-Bo; Mao, Qi-Feng; Jia, Guang-Cheng; Dong, Xue-Jun

2017-07-01

To investigate the value of circulating miR-152 in the early prediction of postoperative biochemical recurrence of prostate cancer. Sixty-six cases of prostate cancer were included in this study, 35 with and 31 without biochemical recurrence within two years postoperatively, and another 31 healthy individuals were enrolled as normal controls. The relative expression levels of circulating miR-152 in the serum of the subjects were detected by qRT-PCR, its value in the early diagnosis of postoperative biochemical recurrence of prostate cancer was assessed by ROC curve analysis, and the correlation of its expression level with the clinicopathological parameters of the patients were analyzed. The expression of circulating miR-152 was significantly lower in the serum of the prostate cancer patients than in the normal controls (t = －5.212, P = 0.001), and so was it in the patients with than in those without postoperative biochemical recurrence (t = －5.727, P = 0.001). The ROC curve for the value of miR-152 in the early prediction of postoperative biochemical recurrence of prostate cancer showed the area under the curve (AUC) to be 0.906 (95% CI: 0.809－0.964), with a sensitivity of 91.4% and a specificity of 80.6%. The expression level of miR-152 was correlated with the Gleason score, clinical stage of prostate cancer, biochemical recurrence, and bone metastasis (P <0.05), decreasing with increased Gleason scores and elevated clinical stage of the malignancy. No correlation, however, was found between the miR-152 expression and the patients' age or preoperative PSA level (P >0.05). The expression level of circulating miR-152 is significantly reduced in prostate cancer patients with biochemical recurrence after prostatectomy and could be a biomarker in the early prediction of postoperative biochemical recurrence of the malignancy.

Formononetin induces the mitochondrial apoptosis pathway in prostate cancer cells via downregulation of the IGF-1/IGF-1R signaling pathway.

PubMed

Huang, Wen-Jun; Bi, Ling-Yun; Li, Zhen-Zhao; Zhang, Xing; Ye, Yu

2013-12-20

Abstract Context: Formononetin, an isoflavone, can inhibit the proliferation of cancer cells, including those of the prostate. However, its antitumor mechanism remains unclear. Aim: To investigate whether the insulin-like growth factor 1 (IGF-1)/insulin-like growth factor 1 receptor (IGF-1 R) signaling pathway mediates the formononetin antitumor effect on prostate cancer cells. Materials and methods: The viability of PC-3 cells was measured by MTT assay 48 h after formononetin treatment (25, 50 and 100 μM). Formononetin-induced cell apoptosis was measured by Hoechst 33258 staining and flow cytometry. Expression of Bax mRNA was detected by real-time PCR, and the expression levels of Bax and IGF-1 R proteins were detected by western blots. Results: At concentrations >12.5 μM, formononetin significantly inhibited the proliferation of human prostate cancer cells. Formononetin increased Bax mRNA and protein expression levels and decreased the expression levels of pIGF-1 R protein in a dose-dependent manner. Conclusion: High concentrations of formononetin-induced apoptosis in androgen-independent prostate cancer cells through inhibition of the IGF-1/IGF-1 R pathway.

Robotic high-intensity focused ultrasound (rHIFU) for the prostate cancer treatment

NASA Astrophysics Data System (ADS)

Solovov, Vyacheslav; Shaplygin, Leonid; Vozdvizhenskiy, Mikhail

2012-11-01

Introduction & Objectives: rHIFU shows a successful treatment for localized prostate cancer (PC). Here we explored the effectiveness of the rHIFU treatment for the prostate cancer, hormone-resistant prostate cancer (HRPC) and failure after external beam radiotherapy (EBRT) and radical prostatectomy (RPE). Materials & Methods: 748 patients were treated in our center between Sep 2007 - February 2012: 137 - hormone-resistance (median time before hormone-resistance 25 months), 286 - received neoadjuvant hormone therapy 6 months, 293 - no treatment before HIFU, 32 - after the EBRT failure. 667 patients underwent TURP+rHIFU, 81 only rHIFU (volume prostate <40cc). Mean follow-up is 38 months (range 3-52). All patients were divided into 3 groups: low risk progression (Gleason <7, stage T1-2N0M0, PSA<20, n= 465), high risk progression - (Gleason ≤9, stage T2-3N0M0, PSA <60, n= 251), after EBRT and RPE failure (n= 39). The mean age of the whole group of patients were 70 (52-89) years, mean prostate volume - 39 (5,5-108) cc. Results: Median PSA level 12 months after rHIFU treatment were 0,04 (0-2,24) ng/ml - low risk group, for high risk group - 0,5 (0-48,4) ng/ml, with failure after EBRT and RPE- 0,5 (0-3,2) ng/ml; 36 months after rHIFU treatment were 0,5 (0,02-3,6) ng/ml - low risk group, for high risk group - 3,2 (0-21,38) ng/ml, with failure after EBRT and RPE - 1,7 (0-9,8) ng/ml. Patients with low risk had 4,5% of progression, with high risk PC - 25%, with failure after EBRT and RPE - 19,6%. Kaplan-Meir analyses of the total group indicated that the risk of progression after 1 year follow-up was 10%, the risk of progression was 23% after 4 years of follow-up. Complications: incontinence I - 17,5%, incontinence II - 7,7%, stricture - 18,2%, fistula - 0,3 %. Conclusions: Our experience shows that rHIFU ablation is safe, minimally invasive, effective treatment with moderate side effects for the PC, hormone-resistant prostate cancer, rHIFU also may be used as a salvage

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.

PubMed

Liao, S B; Cheung, K H; Cheung, M P L; Wong, P F; O, W S; Tang, F

2014-05-01

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. © 2014 American Society of Andrology and European Academy of Andrology.

Effect of Onabotulinum Toxin A on Substance P and Receptor Neurokinin 1 in the Rat Ventral Prostate

PubMed Central

Cakir, Omer Onur; Podlasek, Carol A.; Wood, Douglas; McKenna, Kevin E.; McVary, Kevin T.

2016-01-01

Introduction The objective of this work is to examine if sensory innervation impacts lower urinary tract symptoms (LUTS). Onabotulinum toxin A (BoNTA) has been used for the treatment of overactive and neurogenic bladder and as a treatment for LUTS secondary to benign prostatic hyperplasia (BPH). The mechanism of how BoNTA impacts LUTS/BPH is unclear. In rats, BoNTA injection causes prostate denervation, apoptosis and atrophy. In clinical trials reduced prostate size and LUTS are observed inconsistently, suggesting a neurologic component. We will examine if BoNTA treatment inhibits substance P production in sensory nerve fibers in the rat prostate. Methods Twenty Sprague Dawley rats were divided into four groups including 1X PBS (control, n=6), 2.5 units Onabotulinum toxin A (BoNTA, n=6), 5 units BoNTA (n=6) injected into both lobes of the ventral prostate (VP) and sham surgery (n=2). Rats were Euthanized after one week. Substance P and its receptor neurokinin 1 localization and quantification were performed by counting the number of stained neurons and nerve bundles, by semi-quantitative immunohistochemical analysis and by western analysis. Results Substance P was localized in neuronal axons and bundles in the stroma of the VP but not in the epithelium. Receptor neurokinin 1 was identified in neuronal bundles of the stroma and in columnar epithelium of the VP ducts. Substance P decreased ~90% after BoNTA treatment (p=0.0001) while receptor neurokinin 1 did not change by IHC (p=0.213) or Western (p=0.3675). Conclusions BoNTA treatment decreases substance P in the rat VP. PMID:27144785

Deregulation of MiR-34b/Sox2 Predicts Prostate Cancer Progression.

PubMed

Forno, Irene; Ferrero, Stefano; Russo, Maria Veronica; Gazzano, Giacomo; Giangiobbe, Sara; Montanari, Emanuele; Del Nero, Alberto; Rocco, Bernardo; Albo, Giancarlo; Languino, Lucia R; Altieri, Dario C; Vaira, Valentina; Bosari, Silvano

2015-01-01

Most men diagnosed with prostate cancer will have an indolent and curable disease, whereas approximately 15% of these patients will rapidly progress to a castrate-resistant and metastatic stage with high morbidity and mortality. Therefore, the identification of molecular signature(s) that detect men at risk of progressing disease remains a pressing and still unmet need for these patients. Here, we used an integrated discovery platform combining prostate cancer cell lines, a Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model and clinically-annotated human tissue samples to identify loss of expression of microRNA-34b as consistently associated with prostate cancer relapse. Mechanistically, this was associated with epigenetics silencing of the MIR34B/C locus and increased DNA copy number loss, selectively in androgen-dependent prostate cancer. In turn, loss of miR-34b resulted in downstream deregulation and overexpression of the "stemness" marker, Sox2. These findings identify loss of miR-34b as a robust biomarker for prostate cancer progression in androgen-sensitive tumors, and anticipate a potential role of progenitor/stem cell signaling in this stage of disease.

Deregulation of MiR-34b/Sox2 Predicts Prostate Cancer Progression

PubMed Central

Russo, Maria Veronica; Gazzano, Giacomo; Giangiobbe, Sara; Montanari, Emanuele; Del Nero, Alberto; Rocco, Bernardo; Albo, Giancarlo; Languino, Lucia R.; Altieri, Dario C.; Vaira, Valentina; Bosari, Silvano

2015-01-01

Most men diagnosed with prostate cancer will have an indolent and curable disease, whereas approximately 15% of these patients will rapidly progress to a castrate-resistant and metastatic stage with high morbidity and mortality. Therefore, the identification of molecular signature(s) that detect men at risk of progressing disease remains a pressing and still unmet need for these patients. Here, we used an integrated discovery platform combining prostate cancer cell lines, a Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model and clinically-annotated human tissue samples to identify loss of expression of microRNA-34b as consistently associated with prostate cancer relapse. Mechanistically, this was associated with epigenetics silencing of the MIR34B/C locus and increased DNA copy number loss, selectively in androgen-dependent prostate cancer. In turn, loss of miR-34b resulted in downstream deregulation and overexpression of the “stemness” marker, Sox2. These findings identify loss of miR-34b as a robust biomarker for prostate cancer progression in androgen-sensitive tumors, and anticipate a potential role of progenitor/stem cell signaling in this stage of disease. PMID:26107383

Dietary prevention of hormone refractory prostate cancer in Lobund-Wistar rats: a review of studies in a relevant animal model.

PubMed

Pollard, Morris; Suckow, Mark A

2006-12-01

Lobund-Wistar (LW) rats, which have high testosterone levels, are predisposed to develop hormone-refractory prostate cancer (HRPC) spontaneously and by methylnitrosourea (MNU) induction, and the development of HRPC progresses through 2 stages. This paper reviews several studies in which LW rats were placed on soy-containing diets and were evaluated for development of either spontaneous or MNU-induced prostate cancer. The premalignant, testosterone-dependent stage is inhibited by testosterone deprivation. In the absence of testosterone deprivation, tumorigenesis progresses spontaneously to the testosterone-independent refractory stage. In LW rats: moderate caloric restriction prevented development of spontaneous prostate cancer; dietary 4-hydroxyphenylretinamide prevented MNU-induced prostate cancer; and dietary supplementation with soy protein isolate with high isoflavones prevented spontaneous and induced tumors and led to moderate reduction of serum testosterone. In rats 12 mo of age and younger, changing from the control diet to the soy+isoflavone diet significantly prevented progression of spontaneous tumors to the refractory stage of disease. Tumors that developed spontaneously and after MNU induction showed similar developmental stages and morphology, but MNU-induced tumors had shorter latency periods before development. The accumulated data indicate that soy-based diets are effective in the prevention of prostate cancer.

Cynanchum wilfordii Ameliorates Testosterone-Induced Benign Prostatic Hyperplasia by Regulating 5α-Reductase and Androgen Receptor Activities in a Rat Model

PubMed Central

Lee, Gyuok; Shin, Jawon; Choi, Hakjoon; Jo, Ara; Pan, SangO; Bae, Donghyuck; Lee, Yongwook; Choi, Chulyung

2017-01-01

Benign prostatic hyperplasia (BPH) is characterized by uncontrolled proliferation of the prostate gland. Cynanchum wilfordii has been reported to improve sexual behavior in male rats. In this study, we investigated the protective effect of an aqueous extract of C. wilfordii (CWW) against BPH development in a testosterone-induced BPH rat model. The rats were divided into the following six groups: sham/vehicle; BPH/vehicle; BPH/finasteride; and three CWW doses (50, 100, and 200 mg/kg). After a 4-week treatment with CWW, the rats were euthanized at scheduled times, and their prostates were weighed, followed by a histopathological examination. Prostate growth inhibition rates in rats administered CWW 50, 100, and 200 mg/kg were 54.5%, 51.8%, and 50.1%, respectively. The BPH/CWW group showed decreased serum testosterone and dihydrotestosterone (DHT) levels compared to the BPH/vehicle group. Furthermore, the BPH/CWW group showed reduced prostate testosterone and DHT levels compared to the BPH/vehicle group. Mechanistically, the reverse transcription-polymerase chain reaction revealed downregulated mRNA expression levels of the androgen receptor, 5α-reductase, and B-cell lymphoma-2 (Bcl-2) in the BPH/CWW200 group compared with those in the testosterone-induced groups. In conclusion, these findings show the effectiveness of CWW in slowing the progression of testosterone-induced BPH in rats. PMID:28953224

[Therapeutic efficacy of compound Xuanju capsule on autoimmune prostatitis in rats: an experimental study].

PubMed

Li, Tian-Fu; Wu, Qiu-Yue; Li, Wei-Wei; Zhang, Cui; Li, Na; Shang, Xue-Jun; Xia, Xin-Yi; Xu, Hao-Qin; Huang, Yu-Feng

2014-05-01

To evaluate the therapeutic effect of Compound Xuanju Capsule (CXC) on autoimmune prostatitis in rat models. Sixty healthy male Wistar rats were randomly divided into five groups of equal number: blank control, low-concentration purified prostate protein (low-conc PPP), low-conc PPP + CXC treatment, high-concentration PPP (hi-con PPP), and hi-conc PPP + CXC treatment. Autoimmune prostatitis models were established by intragastric administration of PPP solution at 15 mg/ml (low concentration) and 80 mg/ml, respectively. At 30 days after modeling, the rats in the blank control and low-conc and hi-conc PPP model groups were treated with normal saline, and those in the other two groups with CXC at a daily dose of 0.068 g/ml. At 30, 45, and 60 days, all the animals were sacrificed for observation of pathological changes in the prostate tissue and determination of the levels of IL-8, IL-10, and TNF-alpha in the serum. Compared with the PPP models, the hi-conc PPP + CXC group showed significantly reduced levels of IL-8 and TNF-alpha in the serum at 45 days ([148.54 +/- 17.23] and [62.14 +/- 5.59] pg/ml vs [100.77 +/- 11.08] and [32.63 +/- 2.91] pg/ml, P < 0.05) and at 60 days ([143.69 +/- 17.28] and [59.38 +/- 5.50] pg/mlvs [95.77 +/-10.53] and [29.63 +/- 2.66] pg/ml, P < 0.05), and so did the low-cone PPP + CXC group at 45 days ([128.47 +/- 12.21] and [40.43 +/- 3.64] pg/ml vs [111.76 +/- 10.07] and [35.44 +/- 3.17] pg/ml, P < 0.05) and at 60 days ([131.07 +/- 10.93] and [43.34 +/- 3.91] pg/ml vs [97.46 +/- 8.75] and [30.44 +/- 2.75] pg/ml, P < 0.05). The serum level of IL-10 was remarkably elevated in the hi-cone PPP + CXC group as compared with that of the PPP models at 45 and 60 days ([189.14 +/- 16.78] and [184.14 +/- 15.89] pg/ml vs [230.48 +/- 29.96] and [248.48 +/- 31.03] pg/ml, P < 0.05), and so was it in low-cone PPP + CXC group ([223.14 +/- 17.87] and [224.14 +/- 17.93] pg/ml vs [231.42 +/- 23.18] and [249.42 +/- 24.97] pg/ml, P < 0.05). Pathological

Effect of seabuckthorn leaf extracts on circulating energy fuels, lipid peroxidation and antioxidant parameters in rats during exposure to cold, hypoxia and restraint (C-H-R) stress and post stress recovery.

PubMed

Saggu, Shalini; Kumar, Ratan

2008-06-01

The present study was carried out to study mechanism of adaptogenic activity of seabuckthorn leaf extract, administered orally in rats both in single and five doses at a dose of 100mg/kg body weight 30min prior to C-H-R exposure. The efficacy of the extract was studied on circulating energy fuels, lipid peroxidation and anti-oxidant parameters in rats on attaining the T(rec) 23 degrees C during C-H-R exposure and after recovery (T(rec) 37 degrees C) from C-H-R induced hypothermia. Single dose treatment in rats restricted rise in blood malondialdehyde (MDA) levels and decrease in glutathione (GSH) and catalase (CAT) levels. Both single and five doses also restricted the rise in serum free fatty acids (FFA) and lactate dehydrogenase (LDH) levels on attaining T(rec) 23 degrees C during C-H-R exposure, suggesting more efficient utilization of FFA for energy production and better maintained cell membrane permeability. This suggested that the adaptogenic activity of the extract might be due to its anti-oxidative activity, maintained blood glucose levels, better utilization of FFA and improved cell membrane permeability.

Curcumin sensitizes prostate cancer cells to radiation partly via epigenetic activation of miR-143 and miR-143 mediated autophagy inhibition.

PubMed

Liu, Jianbo; Li, Min; Wang, Yuewei; Luo, Jianchao

2017-08-01

Curcumin has been reported as a radiosensitizer in prostate cancer. But the underlying mechanism is not well understood. In this study, we firstly assessed how curcumin affects the expression of miR-143/miR-145 cluster. Then, we investigated whether miR-143 is involved in regulation of radiosensitivity and its association with autophagy in prostate cancer cells. Our data showed that PC3, DU145 and LNCaP cells treated with curcumin had significantly restored miR-143 and miR-145 expression. Curcumin showed similar effect as 5-AZA-dC on reducing methylation of CpG dinucleotides in miR-143 promoter. In addition, curcumin treatment reduced the expression of DNMT1 and DNMT3B, which contribute to promoter hypermethylation of the miR-143/miR-145 cluster. Therefore, we infer that curcumin can restore miR-143 and miR-145 expression via hypomethylation. MiR-143 overexpression and curcumin pretreatment enhanced radiation induced cancer cell growth inhibition and apoptosis. MiR-143 and curcumin remarkably reduced radiation-induced autophagy in PC3 and DU145 cells. MiR-143 overexpression alone also reduced the basal level of autophagy in DU145 cells. Mechanistically, miR-143 can suppress autophagy in prostate cancer cells at least via downregulating ATG2B. Based on these findings, we infer that curcumin sensitizes prostate cancer cells to radiation partly via epigenetic activation of miR-143 and miR-143 mediated autophagy inhibition.

[Prostatic inflammation-induced chronic pelvic pain: Roles of substance P and c-fos in the spinal cord].

PubMed

Liu, Ying-jia; Song, Guo-hong; Zhang, Chen

2015-08-01

To explore the possible pain mechanism of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). The models of CP/CPPS were established in male Wistar rats by the autoimmune method. The paw withdrawal threshold (PWT) was detected using Von Frey filament. The expressions of the substance P and c-fos in the prostate and spinal L5-S2 segments were determined by immunohistochemistry followed by analysis of their correlation with CP/CPPS. Compared with the control rats, the CP/CPPS models showed significantly decreased PWT (P < 0.05), remarkable prostatic inflammation, enlarged scope of lesions, and obvious interstitial lymphocytic infiltration (P < 0.05). Both the expressions of substance P and c-fos were markedly elevated in the prostate and spinal dorsal horn (L5-S2) of the rat models (P < 0.05), but the expression of substance P in the prostate exhibited no correlation with that in the spinal cord (r = 0.099, P = 0.338), nor did that of c-fos (r = 0.027, P = 0.454). The upregulated expressions of substance P and c-fos in the spinal cord L5-S2 sections may be associated with the pain mechanism of CP/CPPS.

Anti-inflammatory and antiproliferative activities of date palm pollen (Phoenix dactylifera) on experimentally-induced atypical prostatic hyperplasia in rats

PubMed Central

2011-01-01

Background Atypical prostatic hyperplasia (APH) is a pseudoneoplastic lesion that can mimic prostate adenocarcinoma because of its cytologic and architectural features. Suspension of date palm pollen (DPP) is an herbal mixture that is widely used in folk medicine for male infertility. The aim of the present study was to evaluate the effect of DPP suspension and extract on APH-induced rats. Methods APH was induced in adult castrated Wistar rats by both s.c. injection of testosterone (0.5 mg/rat/day) and smearing citral on shaved skin once every 3 days for 30 days. Saw palmetto (100mg/kg), DPP suspension (250, 500 and 1000 mg/kg), and lyophilized DPP extract (150,300 and 600 mg/kg) were given orally daily for 30 days. All medications were started 7 days after castration and along with testosterone and citral. Results The histopathological feature in APH-induced prostate rats showed evidence of hyperplasia and inflammation. Immunohistochemical examination revealed that the expressions of IL-6, IL-8, TNF-α, IGF-1 and clusterin were increased, while the expression of TGF-β1 was decreased that correlates with presence of inflammation. Moreover, histopathological examination revealed increased cellular proliferation and reduced apoptosis in ventral prostate. Both saw palmetto and DPP treatment has ameliorated these histopathological and immunohistochemical changes in APH-induced rats. These improvements were not associated with reduction in the prostatic weight that may be attributed to the persistence of edema. Conclusion DPP may have a potential protective effect in APH-induced Wistar rats through modulation of cytokine expression and/or upregulation of their autocrine/paracrine receptors. PMID:22195697

Protective effect of tadalafil on the functional and structural changes of the rat ventral prostate caused by chronic pelvic ischemia.

PubMed

Zarifpour, Mona; Nomiya, Masanori; Sawada, Norifumi; Andersson, Karl-Erik

2015-02-15

The etiology of Benign Prostatic Hyperplasia (BPH), a common among aged men, is not fully understood, however, in addition to androgens and aging, chronic ischemia has been proposed to contribute. Using an established rat model, we investigated whether chronic ischemia alters the structural and functional properties of the ventral rat prostate, and whether phosphodiesterase type 5 (PDE5) inhibitor (tadalafil) may have a protective action. Adult male Sprague-Dawley rats were divided into control, arterial endothelial injury (AI), and AI with tadalafil treatment (AI-tadalafil) groups. AI and AI-tadalafil groups underwent endothelial injury of the iliac arteries and received a 2% cholesterol diet following AI. AI-tadalafil rats were treated with tadalafil (2 mg/kg/day) orally for 8 weeks after AI. The control group received a regular diet. After 8 weeks, animals were sacrificed, and pharmacological and morphological studies on prostate tissues were performed. Iliac arteries from AI rats displayed neo-intimal formation and luminal occlusion, an effect that was not prevented by tadalafil treatment. In the AI group, there was an obvious epithelial atrophy and a statistically significant increase in collagen fibers compared with the controls. Immunohistochemically, there was an up-regulation of smooth muscle α-actin (SMA). Contractile responses of prostate strips to KCl, electrical field stimulation (EFS), and phenylephrine (PE) were significantly higher after AI than in controls. Chronic treatment with tadalafil prevented the increase in contractile responses in ischemic tissue, and decreased the collagen deposition compared with the AI group. In this rat model, chronic pelvic ischemia caused distinct functional and morphological changes in the prostate. Prostatic tissue from ischemic animals showed an increased contractile response to electrical and pharmacological stimulation, an increase in SMA, and an increased deposition of collagen. All these changes could be

Prostate Cancer Risk and DNA Methylation Signatures in Aging Rats following Developmental BPA Exposure: A Dose-Response Analysis.

PubMed

Prins, Gail S; Ye, Shu-Hua; Birch, Lynn; Zhang, Xiang; Cheong, Ana; Lin, Han; Calderon-Gierszal, Esther; Groen, Jacob; Hu, Wen-Yang; Ho, Shuk-Mei; van Breemen, Richard B

2017-07-11

Previous studies have uncovered heightened prostatic susceptibility to hormone-induced neoplasia from early-life exposure to low-dose bisphenol A (BPA). However, significant data gaps remain that are essential to address for biological relevance and necessary risk assessment. A complete BPA dose-response analysis of prostate lesions across multiple prostatic lobes was conducted that included internal BPA dosimetry, progression to adenocarcinoma with aging and mechanistic connections to epigenetically reprogramed genes. Male neonatal Sprague-Dawley rats were briefly exposed to 0.1 to 5,000 μg BPA/kg BW on postnatal days (PND) 1, 3, and 5. Individual prostate lobes plus periurethral prostatic ducts were evaluated at 7 mo or 1 y of age without or with adult testosterone plus estradiol (T+E) to promote carcinogenesis. DNA methylation of five genes was quantified by bisulfite genomic sequencing in d-200 dorsal prostates across BPA doses. Serum free-BPA and BPA-glucuronide were quantitated in sera of individual PND 3 pups collected 1 hr postexposure utilizing ultra-high-pressure tandem mass spectrometry (UHPLC-MS-MS). The lowest BPA dose initiated maximal hormonal carcinogenesis in lateral prostates despite undetectable free BPA 1 hr postexposure. Further, prostatic intraepithelial neoplasia (PIN) progressed to carcinoma in rats given neonatal low-dose BPA with adult T+E but not in rats given adult T+E alone. The dorsal and ventral lobes and periurethral prostatic ducts exhibited a nonmonotonic dose response with peak PIN, proliferation and apoptotic values at 10–100 μg/kg BW. This was paralleled by nonmonotonic and dose-specific DNA hypomethylation of genes that confer carcinogenic risk, with greatest hypomethylation at the lowest BPA doses. Developmental BPA exposures heighten prostate cancer susceptibility in a complex dose- and lobe-specific manner. Importantly, elevated carcinogenic risk is found at doses that yield undetectable serum free BPA. Dose

Prostate Cancer Risk and DNA Methylation Signatures in Aging Rats following Developmental BPA Exposure: A Dose–Response Analysis

PubMed Central

Ye, Shu-Hua; Birch, Lynn; Zhang, Xiang; Cheong, Ana; Lin, Han; Calderon-Gierszal, Esther; Groen, Jacob; Hu, Wen-Yang; Ho, Shuk-Mei; van Breemen, Richard B.

2017-01-01

Background: Previous studies have uncovered heightened prostatic susceptibility to hormone-induced neoplasia from early-life exposure to low-dose bisphenol A (BPA). However, significant data gaps remain that are essential to address for biological relevance and necessary risk assessment. Objectives: A complete BPA dose–response analysis of prostate lesions across multiple prostatic lobes was conducted that included internal BPA dosimetry, progression to adenocarcinoma with aging and mechanistic connections to epigenetically reprogramed genes. Methods: Male neonatal Sprague-Dawley rats were briefly exposed to 0.1 to 5,000μg BPA/kg BW on postnatal days (PND) 1, 3, and 5. Individual prostate lobes plus periurethral prostatic ducts were evaluated at 7 mo or 1 y of age without or with adult testosterone plus estradiol (T+E) to promote carcinogenesis. DNA methylation of five genes was quantified by bisulfite genomic sequencing in d-200 dorsal prostates across BPA doses. Serum free-BPA and BPA-glucuronide were quantitated in sera of individual PND 3 pups collected 1 hr postexposure utilizing ultra-high-pressure tandem mass spectrometry (UHPLC-MS-MS). Results: The lowest BPA dose initiated maximal hormonal carcinogenesis in lateral prostates despite undetectable free BPA 1 hr postexposure. Further, prostatic intraepithelial neoplasia (PIN) progressed to carcinoma in rats given neonatal low-dose BPA with adult T+E but not in rats given adult T+E alone. The dorsal and ventral lobes and periurethral prostatic ducts exhibited a nonmonotonic dose response with peak PIN, proliferation and apoptotic values at 10–100μg/kg BW. This was paralleled by nonmonotonic and dose-specific DNA hypomethylation of genes that confer carcinogenic risk, with greatest hypomethylation at the lowest BPA doses. Conclusions: Developmental BPA exposures heighten prostate cancer susceptibility in a complex dose- and lobe-specific manner. Importantly, elevated carcinogenic risk is found at

Effects of Kangquan Recipe on sex steroids and cell proliferation in rats with benign prostatic hyperplasia.

PubMed

Huang, Yuan-peng; Du, Jian; Hong, Zhen-feng; Chen, Zhi-qing; Wu, Jin-fa; Zhao, Jin-yan

2009-08-01

To investigate the effects of Kangquan Recipe (KQR) on sex steroids and cell proliferation in an experimental benign prostatic hyperplasia (BPH) model in rats. Seventy-two SD rats were randomly divided into six groups: the normal group, the model group, the finasteride group, and the low-, middle-, and high-dose KQR groups, 12 in each group. Except those in the normal group, the rats were injected with testosterone after castration for the establishment of BPH model and then given respectively with normal saline, finasteride, and low-, middle-, and high-dose of KQR for 30 days. The levels of plasma testosterone (T) and estradiol (E(2)) were determined by enzyme-linked immunosorbent assay (ELISA), and the mRNA expression ) of proliferating cell nuclear antigen (PCNA) in prostate tissue was detected by reverse transcription-polymerase chain reaction (RT-PCR) after administration. Compared with the model group, the prostate weight, the plasma T, and the mRNA expression of PCNA were significantly lower, and the plasma E(2) and the ratio of E(2)/T were higher in the three KQR groups (P<0.05 or P<0.01). There was no significant difference in the prostate weight, plasma T and E(2), and ratio of E(2)/T among the finasteride group and the three KQR groups (P>0.05). The mRNA expressions of PCNA were significantly higher in the middle- and low-dose of KQR groups than those in the finasteride group (P<0.05). KQR shows multitarget effects on experimental BPH rats, and the mechanism might be related with regulating the balance of plasma T and E(2) and decreasing the PCNAmRNA expression in prostate tissue to restrain cell proliferation in a dose-dependent manner.

Selenomethionine and alpha-tocopherol do not inhibit prostate carcinogenesis in the testosterone plus estradiol-treated NBL rat model.

PubMed

Ozten, Nur; Horton, Lori; Lasano, Salamia; Bosland, Maarten C

2010-03-01

Previous studies with selenium and/or vitamin E in prostate carcinogenesis animal models have been negative, but these models may not involve oxidative stress mechanisms. In this study, we examined the potential of selenomethionine and alpha-tocopherol to modulate prostate cancer development in the testosterone plus estradiol-treated NBL rat, a model that does involve sex hormone-induced oxidative stress mechanisms and prostatic inflammation. One week following the implantation with hormone-filled Silastic implants, rats were fed diets containing l-selenomethionine (1.5 or 3.0 mg/kg), DL-alpha-tocopherol acetate (2,000 or 4,000 mg/kg), or a natural ingredient control diet (NIH-07). The development of prostate carcinomas was not affected by dietary treatment with either agent. Food intake, body weight, and mortality were also not affected. The high dose of selenomethionine reduced the severity of epithelial dysplasia in the lateral prostate that was not associated with inflammation, and alpha-tocopherol reduced in a dose-related fashion the incidence of marked inflammation and marked epithelial dysplasia in the lateral prostate, regardless of whether these lesions were associated with inflammation. alpha-Tocopherol significantly increased the incidence of adenocarcinomas of the mammary glands at both dietary concentrations. Collectively, our findings suggest that selenomethionine and alpha-tocopherol supplementation does not prevent prostate cancer in rats fed diets with nutritionally adequate levels of selenium and vitamin E. Importantly, the results of the current animal studies and those reported previously were fully predictive of the outcome of the Selenium and Vitamin E Cancer Prevention Trial.

Selenomethionine and α-Tocopherol do not Inhibit Prostate Carcinogenesis in the Testosterone plus Estradiol-Treated NBL Rat Model

PubMed Central

Özten, Nur; Horton, Lori; Lasano, Salamia; Bosland, Maarten C.

2009-01-01

Previous studies with selenium and/or vitamin E in prostate carcinogenesis animal models have been negative, but these models may not involve oxidative stress mechanisms. In this study, we examined the potential of selenomethionine and α-tocopherol to modulate prostate cancer development in the testosterone plus estradiol-treated NBL rat, a model that does involve sex-hormone induced oxidative stress mechanisms and prostatic inflammation. One week following implantation with hormone-filled Silastic implants, rats were fed diets containing L-selenomethionine (1. 5 or 3. 0 mg/kg), DL-α-tocopherol acetate (2,000 mg/kg or 4,000 mg/kg), or a natural ingredient control diet (NIH-07). Development of prostate carcinomas was not affected by dietary treatment with either agent. Food intake, body weight, and mortality were also not affected. The high dose of selenomethionine reduced the severity of epithelial dysplasia in the lateral prostate that was not associated with inflammation and α-tocopherol reduced in a dose-related fashion the incidence of marked inflammation and marked epithelial dysplasia in the lateral prostate, regardless of whether these lesions were associated with inflammation. α-Tocopherol significantly increased the incidence of adenocarcinomas of the mammary glands at both dietary concentrations. Collectively, our findings suggest that selenomethionine and α-tocopherol supplementation does not prevent prostate cancer in rats fed diets with nutritionally adequate levels of selenium and vitamin E. Importantly, the results of the current animal studies and those reported previously were fully predictive of the outcome of the SELECT trial. PMID:20179302

The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44.

PubMed

Liu, Can; Kelnar, Kevin; Liu, Bigang; Chen, Xin; Calhoun-Davis, Tammy; Li, Hangwen; Patrawala, Lubna; Yan, Hong; Jeter, Collene; Honorio, Sofia; Wiggins, Jason F; Bader, Andreas G; Fagin, Randy; Brown, David; Tang, Dean G

2011-02-01

Cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs, and dysregulation of miRNAs has been implicated in tumorigenesis. CSCs in many tumors--including cancers of the breast, pancreas, head and neck, colon, small intestine, liver, stomach, bladder and ovary--have been identified using the adhesion molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic and tumor-initiating and metastatic capacities are enriched in the CD44(+) cell population, but whether miRNAs regulate CD44(+) prostate cancer cells and prostate cancer metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 target, was underexpressed in CD44(+) prostate cancer cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk or purified CD44(+) prostate cancer cells inhibited clonogenic expansion, tumor regeneration, and metastasis. In contrast, expression of miR-34a antagomirs in CD44(-) prostate cancer cells promoted tumor development and metastasis. Systemically delivered miR-34a inhibited prostate cancer metastasis and extended survival of tumor-bearing mice. We identified and validated CD44 as a direct and functional target of miR-34a and found that CD44 knockdown phenocopied miR-34a overexpression in inhibiting prostate cancer regeneration and metastasis. Our study shows that miR-34a is a key negative regulator of CD44(+) prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs.

hZIP1 zinc uptake transporter down regulation and zinc depletion in prostate cancer

PubMed Central

Franklin, Renty B; Feng, Pei; Milon, B; Desouki, Mohamed M; Singh, Keshav K; Kajdacsy-Balla, André; Bagasra, Omar; Costello, Leslie C

2005-01-01

Background The genetic and molecular mechanisms responsible for and associated with the development and progression of prostate malignancy are largely unidentified. The peripheral zone is the major region of the human prostate gland where malignancy develops. The normal peripheral zone glandular epithelium has the unique function of accumulating high levels of zinc. In contrast, the ability to accumulate zinc is lost in the malignant cells. The lost ability of the neoplastic epithelial cells to accumulate zinc is a consistent factor in their development of malignancy. Recent studies identified ZIP1 (SLC39A1) as an important zinc transporter involved in zinc accumulation in prostate cells. Therefore, we investigated the possibility that down-regulation of hZIP1 gene expression might be involved in the inability of malignant prostate cells to accumulate zinc. To address this issue, the expression of hZIP1 and the depletion of zinc in malignant versus non-malignant prostate glands of prostate cancer tissue sections were analyzed. hZIP1 expression was also determined in malignant prostate cell lines. Results hZIP1 gene expression, ZIP1 transporter protein, and cellular zinc were prominent in normal peripheral zone glandular epithelium and in benign hyperplastic glands (also zinc accumulating glands). In contrast, hZIP1 gene expression and transporter protein were markedly down-regulated and zinc was depleted in adenocarcinomatous glands and in prostate intra-epithelial neoplastic foci (PIN). These changes occur early in malignancy and are sustained during its progression in the peripheral zone. hZIP1 is also expressed in the malignant cell lines LNCaP, PC-3, DU-145; and in the nonmalignant cell lines HPr-1 and BPH-1. Conclusion The studies clearly establish that hZIP1 gene expression is down regulated and zinc is depleted in adenocarcinomatous glands. The fact that all the malignant cell lines express hZIP1 indicates that the down-regulation in adenocarcinomatous

The Role of Stromally Produced Cathepsin D in Promoting Prostate Tumorigenesis

DTIC Science & Technology

2012-09-01

combination with androgen in the NBL rat model produced a 100% incidence of PCa. Treatment with androgen alone induced PCa with a 40% incidence (30...prostate, Eur. Urol. 30, 243–248 (1996). 30. M. C. Bosland, H. Ford, L. Horton, Induction at high incidence of ductal prostate adenocarcinomas in NBL / Cr

Influence of N-methyl-N-nitrosourea, testosterone, and N-(4-hydroxyphenyl)-all-trans-retinamide on prostate cancer induction in Wistar-Unilever rats.

PubMed

McCormick, D L; Rao, K V; Dooley, L; Steele, V E; Lubet, R A; Kelloff, G J; Bosland, M C

1998-08-01

The influence of chemical carcinogen, hormonal stimulation, and chronic dietary administration of the synthetic retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), on the induction of prostate cancer in male Wistar-Unilever rats was determined. Three different tumor induction regimens were used: (a) a single i.v. dose of 50 mg of N-methyl-N-nitrosourea (MNU) per kg body weight, followed by chronic androgen stimulation via s.c. implantation of two silastic capsules containing 40 mg testosterone each; (b) a single i.v. dose of 50 mg of MNU per kg body weight (no testosterone treatment); and (c) chronic androgen stimulation with implanted testosterone capsules (no MNU treatment). In a fourth series of animals, the incidence of spontaneous prostate tumors was determined in groups of rats receiving neither carcinogen nor hormone stimulation. Within each series, parallel groups of animals were fed a control (vehicle-supplemented) diet or control diet supplemented with 4-HPR beginning 1 day after carcinogen administration; retinoid administration was continuous until termination of the study at 450 days. The incidence of accessory sex gland cancer in rats treated sequentially with MNU + testosterone was >60%, in comparison with cancer incidences of <20% in rats receiving MNU only and <5% in rats treated with testosterone only. No spontaneous accessory sex gland tumors were observed in rats receiving no carcinogen and no testosterone. Tumor induction in the accessory sex glands by MNU + testosterone was relatively specific for the prostate: the incidence of carcinoma of the dorsolateral/anterior prostate was more than 5-fold greater than the incidence of cancer present only in the seminal vesicle. 4-HPR conferred no protection against cancer induction in the prostate by any regimen of MNU and/or testosterone. These results demonstrate the importance of both carcinogen exposure and hormone stimulation on the induction of neoplasia in the prostate of Wistar

Transdifferentiated rat pancreatic progenitor cells (AR42J-B13/H) respond to phenobarbital in a rat hepatocyte-specific manner.

PubMed

Osborne, M; Haltalli, M; Currie, R; Wright, J; Gooderham, N J

2016-07-01

Phenobarbital (PB) is known to produce species-specific effects in the rat and mouse, being carcinogenic in certain mouse strains, but only in rats if treated after a DNA damaging event. PB treatment in the rat and mouse also produces disparate effects on cell signalling and miRNA expression profiles. These responses are induced by short term and prolonged PB exposure, respectively, with the latter treatments being difficult to examine mechanistically in primary hepatocytes due to rapid loss of the original hepatic phenotype and limited sustainability in culture. Here we explore the rat hepatocyte-like B13/H cell line as a model for hepatic response to PB exposure in both short-term and longer duration treatments. We demonstrate that PB with Egf treatment in the B13/H cells resulted in a significant increase in Erk activation, as determined by the ratio of phospho-Erk to total Erk, compared to Egf alone. We also show that an extended treatment with PB in the B13/H cells produces a miRNA response similar to that seen in the rat in vivo, via the time-dependent induction of miR-182/96. Additionally, we confirm that B13/H cells respond to Car activators in a typical rat-specific manner. These data suggest that the B13/H cells produce temporal responses to PB that are comparable to those reported in short-term primary rat hepatocyte cultures and in the longer term are similar to those in the rat in vivo. Finally, we also show that Car-associated miR-122 expression is decreased by PB treatment in B13/H cells, a PB-induced response that is common to the rat, mouse and human. We conclude that the B13/H cell system produces a qualitative response comparable to the rat, which is different to the response in the mouse, and that this model could be a useful tool for exploring the functional consequences of PB-sensitive miRNA changes and resistance to PB-mediated tumours in the rat. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Study on the inhibition of Mfn1 by plant-derived miR5338 mediating the treatment of BPH with rape bee pollen.

PubMed

Chen, Xuan; Wu, Ren-Zhao; Zhu, Yong-Qiang; Ren, Ze-Ming; Tong, Ye-Ling; Yang, Feng; Dai, Guan-Hai

2018-01-30

Recent studies have found that plant derived microRNA can cross-kingdom regulate the expression of genes in humans and other mammals, thereby resisting diseases. Can exogenous miRNAs cross the blood-prostate barrier and entry prostate then participate in prostate disease treatment? Using HiSeq sequencing and RT-qPCR technology, we detected plant miRNAs that enriched in the prostates of rats among the normal group, BPH model group and rape bee pollen group. To forecast the functions of these miRNAs, the psRobot software and TargetFinder software were used to predict their candidate target genes in rat genome. The qRT-PCR technology was used to validate the expression of candidate target genes. Plant miR5338 was enriched in the posterior lobes of prostate gland of rats fed with rape bee pollen, which was accompanied by the improvement of BPH. Among the predicted target genes of miR5338, Mfn1 was significantly lower in posterior lobes of prostates of rats in the rape bee pollen group than control groups. Further experiments suggested that Mfn1 was highly related to BPH. These results suggesting that plant-derived miR5338 may involve in treatment of rat BPH through inhibiting Mfn1 in prostate. These results will provide more evidence for plant miRNAs cross-kingdom regulation of animal gene, and will provide preliminary theoretical and experimental basis for development of rape bee pollen into innovative health care product or medicine for the treatment of BPH.

Management of experimental benign prostatic hyperplasia in rats using a food-based therapy containing Telfairia occidentalis seeds.

PubMed

Ejike, Chukwunonso E C C; Ezeanyika, Lawrence U S

2011-01-01

The usefulness of diet containing Telfairia occidentalis seeds, in managing benign prostatic hyperplasia (BPH) in rats was studied. Twenty male Wistar rats were divided into four equal groups. BPH was induced by sub-cutaneous injection of dihydrotestosterone (DHT) and estradiol valerate (ratio, 10:1) every other day for 28 days. Rats in the test group were placed on the test diet for 7 days following disease induction. One control group (DC) was fed on a normal diet for 7 days following disease induction. Two other control groups, HC and HDC, were given sub-cutaneous olive oil (vehicle) for the same duration, and placed on the test diet and normal diet, respectively. Markers of BPH, and hormone profile were determined using standard methods. The results show that relative prostate weight and protein content of the prostates were lower [albeit not significantly (p>0.05)] in the test group, relative to the DC group. Serum prostatic acid phosphatase concentrations (U/L) decreased significantly (p<0.05) from 2.9 ± 0.2 in the DC group to 2.1 ± 0.7 in the test group. Histological findings corroborate these data. The testosterone: estradiol ratio (× 10(3)) was increased from 4.0 ± 0.2 in the DC group to 4.6 ± 0.2 in the test group. The test diet reduced the mass and secretory activity of the enlarged prostate and may act by increasing the testosterone: estradiol ratio.

Pharmacokinetics and Metabolism of (R,R)-Methoxyfenoterol in Rat

PubMed Central

Siluk, Danuta; Mager, Donald E.; Kim, Hee Seung; Wang, Yan; Furimsky, Anna M.; Ta, Amy; Iyer, Lalitha V.; Green, Carol E.; Wainer, Irving W.

2010-01-01

(R,R)-Fenoterol (Fen), a β2-adrenoceptor agonist, is under clinical investigation in the treatment of congestive heart disease. The pharmacokinetics and metabolism of the 4-methoxyphenyl derivative of (R,R)-Fen, (R,R)-MFen, have been determined following intravenous and oral administration to the rat and compared with corresponding results obtained with (R,R)-Fen. Results of the study suggest that (R,R)-MFen can offer pharmacokinetic and metabolic advantages in comparison to an earlier (R,R)-Fen.The oral administration revealed that the net exposure of (R,R)-MFen was about three-fold higher than that of (R,R)-Fen (7.2 versus 2.3 min × nmol ml-1), while intravenous administration proved that the clearance was significantly reduced, 48 versus 146 ml min-1 kg-1, the T1/2 was significantly longer, 152.9 versus 108.9 min and the area under the curve (AUC) was significantly increased, 300 versus 119 min × nmol ml-1.(R,R)-MFen was primarily cleared by glucuronidation associated with significant presystemic glucuronidation of the compound. After intravenous and oral administration of (R,R)-MFen, (R,R)-Fen and (R,R)-Fen-G were detected in the urine samples indicating that (R,R)-MFen was O-demethylated and subsequently conjugated to (R,R)-Fen-G. The total (R,R)-Fen and (R,R)-Fen-G as a percentage of the dose after intravenous administration was 3.6% while after oral administration was 0.3%, indicating that only a small fraction of the drug escaped presystemic glucuronidation and was available for O-demethylation.The glucuronidation pattern was confirmed by the results from in vitro studies where incubation of (R,R)-MFen with rat hepatocytes produced (R,R)-MFen-G, (R,R)-Fen and (R,R)-Fen-G, while incubation with rat intestinal microsomes only resulted in the formation of (R,R)-MFen-G. PMID:20039779

Pharmacokinetics and metabolism of (R,R)-methoxyfenoterol in rat.

PubMed

Siluk, D; Mager, D E; Kim, H S; Wang, Y; Furimsky, A M; Ta, A; Iyer, L V; Green, C E; Wainer, I W

2010-03-01

(R,R)-fenoterol (Fen), a beta(2)-adrenoceptor agonist, is under clinical investigation in the treatment of congestive heart disease. The pharmacokinetics and metabolism of the 4-methoxyphenyl derivative of (R,R)-Fen, (R,R)-MFen, have been determined following intravenous and oral administration to the rat and compared with corresponding results obtained with (R,R)-Fen. Results from the study suggest that (R,R)-MFen can offer pharmacokinetic and metabolic advantages in comparison to an earlier (R,R)-Fen. The oral administration revealed that the net exposure of (R,R)-MFen was about three-fold higher than that of (R,R)-Fen (7.2 versus 2.3 min x nmol ml(-1)), while intravenous administration proved that the clearance was significantly reduced, 48 versus 146 ml min(-1) kg(-1), the T(1/2) was significantly longer, 152.9 versus 108.9 min, and the area under the curve (AUC) was significantly increased, 300 versus 119 min x nmol ml(-1). (R,R)-MFen was primarily cleared by glucuronidation associated with significant presystemic glucuronidation of the compound. After intravenous and oral administration of (R,R)-MFen, (R,R)-Fen and (R,R)-Fen-G were detected in the urine samples indicating that (R,R)-MFen was O-demethylated and subsequently conjugated to (R,R)-Fen-G. The total (R,R)-Fen and (R,R)-Fen-G as a percentage of the dose after intravenous administration was 3.6%, while after oral administration was 0.3%, indicating that only a small fraction of the drug escaped presystemic glucuronidation and was available for O-demethylation. The glucuronidation pattern was confirmed by the results from in vitro studies where incubation of (R,R)-MFen with rat hepatocytes produced (R,R)-MFen-G, (R,R)-Fen and (R,R)-Fen-G, while incubation with rat intestinal microsomes only resulted in the formation of (R,R)-MFen-G.

Muscarinic and alpha 1-adrenergic receptor binding characteristics of saw palmetto extract in rat lower urinary tract.

PubMed

Suzuki, Mayumi; Oki, Tomomi; Sugiyama, Tomomi; Umegaki, Keizo; Uchida, Shinya; Yamada, Shizuo

2007-06-01

To elucidate the in vitro and ex vivo effects of saw palmetto extract (SPE) on autonomic receptors in the rat lower urinary tract. The in vitro binding affinities for alpha 1-adrenergic, muscarinic, and purinergic receptors in the rat prostate and bladder were measured by radioligand binding assays. Rats received vehicle or SPE (0.6 to 60 mg/kg/day) orally for 4 weeks, and alpha 1-adrenergic and muscarinic receptor binding in tissues of these rats were measured. Saw palmetto extract inhibited specific binding of [3H]prazosin and [N-methyl-3H]scopolamine methyl chloride (NMS) but not alpha, beta-methylene adenosine triphosphate [2,8-(3)H]tetrasodium salt in the rat prostate and bladder. The binding activity of SPE for muscarinic receptors was four times greater than that for alpha 1-adrenergic receptors. Scatchard analysis revealed that SPE significantly reduced the maximal number of binding sites (Bmax) for each radioligand in the prostate and bladder under in vitro condition. Repeated oral administration of SPE to rats brought about significant alteration in Bmax for prostatic [3H]prazosin binding and for bladder [3H]NMS binding. Such alteration by SPE was selective to the receptors in the lower urinary tract. Saw palmetto extract exerts significant binding activity on autonomic receptors in the lower urinary tract under in vitro and in vivo conditions.

Acarbose reduces blood glucose by activating miR-10a-5p and miR-664 in diabetic rats.

PubMed

Zhang, Qian; Xiao, Xinhua; Li, Ming; Li, Wenhui; Yu, Miao; Zhang, Huabing; Wang, Zhixin; Xiang, Hongding

2013-01-01

MicroRNAs (miRNAs) are non-coding RNA molecules involved in the post-transcriptional regulation of a large number of genes, including those involved in glucose metabolism. Acarbose is an α-glucosidase inhibitor that improves glycemic control by decreasing the intestinal absorption of glucose, thereby decreasing the elevation of postprandial blood glucose. However, acarbose is poorly absorbed into the blood stream from the gut. Therefore, the exact mechanisms by which acarbose affects glucose metabolism are unclear. This study investigated the effect of acarbose on glucose metabolism in diabetic rats and tested the hypothesis that acarbose acts directly through miRNA-regulated expression in the intestinal epithelium. Rats were divided into four groups: a control group, a diabetic group (DM), a low dose of acarbose group (AcarL) and a high dose of acarbose group (AcarH). Ileum samples were analyzed using miRCURY LNA™ microRNA Array, qPCR and immunohistochemistry. We found that 8-week treatment with acarbose significantly decreased fasting blood glucose. Oral glucose tolerance tests (OGTT) showed that blood glucose was significantly reduced in the AcarL and AcarH groups at 30 min, 60 min and 120 min after oral glucose administration. We found that miR-151*, miR-10a-5p, miR-205, miR-17-5p, miR-145 and miR-664 were up-regulated in the AcarH group, while miR-541 and miR-135b were down-regulated. Through target gene analysis, real time PCR and immunohistochemistry verification, we found that these miRNAs suppressed the expression of proinflammatory cytokines [IL6 (interleukin 6) and TNF (tumor necrosis factor)] and mitogen activated protein kinase 1 (MAPK1). Our data suggest that acarbose can improve blood glucose in diabetic rats through the MAPK pathway and can down-regulate proinflammatory factors by activating miR-10a-5p and miR-664 in the ileum.

Acarbose Reduces Blood Glucose by Activating miR-10a-5p and miR-664 in Diabetic Rats

PubMed Central

Zhang, Qian; Xiao, Xinhua; Li, Ming; Li, Wenhui; Yu, Miao; Zhang, Huabing; Wang, Zhixin; Xiang, Hongding

2013-01-01

MicroRNAs (miRNAs) are non-coding RNA molecules involved in the post-transcriptional regulation of a large number of genes, including those involved in glucose metabolism. Acarbose is an α-glucosidase inhibitor that improves glycemic control by decreasing the intestinal absorption of glucose, thereby decreasing the elevation of postprandial blood glucose. However, acarbose is poorly absorbed into the blood stream from the gut. Therefore, the exact mechanisms by which acarbose affects glucose metabolism are unclear. This study investigated the effect of acarbose on glucose metabolism in diabetic rats and tested the hypothesis that acarbose acts directly through miRNA-regulated expression in the intestinal epithelium. Rats were divided into four groups: a control group, a diabetic group (DM), a low dose of acarbose group (AcarL) and a high dose of acarbose group (AcarH). Ileum samples were analyzed using miRCURY LNA™ microRNA Array, qPCR and immunohistochemistry. We found that 8-week treatment with acarbose significantly decreased fasting blood glucose. Oral glucose tolerance tests (OGTT) showed that blood glucose was significantly reduced in the AcarL and AcarH groups at 30 min, 60 min and 120 min after oral glucose administration. We found that miR-151*, miR-10a-5p, miR-205, miR-17-5p, miR-145 and miR-664 were up-regulated in the AcarH group, while miR-541 and miR-135b were down-regulated. Through target gene analysis, real time PCR and immunohistochemistry verification, we found that these miRNAs suppressed the expression of proinflammatory cytokines [IL6 (interleukin 6) and TNF (tumor necrosis factor)] and mitogen activated protein kinase 1 (MAPK1). Our data suggest that acarbose can improve blood glucose in diabetic rats through the MAPK pathway and can down-regulate proinflammatory factors by activating miR-10a-5p and miR-664 in the ileum. PMID:24260283

An improved light microscopical histoquantitative method for the stereological analysis of the rat ventral prostate lobe.

PubMed

Romppanen, T; Huttunen, E; Helminen, H J

1980-07-01

An improved light microscopical histoquantitative method for the analysis of the stereologic structure of the ventral lobe of the rat prostate is introduced. From paraffin-embedded tissue sections, volumetric fractions of the acinar parenchyma, the glandular epithelium, the glandular lumen, and the interacinar tissue were determined. The surface density of the glandular epithelium and the length density of the glandular tubules per cubic millimeter of tissue were also calculated. The corresponding total amount/quantity of each tissue compartment was computed for the whole ventral lobe based on the weight of the lobe. Using established stereologic laws, the height of the epithelium, the diameter of the glandular tubules, the free distance between the glandular tubules, and the distance between the glandular centers (means) were determined. The fitness of the method was tested by analyzing, in addition to normal prostates, ventral prostates of rats castrated 30 days before sacrifice.

Tumor-targeting Salmonella typhimurium A1-R inhibits human prostate cancer experimental bone metastasis in mouse models.

PubMed

Toneri, Makoto; Miwa, Shinji; Zhang, Yong; Hu, Cameron; Yano, Shuya; Matsumoto, Yasunori; Bouvet, Michael; Nakanishi, Hayao; Hoffman, Robert M; Zhao, Ming

2015-10-13

Bone metastasis is a frequent occurrence in prostate cancer patients and often is lethal. Zoledronic acid (ZOL) is often used for bone metastasis with limited efficacy. More effective models and treatment methods are required to improve the outcome of prostate cancer patients. In the present study, the effects of tumor-targeting Salmonella typhimurium A1-R were analyzed in vitro and in vivo on prostate cancer cells and experimental bone metastasis. Both ZOL and S. typhimurium A1-R inhibited the growth of PC-3 cells expressing red fluorescent protien in vitro. To investigate the efficacy of S. typhimurium A1-R on prostate cancer experimental bone metastasis, we established models of both early and advanced stage bone metastasis. The mice were treated with ZOL, S. typhimurium A1-R, and combination therapy of both ZOL and S. typhimurium A1-R. ZOL and S. typhimurium A1-R inhibited the growth of solitary bone metastases. S. typhimurium A1-R treatment significantly decreased bone metastasis and delayed the appearance of PC-3 bone metastases of multiple mouse models. Additionally, S. typhimurium A1-R treatment significantly improved the overall survival of the mice with multiple bone metastases. The results of the present study indicate that S. typhimurium A1-R is useful to prevent and inhibit prostate cancer bone metastasis and has potential for future clinical use in the adjuvant setting.

Flaxseed reduces epithelial proliferation but does not affect basal cells in induced benign prostatic hyperplasia in rats.

PubMed

de Amorim Ribeiro, Ilma Cely; da Costa, Carlos Alberto Soares; da Silva, Vivian Alves Pereira; Côrrea, Lanna Beatriz Neves Silva; Boaventura, Gilson Teles; Chagas, Mauricio Alves

2017-04-01

This study aimed to quantitatively and qualitatively evaluate the effects of a flaxseed-based diet on the histoarchitecture of the prostate of normal Wistar rats and of rats with induced BPH. The study included four experimental groups of ten animals each: casein control group (CCG), who were fed a casein-based diet; flaxseed control group (FCG), who were fed a flaxseed-based diet; hyperplasia-induced casein group (HICG), who were fed a casein-based diet; and hyperplasia-induced flaxseed group (HIFG), who were fed a flaxseed-based diet. Hyperplasia was induced by the subcutaneous implantation of silicone pellets containing testosterone propionate. After 20 weeks, the rats were euthanized and their prostate fixed in buffered formalin. Tissue sections were stained with HE, picrosirius red and immunostained for nuclear antigen p63. Histomorphometric analysis evaluated the epithelial thickness, epithelial area, individual luminal area, and total area of prostatic alveoli. The mean epithelial thickness obtained for HIFG and HICG was 16.52 ± 1.65 and 20.58 ± 2.86 µm, respectively. The mean epithelial thickness in HICG was greater than that in the other groups tested. HIFG had a smaller epithelial thickness and lower percentage of papillary projections in the prostatic alveoli. No significant difference was observed between CCG and FCG. The total area and mean alveolar area showed no significant differences between the groups. The number of cells immunostained for p63 was not significantly different between the groups evaluated. These results suggest that flaxseed has a protective effect on the prostate epithelium in BPH-induced animals.

Prevalence of Corynebacterial 16S rRNA Sequences in Patients with Bacterial and “Nonbacterial” Prostatitis

PubMed Central

Tanner, Michael A.; Shoskes, Daniel; Shahed, Asha; Pace, Norman R.

1999-01-01

The etiology of chronic prostatitis syndromes in men is controversial, particularly when positive cultures for established uropathogens are lacking. Although identification of bacteria in prostatic fluid has relied on cultivation and microscopy, most microorganisms in the environment, including some human pathogens, are resistant to cultivation. We report here on an rRNA-based molecular phylogenetic approach to the identification of bacteria in prostate fluid from prostatitis patients. Positive bacterial signals were seen for 65% of patients with chronic prostatitis overall. Seven of 11 patients with bacterial signals but none of 6 patients without bacterial signals were cured with antibiotic-based therapy. Results indicate the occurrence in the prostate fluid of a wide spectrum of bacterial species representing several genera. Most rRNA genes were closely related to those of species belonging to the genera Corynebacterium, Staphylococcus, Peptostreptococcus, Streptococcus, and Escherichia. Unexpectedly, a wide diversity of Corynebacterium species was found in high proportion compared to the proportions of other bacterial species found. A subset of these 16S rRNA sequences represent those of undescribed species on the basis of their positions in phylogenetic trees. These uncharacterized organisms were not detected in control samples, suggesting that the organisms have a role in the disease or are the consequence of the disease. These studies show that microorganisms associated with prostatitis generally occur as complex microbial communities that differ between patients. The results also indicate that microbial communities distinct from those associated with prostatitis may occur at low levels in normal prostatic fluid. PMID:10325338

Carcinogenic effects of cadmium in the noble (NBL/Cr) rat: induction of pituitary, testicular, and injection site tumors and intraepithelial proliferative lesions of the dorsolateral prostate.

PubMed

Waalkes, M P; Anver, M; Diwan, B A

1999-12-01

Cadmium is a known human carcinogen based on findings of lung cancer in exposed populations. A more controversial target site for cadmium is the human prostate gland, for which some studies indicate a link between cadmium exposure and cancer. Our work in various strains of Wistar rats has shown that cadmium can induce tumors in the ventral lobe of the prostate. The relevance of this type of lesion to human prostate cancer has been questioned because the ventral lobe of the rat prostate, unlike the dorsolateral lobe, has no embryological homolog in the human gland. In this study we investigated the chronic toxic and carcinogenic effects of cadmium in the Noble (NBL/Cr) rat, with particular attention to lesions of the prostate. Cadmium chloride (CdCl2) was given as a single sc injection (0, 1, 2, 4, 8, 16, or 32 micromol/kg) to groups (initially n = 30) of 10-week-old rats. Rats were observed for up to 72 weeks following exposure. In rats that were injected with the lower doses of cadmium (< or =4 micromol/kg), a clear dose-related increase in proliferative lesions of the dorsolateral prostate occurred (0 micromol/kg = 36% incidence, 1 micromol/kg = 62%, 2 micromol/kg = 65%; 4 micromol/kg = 79%; trend p < 0.003). Lesions were described as intraepithelial hyperplasia with occasional areas of atypical epithelial cells, without stromal invasion. At higher doses (> or =8 micromol/kg) the proliferative-lesion response in the dorsolateral prostate gradually declined to near control levels (8 micromol/kg = 63%; 16 micromol/kg = 60%; 32 micromol/kg = 52%). The loss of prostatic response at the higher doses of cadmium was probably due to loss of testicular function secondary to cadmium treatment. This was reflected in a very high incidence (>90%) of lesions, indicative of testicular hypofunction, including tubular degeneration, mineralization, and interstitial (Leydig) cell tumors, at doses in excess of 16 micromol/kg. Malignant injection-site sarcomas occurred at the two

Hsa-miR-146a-5p modulates androgen-independent prostate cancer cells apoptosis by targeting ROCK1.

PubMed

Xu, Bin; Huang, Yeqing; Niu, Xiaobing; Tao, Tao; Jiang, Liang; Tong, Na; Chen, Shuqiu; Liu, Ning; Zhu, Weidong; Chen, Ming

2015-12-01

MicroRNAs (miRNAs) have been demonstrated playing important roles in the procession of prostate cancer cells transformation from androgen-dependence to androgen-independence. We conducted the miRNA microarray and realtime PCR analyses in both androgen-dependent (ADPC) and androgen-independent prostate cancer (AIPC) tissues. We also explored the role of hsa-miR-146a-5p (miR-146a) in MSKCC prostate cancer clinical database. Moreover, the impact of miR-146a on prostate cancer cells apoptosis were detected by Hoechst staining and fluorescence-activated cell sorter (FACS). Its target is predicted by DIANA LAB online database and the result was assumed by western blotting and luciferase assay. We demonstrated that miR-146a was down-regulated in AIPC tissues and cell lines compared to that in the ADPC tissues. In MSKCC data re-analyses, we found that miR-146a was underexpressed in metastatic prostate cancer tissues and those with Gleason score >8, moreover, low level of miR-146a represented a high biochemical relapse rate after radical prostatectomy. In the functional analyses, we transfected miR-146a mimics into CPRC cell lines and found miR-146a induced cells apoptosis. In mechanic analyses, we found that miR-146a inhibited the basal level of Rho-associated, coiled-coil containing protein kinase 1 (ROCK1) expression by targeting its 3'UTR and an inverse correlation of expression between miR-146a and ROCK1 was observed. Moreover, caspase 3 activity was stimulated by miR-146a overexpression. miR-146a has a critical role in the process of AIPC prostate cancer cells apoptosis through regulation of ROCK/Caspase 3 pathway. Targeting this pathway may be a promising therapeutic strategy for future personalized anti-cancer treatment. © 2015 Wiley Periodicals, Inc.

Mitigation of arsenic-induced acquired cancer phenotype in prostate cancer stem cells by miR-143 restoration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ngalame, Ntube N.O., E-mail: ngalamenn@niehs.nih.g

Inorganic arsenic, an environmental contaminant and a human carcinogen is associated with prostate cancer. Emerging evidence suggests that cancer stem cells (CSCs) are the driving force of carcinogenesis. Chronic arsenic exposure malignantly transforms the human normal prostate stem/progenitor cell (SC) line, WPE-stem to arsenic-cancer SCs (As-CSCs), through unknown mechanisms. MicroRNAs (miRNAs) are small, non-coding RNAs that negatively regulate gene expression at the posttranscriptional level. In prior work, miR-143 was markedly downregulated in As-CSCs, suggesting a role in arsenic-induced malignant transformation. In the present study, we investigated whether loss of miR-143 expression is important in arsenic-induced transformation of prostate SCs. Restorationmore » of miR-143 in As-CSCs was achieved by lentivirus-mediated miR-143 overexpression. Cells were assessed bi-weekly for up to 30 weeks to examine mitigation of cancer phenotype. Secreted matrix metalloproteinase (MMP) activity was increased by arsenic-induced malignant transformation, but miR-143 restoration decreased secreted MMP-2 and MMP-9 enzyme activities compared with scramble controls. Increased cell proliferation and apoptotic resistance, two hallmarks of cancer, were decreased upon miR-143 restoration. Increased apoptosis was associated with decreased BCL2 and BCL-XL expression. miR-143 restoration dysregulated the expression of SC/CSC self-renewal genes including NOTCH-1, BMI-1, OCT4 and ABCG2. The anticancer effects of miR-143 overexpression appeared to be mediated by targeting and inhibiting LIMK1 protein, and the phosphorylation of cofilin, a LIMK1 substrate. These findings clearly show that miR-143 restoration mitigated multiple cancer characteristics in the As-CSCs, suggesting a potential role in arsenic-induced transformation of prostate SCs. Thus, miR-143 is a potential biomarker and therapeutic target for arsenic-induced prostate cancer. - Highlights: • Chronic arsenic exposure

[Overexpression of miR-519d-3p inhibits the proliferation of DU-145 prostate cancer cells by reducing TRAF4].

PubMed

Li, Xiaohui; Han, Xingtao; Yang, Jinhui; Sun, Jiantao; Wei, Pengtao

2018-01-01

Objective To observe the effect of microRNA-519d-3p (miR-519d-3p) on the proliferation of prostate cancer cells and explore the possible molecular mechanism. Methods The expression level of miR-519d-3p in PC-3, DU-145, 22RV1, PC-3M, LNCaP human prostate cancer cells and RWPE-1 human normal prostate epithelial cells was detected by real-time quantitative PCR. miR-519d-3p mimics or negative control microRNAs (miR-NC) was transfected into the prostate cancer cells with the lowest level of miR-519d-3p expression. Transfection efficiency was examined. The effect of miR-519d-3p on the cell cycle of prostate cancer was detected by flow cytometry. MTT assay and plate clone formation assay were used to detect its effect on the proliferation of prostate cancer cells. Bioinformatics software was used to predict and dual luciferase reporter assay was used to validate the target gene of miR-519d-3p. Real-time quantitative PCR was used to detect the expression of miR-519d-3p target gene. Western blot analysis was used to detect the expression of target gene protein and downstream protein. Results The expression of miR-519d-3p in normal prostate epithelial cells was significantly higher than that in prostate cancer cells, and the lowest was found in DU-145 cells. After transfected with miR-519d-3p mimics, the expression level of miR-519d-3p in DU-145 cells increased significantly. Bioinformatics prediction and dual luciferase reporter gene confirmed that tumor necrosis factor receptor associated factor 4 (TRAF4) was the target gene of miR-519d-3p. Overexpression of miR-519d-3p significantly reduced the expression of TRAF4 gene and its downstream TGF-β signaling pathway proteins in the prostate cancer cells. Conclusion The expression of miR-519d-3p is down-regulated in prostate cancer cells. Overexpression of miR-519d-3p can inhibit the proliferation of prostate cancer cells. The possible mechanism is that miR-519d-3p inhibits the expression of TRAF4.

A selective androgen receptor modulator with minimal prostate hypertrophic activity restores lean body mass in aged orchidectomized male rats.

PubMed

Allan, George; Sbriscia, Tifanie; Linton, Olivia; Lai, Muh-Tsann; Haynes-Johnson, Donna; Bhattacharjee, Sheela; Ng, Raymond; Sui, Zhihua; Lundeen, Scott

2008-06-01

Androgens are required for the maintenance of normal sexual activity in adulthood and for enhancing muscle growth and lean body mass in adolescents and adults. Androgen receptor (AR) ligands with tissue selectivity (selective androgen receptor modulators, or SARMs) have potential for treating muscle wasting, hypogonadism of aging, osteoporosis, female sexual dysfunction, and other indications. JNJ-37654032 is a nonsteroidal AR ligand with mixed agonist and antagonist activity in androgen-responsive cell-based assays. It is an orally active SARM with muscle selectivity in orchidectomized rat models. It stimulated growth of the levator ani muscle with ED(50) 0.8 mg/kg, stimulating maximal growth at a dose of 3mg/kg. In contrast, it stimulated ventral prostate growth to 21% of its full size at 3mg/kg. At the same time, JNJ-37654032 reduced prostate weight in intact rats by 47% at 3mg/kg, while having no inhibitory effect on muscle. Using magnetic resonance imaging to monitor body composition, JNJ-37654032 restored about 20% of the lean body mass lost following orchidectomy in aged rats. JNJ-37654032 reduced follicle-stimulating hormone levels in orchidectomized rats and reduced testis size in intact rats. JNJ-37654032 is a potent prostate-sparing SARM with the potential for clinical benefit in muscle-wasting diseases.

hsa-miR-135a-1 inhibits prostate cancer cell growth and migration by targeting EGFR.

PubMed

Xu, Bin; Tao, Tao; Wang, Yiduo; Fang, Fang; Huang, Yeqing; Chen, Shuqiu; Zhu, Weidong; Chen, Ming

2016-10-01

Prostate cancer is one of the leading causes of death in men worldwide. Differentially expressed microRNAs (miRNAs) are associated with metastatic prostate cancer. However, their potential roles for affecting prostate cancer initiation and progression remain largely unknown. Here, we examined the aberrant expression profiles of miRNAs in human metastatic prostate cancer tissues. We further validated our miRNA expression data using two large, independent clinical prostate cancer datasets from the Memorial Sloan Kettering Cancer Center (MSKCC) and The Cancer Genome Atlas (TCGA). Our data support a model in which hsa-miR-135-1 acts as a potential tumor suppressor in metastatic prostate cancer. First, its downregulation was positively correlated with late TNM stage, high Gleason score, and adverse prognosis. Second, cell growth, cell cycle progression, cell migration and invasion, and xenograft tumor formation were dramatically inhibited by miR-135a overexpression. Third, in the microarray gene expression data analysis using Gene Set Enrichment Analysis (GSEA), Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis, Ingenuity Pathway Analysis (IPA), and Oncomine concept analysis, we showed that miR-135a targets multiple oncogenic pathways including epidermal growth factor receptor (EGFR), which we verified using functional experimental assays. These results help advance our understanding of the function of miRNAs in metastatic prostate cancer and provide a basis for further clinical investigation.

Characterization of fibroblast-free CWR-R1ca castration-recurrent prostate cancer cell line.

PubMed

Shourideh, Mojgan; DePriest, Adam; Mohler, James L; Wilson, Elizabeth M; Koochekpour, Shahriar

2016-09-01

The previously established CWR-R1 cell line has been used as an in vitro model representing castration-recurrent prostate cancer. Microscopic observation of subconfluent cells demonstrated two distinct cellular morphologies: polygonal closely aggregated epithelial cells surrounded by bipolar fibroblastic cells with long processes. This study sought to establish and characterize a fibroblast-free derivative of the CWR-R1 cell line. The CWR-R1ca cell line was established from CWR-R1 cells by removing fibroblasts using multiple cycles of short-term trypsinization, cloning, and pooling single-cell colonies. Authentication of fibroblast-free CWR-R1ca cells was demonstrated by analyzing the expression of cytodifferentiation and prostate-associated markers, DNA and cytogenetic profiling, and growth pattern in the absence or presence of androgen. CWR-R1ca is an androgen-sensitive cell line that expresses the androgen receptor (AR) and its splice variant 7 and the luminal epithelia markers, CK-8, CK-18, and c-Met. CWR-R1fb fibroblasts isolated from CWR-R1 cells express AR, hepatocyte growth factor-α, and mouse β-actin but not AR-V7 or epithelial markers. Cytogenetic analysis of CWR-R1ca cells revealed a hyperdiploid male with numerical gains in chromosomes 1, 7, 8, 10, 11, and 12, deletion of one chromosome 2 allele, structural abnormalities that include der(1)t(1:4), der(4)t(2:4), der(10)t(4:10), and an unbalanced reciprocal translocation between chromosome 6 and 14. DNA-profiling revealed that CWR-R1ca cells had significant short-tandem repeat marker homology with CWR22Pc and CWR22Rv1 cell lines, which indicated lineage derivation from CWR22 prostate cancer xenografts. CWR-R1ca cells were responsive to the growth stimulatory effects of dihydrotestosterone (DHT) in the femtomolar range. This study establishes CWR-R1ca cells as a fibroblast-free derivative of the castration-recurrent CWR-R1 cell line. Prostate 76:1067-1077, 2016. © 2016 Wiley Periodicals, Inc. © 2016

Androgen receptor regulated microRNA miR-182-5p promotes prostate cancer progression by targeting the ARRDC3/ITGB4 pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yao, Jingjing; Xu, Chen; Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, 415th Feng Yang Road, Shanghai, 200003

Abstracts: MicroRNAs (miRNAs) are important endogenous gene regulators that play key roles in prostate cancer development and metastasis. However, specific miRNA expression patterns in prostate cancer tissues from Chinese patients remain largely unknown. In this study, we compared miRNA expression patterns in 65 pairs of prostate cancer and para-cancer tissues by RNA sequencing and found that miR-182-5p was the most up-regulated miRNA in prostate cancer tissues. The result was validated using realtime PCR in 18 pairs of prostate cancer and para-cancer tissues. In in vitro analysis, it was confirmed that miR-182-5p promotes prostate cancer cell proliferation, invasion and migration and inhibitmore » apoptosis. In addition, the androgen receptor directly regulated the transcription of miR-182-5p, which could target to the 3′UTR of ARRDC3 mRNA and affect the expression of ARRDC3 and its downstream gene ITGB4. For the in vivo experiment, miR-182-5p overexpression also promoted the growth and progression of prostate cancer tumors. In this regard, we suggest that miR-182-5p may be a key androgen receptor-regulated factor that contributes to the development and metastasis of Chinese prostate cancers and may be a potential target for the early diagnosis and therapeutic studies of prostate cancer. -- Highlights: •miR-182-5p is the mostly up-regulated miRNA in Chinese prostate cancer. •miR-182-5p is regulated by androgen receptor. •miR-182-5p promotes prostate cancer progression. •miR-182-5p regulates ARRDC3/ITGB4 pathway.« less

Expression of Pleiotrophin in the Prostate is Androgen Regulated and it Functions as an Autocrine Regulator of Mesenchyme and Cancer Associated Fibroblasts and as a Paracrine Regulator of Epithelia

PubMed Central

Orr, Brigid; Vanpoucke, Griet; Grace, O Cathal; Smith, Lee; Anderson, Richard A; Riddick, Antony CP; Franco, Omar E; Hayward, Simon W; Thomson, Axel A

2011-01-01

BACKGROUND Androgens and paracrine signaling from mesenchyme/stroma regulate development and disease of the prostate, and gene profiling studies of inductive prostate mesenchyme have identified candidate molecules such as pleiotrophin (Ptn). METHODS Ptn transcripts and protein were localized by in situ and immunohistochemistry and Ptn mRNA was quantitated by Northern blot and qRT-PCR. Ptn function was examined by addition of hPTN protein to rat ventral prostate organ cultures, primary human fetal prostate fibroblasts, prostate cancer associated fibroblasts, and BPH1 epithelia. RESULTS During development, Ptn transcripts and protein were expressed in ventral mesenchymal pad (VMP) and prostatic mesenchyme. Ptn was localized to mesenchyme surrounding ductal epithelial tips undergoing branching morphogenesis, and was located on the surface of epithelia. hPTN protein stimulated branching morphogenesis and stromal and epithelial proliferation, when added to rat VP cultures, and also stimulated growth of fetal human prostate fibroblasts, prostate cancer associated fibroblasts, and BPH1 epithelia. PTN mRNA was enriched in patient-matched normal prostate fibroblasts versus prostate cancer associated fibroblasts. PTN also showed male enriched expression in fetal human male urethra versus female, and between wt male and ARKO male mice. Transcripts for PTN were upregulated by testosterone in fetal human prostate fibroblasts and organ cultures of female rat VMP. Ptn protein was increased by testosterone in organ cultures of female rat VMP and in rat male urethra compared to female. CONCLUSIONS Our data suggest that in the prostate Ptn functions as a regulator of both mesenchymal and epithelial proliferation, and that androgens regulate Ptn levels. Prostate 71:305–317, 2011. © 2010 Wiley-Liss, Inc. PMID:20812209

Investigation of a Putative Estrogen-Imprinting Gene, Phosphodiesterase Type IV Variant (PDE4D4), in Determining Prostate Cancer Risk

DTIC Science & Technology

2007-04-01

ductal prostate adenocarcinomas in NBL / Cr and Sprague-Dawley Hsd:SD rats treated with a combination of testosterone and estradiol-17h or...Androl 1981;2(6):293–9. 80] Bosland MC, Ford H, Horton L. Induction at high incidence of ductal prostate adenocarcinomas in NBL /Cr and Sprague–Dawley

Effects of 2,4-dichlorophenoxyacetic acid on the ventral prostate of rats during the peri-pubertal, pubertal and adult stage.

PubMed

Pochettino, Arístides A; Hapon, María Belén; Biolatto, Silvana M; Madariaga, María José; Jahn, Graciela A; Konjuh, Cintia N

2016-10-01

The herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) is used on a wide variety of terrestrial and aquatic broadleaf weeds. 2,4-D has been shown to produce a wide range of adverse effects on animal and human health. The aim of the current study was to evaluate the effects of pre- and postnatal exposure to 2,4-D on rat ventral prostate (VP). Pregnant rats were exposed daily to oral doses of 70 mg/kg/day of 2,4-D from 16 days of gestation up to 23 days after delivery. Then, the treated groups (n = 8) were fed with a 2,4-D added diet until sacrificed by decapitation on postnatal day (PND) 45, 60, or 90. Morphometric studies were performed and androgen receptor (AR) protein levels in the VP were determined. AR, insulin-like growth factor-I (IGF-1) and insulin-like growth factor-I receptor (IGF-1R) mRNA expression in the VP along with testosterone (T), dihydroxytestosterone (DHT), growth hormone (GH) and IGF-1 serum levels were also determined to ascertain whether these parameters were differentially affected. Results of this study showed that 2,4-D exposure during gestation and until adulthood altered development of the prostate gland in male rats, delaying it at early ages while increasing its size in adults, indicate that 2,4-D could behave as endocrine disruptors (EDs).

The Histamine H1 Receptor Participates in the Increased Dorsal Telencephalic Neurogenesis in Embryos from Diabetic Rats.

PubMed

Solís, Karina H; Méndez, Laura I; García-López, Guadalupe; Díaz, Néstor F; Portillo, Wendy; De Nova-Ocampo, Mónica; Molina-Hernández, Anayansi

2017-01-01

Increased neuron telencephalic differentiation during deep cortical layer formation has been reported in embryos from diabetic mice. Transitory histaminergic neurons within the mesencephalon/rhombencephalon are responsible for fetal histamine synthesis during development, fibers from this system arrives to the frontal and parietal cortex at embryo day (E) 15. Histamine is a neurogenic factor for cortical neural stem cells in vitro through H 1 receptor (H 1 R) which is highly expressed during corticogenesis in rats and mice. Furthermore, in utero administration of an H 1 R antagonist, chlorpheniramine, decreases the neuron markers microtubuline associated protein 2 (MAP2) and forkhead box protein 2. Interestingly, in the diabetic mouse model of diabetes induced with streptozotocin, an increase in fetal neurogenesis in terms of MAP2 expression in the telencephalon is reported at E11.5. Because of the reported effects on cortical neuron differentiation of maternal diabetes in one hand and of histamine in the other, here the participation of histamine and H 1 R on the increased dorsal telencephalic neurogenesis was explored. First, the increased neurogenesis in the dorsal telencephalon at E14 in diabetic rats was corroborated by immunohistochemistry and Western blot. Then, changes during corticogenesis in the level of histamine was analyzed by ELISA and in H 1 R expression by qRT-PCR and Western blot and, finally, we tested H 1 R participation in the increased dorsal telencephalic neurogenesis by the systemic administration of chlorpheniramine. Our results showed a significant increase of histamine at E14 and in the expression of the receptor at E12. The administration of chlorpheniramine to diabetic rats at E12 prevented the increased expression of βIII-tubulin and MAP2 mRNAs (neuron markers) and partially reverted the increased level of MAP2 protein at E14, concluding that H 1 R have an important role in the increased neurogenesis within the dorsal telencephalon of

Dietary soy and tea mitigate chronic inflammation and prostate cancer via NFκB pathway in the Noble rat model

PubMed Central

Hsu, Anna; Bruno, Richard S.; Löhr, Christiane V.; Taylor, Alan W.; Dashwood, Rodrick H.; Bray, Tammy M.; Ho, Emily

2010-01-01

Chronic inflammation and nuclear factor-kappa B (NFκB) have been implicated in prostate cancer development; thus, dietary factors that inhibit NFκB may serve as effective chemo-preventative agents. Prostate cancer risk is significantly lower in Asian countries compared to the US, which has prompted interest in the potential chemopreventative action of Asian dietary components such as soy and green tea. This study examined the effects of dietary soy and tea on NFκB activation and inflammation in vivo using a hormone-induced rat model for prostate cancer. Male Noble rats implanted with estradiol and testosterone were divided into 4 dietary groups: control, soy, tea, or soy+ tea. NFκB activation and inflammatory cytokines were measured post implantation. The combination of soy and tea suppressed NFκB p50 binding activity and protein levels via induction of IκBα. Soy and tea also decreased prostate inflammatory infiltration, increased Bax/BcL2 ratio, and decreased protein expression of TNFα, IL-6 and IL1-β compared to control. Soy and tea attenuated prostate malignancy by decreasing prostate hyperplasia. These effects were not apparent in groups treated with soy or tea alone. The ongoing in vivo studies thus far suggest that combination of foods, such as soy and tea, may inhibit hormone-induced pro-inflammatory NFκB signals that contribute to prostate cancer development. PMID:20801632

Global analysis of H3K27me3 as an epigenetic marker in prostate cancer progression.

PubMed

Ngollo, Marjolaine; Lebert, Andre; Daures, Marine; Judes, Gaelle; Rifai, Khaldoun; Dubois, Lucas; Kemeny, Jean-Louis; Penault-Llorca, Frederique; Bignon, Yves-Jean; Guy, Laurent; Bernard-Gallon, Dominique

2017-04-12

H3K27me3 histone marks shape the inhibition of gene transcription. In prostate cancer, the deregulation of H3K27me3 marks might play a role in prostate tumor progression. We investigated genome-wide H3K27me3 histone methylation profile using chromatin immunoprecipitation (ChIP) and 2X400K promoter microarrays to identify differentially-enriched regions in biopsy samples from prostate cancer patients. H3K27me3 marks were assessed in 34 prostate tumors: 11 with Gleason score > 7 (GS > 7), 10 with Gleason score ≤ 7 (GS ≤ 7), and 13 morphologically normal prostate samples. Here, H3K27me3 profiling identified an average of 386 enriched-genes on promoter regions in healthy control group versus 545 genes in GS ≤ 7 and 748 genes in GS > 7 group. We then ran a factorial discriminant analysis (FDA) and compared the enriched genes in prostate-tumor biopsies and normal biopsies using ANOVA to identify significantly differentially-enriched genes. The analysis identified ALG5, EXOSC8, CBX1, GRID2, GRIN3B, ING3, MYO1D, NPHP3-AS1, MSH6, FBXO11, SND1, SPATS2, TENM4 and TRA2A genes. These genes are possibly associated with prostate cancer. Notably, the H3K27me3 histone mark emerged as a novel regulatory mechanism in poor-prognosis prostate cancer. Our findings point to epigenetic mark H3K27me3 as an important event in prostate carcinogenesis and progression. The results reported here provide new molecular insights into the pathogenesis of prostate cancer.

A selective androgen receptor modulator that reduces prostate tumor size and prevents orchidectomy-induced bone loss in rats.

PubMed

Allan, George; Lai, Muh-Tsann; Sbriscia, Tifanie; Linton, Olivia; Haynes-Johnson, Donna; Bhattacharjee, Sheela; Dodds, Robert; Fiordeliso, James; Lanter, James; Sui, Zhihua; Lundeen, Scott

2007-01-01

The pharmacological activity of JNJ-26146900 is described. JNJ-26146900 is a nonsteroidal androgen receptor (AR) ligand with tissue-selective activity in rats. The compound was evaluated in in vitro and in vivo models of AR activity. It binds to the rat AR with a K(i) of 400nM and acts as a pure androgen antagonist in an in vitro cell-based assay. Its in vitro profile is similar to the androgen antagonist bicalutamide (Casodex). In intact rats, JNJ-26146900 reduces ventral prostate weight with an oral potency (ED(50)) of 20-30mg/kg, again comparable to that of bicalutamide. JNJ-26146900 prevented prostate tumor growth in the Dunning rat model, maximally inhibiting growth at a dose of 10mg/kg. It slowed tumor growth significantly in a CWR22-LD1 mouse xenograft model of human prostate cancer. It was tested in aged male rats for its ability to prevent bone loss and loss of lean body mass following orchidectomy. After 6 weeks of dosing, bone volume decreased by 33% in orchidectomized versus intact vehicle-treated rats with a probability (P) of less than 0.05, as measured by micro-computerized tomography analysis. At a dose of 30mg/kg, JNJ-26146900 significantly reduced castration-induced tibial bone loss as indicated by the following parameters: bone volume, trabecular connectivity, trabecular number and spacing between trabeculae. Bone mineral density decreased from 229+/-34mg/cm(3) of hydroxyapatite to 166+/-26mg/cm(3) following orchidectomy, and was maintained at 194+/-20mg/cm(3) with JNJ-26146900 treatment (P<0.05 relative to orchidectomy alone). Using magnetic resonance imaging, the compound was found to partially prevent orchidectomy-induced loss of lean body mass. Our data show that selective androgen receptor modulators (SARMs) have the potential for anabolic effects on bone and muscle while maintaining therapeutic efficacy in prostate cancer.

[Reduced zinc concentration in expressed prostatic secretion relates to the pain symptoms of types Ⅲ and Ⅳ prostatitis].

PubMed

Mo, Lin-Jian; Chen, Xi; Wang, Xiao-Ming; Li, Guang-Yu; Zhang, Xun; Huang, Shan; Xie, Zhi-Bin; Mo, Zeng-Nan

2016-06-01

To determine the zinc levels in the expressed prostatic secretion (EPS) of the patients with different types of chronic nonbacterial prostatitis, and explore the reference value of zinc concentration in EPS in the diagnosis and treatment of prostatitis. We collected EPS samples from 35 healthy men and 173 patients with chronic nonbacterial prostatitis, including 65 cases of type ⅢA, 69 cases of type ⅢB, and 39 cases of type Ⅳ, according to the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI). We compared the zinc levels in the EPS samples among different groups and analyzed the correlations of zinc concentration with the NIH-CPSI scores, WBC count, pH value, and age of the subjects. The participants were aged 17－65 (32.5±8.5) years. The zinc concentrations in the EPS were significantly lower in the ⅢA (［162.2±10.8］ μg/ml) and ⅢB (［171.2±12.0］ μg/ml) than in the Ⅳ (［234.6±17.9］ μg/ml) (P<0.05 ) and the control group (［259.5±14.6］ μg/ml) (P<0.05 ). The zinc level was correlated negatively with the NIH-CPSI pain score (r=－0.248, P<0.01), quality of life score (r=－0.232, P<0.01), severity score (r=－0.270, P<0.01), total NIH-CPSI score (r=－0.281, P<0.01), and the pH value in EPS (r=－0.208, P<0.01), but showed no correlation with the WBC count and age of the subjects. The reduced zinc concentration in the EPS of the patients with chronic nonbacterial prostatitis may be associated with the pain symptoms of the disease, which suggests the potential reference value of measuring the zinc concentration in EPS in the diagnosis and treatment of prostatitis.

Mechanism of Mongolian medical warm acupuncture in treating insomnia by regulating miR-101a in rats with insomnia.

PubMed

Bo, Agula; Si, Lengge; Wang, Yuehong; Bao, Lidao; Yuan, Hongwei

2017-07-01

MicroRNAs (miRNAs or miRs) and the target genes before and after warm acupuncture at the genetic level were assessed, and the cytokines and neurotransmitters related to insomnia were studied. Male Sprague-Dawley rats were used to create PCPA insomnia rat models and randomly divided into the normal, model, warm acupuncture, and drug groups. The Dinghui Acupoint, Heyi Acupoint, and Xin Acupoint were inserted in the Mongolian medicine warm acupuncture group. The differential expression profile of microRNA in the brain tissue of the insomnia rats was determined before and after Mongolian medicine warm acupuncture for establishment of miR-101a mimics and inhibitor. qPCR was used to detect the expression level of miR-101a. Western blotting was used to detect the expression level of PAX8. The rats receiving Mongolian medicine warm acupuncture had 141 miRNAs with differential expression compared with the normal rats. The expression level of miR-101a in the cells of the hippocampus of the insomnia rats transfected with miR-101a mimics increased significantly at 72 h (P<0.05). The activity of the neuronal cells transfected with miR-101a inhibitor increased significantly at 72 h (P<0.05). The western blotting result indicated that the expression of the PAX8 protein in the neuronal cells of the insomnia model rats was inhibited and downregulated significantly at 72 h after addition of miR-101a mimics compared with that in the scramble added group (P<0.01). The levels of the interleukins IL-1, IL-2, and IL-6 and the tumor necrosis factor-α in the hypothalamus, hippocampus, and prefrontal cortex decreased significantly compared with those in the blank control group (P<0.05). The levels of noradrenaline, dopamine, and glutamic decreased significantly following warm acupuncture or western medicine treatment (P<0.05). In conclusion, this study demonstrates that the upregulation of miR-101a in the rats treated with warm acupuncture is directly associated with PAX8 regulation.

Mechanism of Mongolian medical warm acupuncture in treating insomnia by regulating miR-101a in rats with insomnia

PubMed Central

Bo, Agula; Si, Lengge; Wang, Yuehong; Bao, Lidao; Yuan, Hongwei

2017-01-01

MicroRNAs (miRNAs or miRs) and the target genes before and after warm acupuncture at the genetic level were assessed, and the cytokines and neurotransmitters related to insomnia were studied. Male Sprague-Dawley rats were used to create PCPA insomnia rat models and randomly divided into the normal, model, warm acupuncture, and drug groups. The Dinghui Acupoint, Heyi Acupoint, and Xin Acupoint were inserted in the Mongolian medicine warm acupuncture group. The differential expression profile of microRNA in the brain tissue of the insomnia rats was determined before and after Mongolian medicine warm acupuncture for establishment of miR-101a mimics and inhibitor. qPCR was used to detect the expression level of miR-101a. Western blotting was used to detect the expression level of PAX8. The rats receiving Mongolian medicine warm acupuncture had 141 miRNAs with differential expression compared with the normal rats. The expression level of miR-101a in the cells of the hippocampus of the insomnia rats transfected with miR-101a mimics increased significantly at 72 h (P<0.05). The activity of the neuronal cells transfected with miR-101a inhibitor increased significantly at 72 h (P<0.05). The western blotting result indicated that the expression of the PAX8 protein in the neuronal cells of the insomnia model rats was inhibited and downregulated significantly at 72 h after addition of miR-101a mimics compared with that in the scramble added group (P<0.01). The levels of the interleukins IL-1, IL-2, and IL-6 and the tumor necrosis factor-α in the hypothalamus, hippocampus, and prefrontal cortex decreased significantly compared with those in the blank control group (P<0.05). The levels of noradrenaline, dopamine, and glutamic decreased significantly following warm acupuncture or western medicine treatment (P<0.05). In conclusion, this study demonstrates that the upregulation of miR-101a in the rats treated with warm acupuncture is directly associated with PAX8 regulation. PMID

Loss of miR-100 enhances migration, invasion, epithelial-mesenchymal transition and stemness properties in prostate cancer cells through targeting Argonaute 2.

PubMed

Wang, Min; Ren, Dong; Guo, Wei; Wang, Zeyu; Huang, Shuai; Du, Hong; Song, Libing; Peng, Xinsheng

2014-07-01

Evidence in literature has demonstrated that some microRNAs (miRNAs) play a pivotal role in most solid tumor metastasis. Previous studies have showed that miR-100 is downregulated in human prostate cancer tissue compared to normal prostate and also significantly decreased in bone metastatic prostate cancer samples compared with primary prostate cancer. Argonaute 2 (AGO2) is the core effector protein of the miRNA-induced silencing complex and overexpression of AGO2 might enhance tumor metastasis. However, it is unknown whether and how miR-100 and AGO2 regulates metastasis of prostate cancer. Here, we report that miR-100 negatively regulated migration, invasion, epithelial-mesenchymal transition (EMT), colony formation, spheroid formation and expression of the stemness factors c-Myc, Oct4 and Klf4 in PC-3 and DU145 cells. Furthermore, miR-100 expression was negatively correlated with bone metastasis of prostate cancer patients. Notably, luciferase assay showed that AGO2 was a direct target of miR-100. Downregulation of AGO2 repressed migration, invasion, EMT and stemness of prostate cancer cells, and reversed the effects seen with miR-100 downregulation. Downregulation of AGO2 enhanced expression of miR-34a and miR-125b which can suppress migration, invasion, EMT and stemness of cancer cells. Taken together, our findings indicate that loss of miR-100 promotes the metastatic ability of prostate cancer cells at least partially by upregulating AGO2 expression through modulating migration, invasion, EMT and stemness of cancer cells, and suggest that miR-100/AGO2 may play an important role in regulating the metastasis of prostate cancer and is a potential target of prevention and therapy.

Notoginsenoside R1 attenuates renal ischemia-reperfusion injury in rats.

PubMed

Liu, Wen-Jun; Tang, Hong-Tai; Jia, Yi-Tao; Ma, Bing; Fu, Jin-Feng; Wang, Yu; Lv, Kai-Yang; Xia, Zhao-Fan

2010-09-01

Ischemia-reperfusion (I/R) injury of the kidney is a complex pathophysiological process and a major cause of acute renal failure. It has been shown that I/R injury is related to inflammatory responses and activation of apoptotic pathways. Inhibition of certain elements of inflammatory responses and apoptotic pathway seemed to ameliorate renal I/R injury. As an effective element of Panax notoginseng, NR1 has antioxidant, anti-inflammatory, antiapoptotic, and immune-stimulatory activities. Therefore, we speculate that NR1 can attenuate renal I/R injury. Ischemia-reperfusion injury was induced by renal pedicle ligation followed by reperfusion along with a contralateral nephrectomy. Male Sprague-Dawley rats were randomized to four groups: sham group, I/R control group, NR1-1 group (rats treated with NR1, 20 mg.kg.d) and NR1-2 group (rats treated with NR1, 40 mg.kg.d). All animals were killed 72 h after I/R induction. Blood and renal tissues were collected. Renal dysfunction was observed by the level of serum creatinine and histological evaluation. Apoptosis and inflammatory response in the tissue of kidney were detected mainly with molecular biological methods. NR1 attenuated I/R-induced renal dysfunction as indicated by the level of serum creatinine and histological evaluation. It prevented the I/R-induced increases in the levels of proinflammatory cytokine TNF-alpha, myeloperoxidase activity, phosphorylation of p38, and activation of nuclear factor kappaB with cell apoptosis in the kidney and enhanced expression of antiapoptosis cytokine bcl-2. Treatment with NR1 improves renal function after I/R associated with a significant reduction in cell apoptosis and inflammatory responses, which may be related to p38 and nuclear factor kappaB inhibition.

Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6.

PubMed Central

Bajusz, S; Janaky, T; Csernus, V J; Bokser, L; Fekete, M; Srkalovic, G; Redding, T W; Schally, A V

1989-01-01

The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Of the peptides prepared, [D-Mel6]LH-RH (SB-05) and [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,Arg5,D-Mel6,D-Ala10++ +]LH-RH [SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine] possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel6 analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells. PMID:2548207

Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6.

PubMed

Bajusz, S; Janaky, T; Csernus, V J; Bokser, L; Fekete, M; Srkalovic, G; Redding, T W; Schally, A V

1989-08-01

The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Of the peptides prepared, [D-Mel6]LH-RH (SB-05) and [Ac-D-Nal(2)1,D-Phe(pCl)2,D-Pal(3)3,Arg5,D-Mel6,D-Ala10++ +]LH-RH [SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine] possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel6 analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells.

A selective androgen receptor modulator with minimal prostate hypertrophic activity enhances lean body mass in male rats and stimulates sexual behavior in female rats.

PubMed

Allan, George F; Tannenbaum, Pamela; Sbriscia, Tifanie; Linton, Olivia; Lai, Muh-Tsann; Haynes-Johnson, Donna; Bhattacharjee, Sheela; Zhang, Xuqing; Sui, Zhihua; Lundeen, Scott G

2007-08-01

Androgen receptor (AR) ligands with tissue selectivity (selective androgen receptor modulators, or SARMs) have potential for treating muscle wasting, hypogonadism of aging, osteoporosis, female sexual dysfunction, and other indications. JNJ-28330835 is a nonsteroidal AR ligand with mixed agonist and antagonist activity in androgen-responsive cell-based assays. It is an orally active SARM with muscle selectivity in orchidectomized rat models. It stimulated growth of the levator ani muscle, stimulating maximal growth at a dose of 10 mg/kg. At the same time, JNJ-28330835 reduced prostate weight in intact rats by a mean of 30% at 10 mg/kg, while having no inhibitory effect on muscle. Using magnetic resonance imaging (MRI) to monitor body composition, it prevented half of the loss of lean body mass associated with orchidectomy, and restored about 30% of lost lean mass to aged orchidectomized rats. It had agonist effects on markers of both osteoclast and osteoblast activity, suggesting that it reduces bone turnover. In a model of sexual behavior, JNJ-28330835 enhanced the preference of ovariectomized female rats for sexually intact male rats over nonsexual orchidectomized males. JNJ-28330835 is a prostate-sparing SARM with the potential for clinically beneficial effects in muscle-wasting diseases and sexual function disorders.

L-selenomethionine does not protect against testosterone plus 17β-estradiol-induced oxidative stress and preneoplastic lesions in the prostate of NBL rats.

PubMed

Özten, Nur; Schlicht, Michael; Diamond, Alan M; Bosland, Maarten C

2014-01-01

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.

Establishment of a rat model of chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) induced by immunization with a novel peptide T2.

PubMed

Ihsan, Awais Ullah; Khan, Farhan Ullah; Nawaz, Waqas; Khan, Muhammad Zahid; Yang, Mengqi; Zhou, Xiaohui

2017-07-01

The exact etiological mechanism of Chronic Prostatitis/chronic pelvic pain syndrome (CP/CPPS) is still unclear however autoimmunity is the most valid theory. We developed a rat model of Chronic Prostatitis/chronic pelvic pain syndrome by using a novel peptide (T2) isolated from TRPM8. This model might be beneficial in elucidating mechanisms involved in the pathogenesis of Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS). 40 male Sprague-Dawley rats with an average weight of 180-220g were equally distributed into five groups. The normal control group was injected with normal saline (.9% NACL), the CFA group with CFA, AL(OH)3 group was given AL(OH)3 injection, T2 group using a novel peptide T2 and T2+AL(OH)3+CFA group was injected with T2+AL(OH)3+CFA. Dosing to all rat groups were injected subcutaneously. Hematoxylin and eosin staining and Immunohistochemistry were used to investigate inflammatory cell infiltration and IL-1β in the prostate tissue respectively. ELISA technique was used to measure the serum level of CRP and TNF-α. T-test was used to analyze the results. Maximum infiltration of inflammatory cells and the highest level of IL-1β in the prostate tissue was observed in T2+AL(OH)3+CFA group as revealed by histopathology and Immunohistochemistry, respectively. Furthermore, T2+AL(OH)3+CFA group attained the peak value of serum TNF-α and CRP as determined by ELISA technique. Our results demonstrated that T2 in combination with AL(OH)3 and CFA induced severe Prostatitis in rats. We believe that our present model will be highly beneficial for investigation of the pathophysiology of Chronic Prostatitis/Chronic Pelvic Pain Syndrome. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Functional involvement of the organic cation transporter 2 (rOct2) in the renal uptake of organic cations in rats.

PubMed

Umehara, K-I; Iwatsubo, T; Noguchi, K; Kamimura, H

2008-01-01

This study examined the contribution made by organic cation transporters (hOCT/rOct) to the saturable component of the renal uptake of 1-methyl-4-phenylpyridinium, tetraethylammonium (TEA), cimetidine and metformin into rOct2-expressing HEK293 cells and rat kidney slices. All the test compounds accumulated in the rat kidney slices in a carrier-mediated manner. The Michaelis- Menten constant (K(m)) values for saturable uptake of TEA, cimetidine and metformin into rat kidney slices were relatively comparable with those for the rOct2-expressing HEK293 cells. In addition, the relative uptake activity values of TEA, cimetidine and metformin in rat kidney slices were similar to those in rOct2-expressing HEK293 cells. This suggests that the saturable components involved in the renal uptake of TEA, cimetidine and metformin are mediated mainly by rOct2. The saturable uptake profile of cationic compounds into rat kidney can be evaluated in both cDNA-expressing cells and rat kidney slices, as well as the transporter expression pattern. This approach can also be used to estimate the saturable uptake mechanism of cationic compounds into the human kidney when human kidney slices and hOCT2-expressing cells are used.

Hypoadiponectinemia, elevated iron and high-sensitivity C-reactive protein levels and their relation with prostate size in benign prostatic hyperplasia.

PubMed

Nandeesha, H; Eldhose, A; Dorairajan, L N; Anandhi, B

2017-09-01

Elevated iron, high-sensitivity C-reactive protein (CRP) and hypoadiponectinemia are known to initiate tumour development. There is paucity of data regarding the above-mentioned parameters and their relation with prostate size in benign prostatic hyperplasia (BPH). The present study was designed to assess the levels of iron, hs-CRP and adiponectin levels and their association with prostate size in BPH patients. A total of 37 BPH cases and 36 controls were enrolled in the study. Iron, hs-CRP and adiponectin were estimated in both the groups. Iron and hs-CRP were significantly increased and adiponectin was significantly reduced in BPH cases when compared with controls. Iron (r = .397, p = .015), hs-CRP (r = .341, p = .039) and adiponectin (r = -.464, p = .004) were significantly associated with prostate size in BPH cases. Multivariate linear regression analysis showed that iron acts as predictor of prostate size in BPH (R 2  = 0.395, β = 0.526, p = .001). We conclude that iron and hs-CRP are elevated and adiponectin is reduced in BPH cases and associated with prostate size. © 2016 Blackwell Verlag GmbH.

Bisphenol A Disrupts HNF4α-Regulated Gene Networks Linking to Prostate Preneoplasia and Immune Disruption in Noble Rats

PubMed Central

Lam, Hung-Ming; Chen, Jing; Medvedovic, Mario; Tam, Neville Ngai Chung

2016-01-01

Exposure of humans to bisphenol A (BPA) is widespread and continuous. The effects of protracted exposure to BPA on the adult prostate have not been studied. We subjected Noble rats to 32 weeks of BPA (low or high dose) or 17β-estradiol (E2) in conjunction with T replenishment. T treatment alone or untreated groups were used as controls. Circulating T levels were maintained within the physiological range in all treatment groups, whereas the levels of free BPA were elevated in the groups treated with T+low BPA (1.06 ± 0.05 ng/mL, P < .05) and T+high BPA (10.37 ± 0.43 ng/mL, P < .01) when compared with those in both controls (0.1 ± 0.05 ng/mL). Prostatic hyperplasia, low-grade prostatic intraepithelial neoplasia (PIN), and marked infiltration of CD4+ and CD8+ T cells into the PIN epithelium (P < .05) were observed in the lateral prostates (LPs) of T+low/high BPA-treated rats. In contrast, only hyperplasia and high-grade PIN, but no aberrant immune responses, were found in the T+E2-treated LPs. Genome-wide transcriptome analysis in LPs identified differential changes between T+BPA vs T+E2 treatment. Expression of multiple genes in the regulatory network controlled by hepatocyte nuclear factor 4α was perturbed by the T+BPA but not by the T+E2 exposure. Collectively these findings suggest that the adult rat prostate, under a physiologically relevant T environment, is susceptible to BPA-induced transcriptomic reprogramming, immune disruption, and aberrant growth dysregulation in a manner distinct from those caused by E2. They are more relevant to our recent report of higher urinary levels BPA found in patients with prostate cancer than those with benign disease. PMID:26496021

miR-494 up-regulates the PI3K/Akt pathway via targetting PTEN and attenuates hepatic ischemia/reperfusion injury in a rat model.

PubMed

Su, Song; Luo, De; Liu, Xiangdong; Liu, Jiang; Peng, Fangyi; Fang, Cheng; Li, Bo

2017-10-31

A rat HIRI model was constructed and treated with an intraperitoneal injection of agomir- miR-494 or agomir-NC (negative control) for 7 days after the surgery. The pathophysiological changes in sham-operated rats, HIRI, HIRI + agomir- miR-494 , and HIRI + agomir-NC were compared. The effect of miR-494 was also assessed in an H 2 O 2 -induced apoptosis model. Hepatic AML12 cells were transfected with mimics NC or miR-494 mimics, followed by 6-h H 2 O 2 treatment. Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry, respectively. Further, the miR-494 target gene was identified by luciferase reporter assay, and verified both in vitro and in vivo experiments. The activity of AKT pathway was further analyzed in vivo by Western blot. HIRI + agomir- miR-494 rats exhibited significantly higher miR-494 expression, lower serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and glutamate dehydrogenase (GLDH) level, lower hepatic MDA, TOA, and OSI, alleviated hepatic necrosis, reduced hepatocyte apoptosis, and decreased expression of apoptosis-related proteins, when compared with HIRI + agomir-NC rats ( P <0.05 or 0.01). After H 2 O 2 treatment, AML-12 cells transfected with miR-494 mimics had significantly higher proliferation and lower apoptosis rate compared with mimics NC group ( P <0.01). PTEN was identified as an miR-494 target gene. PTEN expression was significantly down-regulated in AML12 cells transfected with miR-494 mimics, and was up-regulated by treatment of miR-494 inhibitor ( P <0.01). Moreover, HIRI + agomir- miR-494 rats exhibited significantly lower PTEN expression, and higher p-AKT, p-mTOR, and p-p70S6K levels compared with HIRI + agomir-NC rats. Therefore, miR-494 protected rats against hepatic ischemia/reperfusion (I/R) injury through down-regulating its downstream target gene PTEN , leading to the activation of PI3K/AKT signaling pathway. © 2017 The Author(s).

[Over-expression of miR-151a-3p inhibits proliferation and migration of PC-3 prostate cancer cells].

PubMed

Zhang, Yi; Hao, Tongtong; Zhang, Han; Wei, Pengtao; Li, Xiaohui

2018-03-01

Objective To observe the effect of microRNA-151a-3p (miR-151a-3p) up-regulation on the proliferation and migration of prostate cancer cells and explore the possible molecular mechanism. Methods The expression of miR-151a-3p in PC-3M, C4-2B, 22RV1, DU-145, PC-3, LNCap human prostate cancer cells and RWPE-1 human normal prostate epithelial cells was detected by real-time fluorescence quantitative PCR. PC-3 cells with the lowest expression of miR-151a-3p were used for subsequent experiments. Bioinformatics and dual-luciferase reporter assay were performed to predict and test potential target genes of miR-151a-3p. The miR-151a-3p mimics or negative control microRNAs (miR-NCs) were transfected into PC-3 cells. Real-time fluorescence quantitative PCR was used to detect the expression of miR-151a-3p and potential target gene mRNA. The protein expressions of target genes and downstream signaling pathway proteins were analyzed by Western blotting. The proliferation of PC-3 cells was examined by MTT assay, and the migration of PC-3 cells was detected by Transwell TM assay. Results The expression level of miR-151a-3p in the prostate cancer cells was significantly lower than that in RWPE-1 normal human prostate epithelial cells. PC-3 cells had the lowest expression level of miR-151a-3p. The bioinformatics and dual-luciferase reporter assay showed that NEK2 was the potential target gene for miR-151a-3p. After transfection with miR-151a-3p mimics, the expression of miR-151a-3p in PC-3 cells significantly increased and the expression of NEK2 mRNA significantly decreased. The protein expressions of PI3K-AKT-mTOR signaling pathway were also reduced. Up-regulation of miR-151a-3p significantly inhibited the proliferation and migration of PC-3 cells. Conclusion The expression of miR-151a-3p is reduced in prostate cancer cells. Up-regulation of miR-151a-3p can inhibit the proliferation and migration of P-3 in prostate cancer by decreasing the expression of NEK2 and PI3K

The anti-oestrogen fulvestrant (ICI 182,780) reduces the androgen receptor expression, ERK1/2 phosphorylation and cell proliferation in the rat ventral prostate.

PubMed

Fernandes, S A F; Gomes, G R O; Siu, E R; Damas-Souza, D M; Bruni-Cardoso, A; Augusto, T M; Lazari, M F M; Carvalho, H F; Porto, C S

2011-10-01

This study proposed to investigate further the role of oestrogens during pubertal growth of rat ventral prostate, by analysing the effect of anti-oestrogen fulvestrant (ICI 182,780) on the expression of androgen (AR) and oestrogen receptors (ESR1 and ESR2), mitogen-activated protein kinase (ERK1/2) phosphorylation, and expression of Ki-67, a biomarker for cell proliferation. Ventral prostates were obtained from 90-day-old rats treated once a week for 2 months with vehicle (control) or ICI 182,780 (10 mg/rat, s.c.). Transcripts for AR, ESR1 and ESR2 were evaluated by quantitative real-time polymerase chain reaction. Expression of AR, ESR1, ESR2, total and phospho-ERK1/2 was analysed by Western blot or immunofluorescence. Ki-67-positive cells and myosin heavy chain were detected by immunohistochemistry. Cylindrical epithelial cells slightly taller, epithelial dysplasia and an increase in smooth muscle layer were observed in the ventral prostate from ICI 182,780-treated rats. ICI 182,780 did not change the mRNA, but decreased the protein levels for AR in the ventral prostate. The expression of ESR1 (mRNA and protein) was upregulated by ICI 182,780, but no changes were observed on ESR2 expression (mRNA and protein). ICI 182,780 decreased the phosphorylation state of ERK1/2, with no changes in total ERK1/2 levels. Ki-67-positive cells in the ventral prostate were also decreased by ICI 182,780. In conclusion, ICI 182,780 induces downregulation of AR expression and may block the translocation of ESR1 and ESR2 from the nucleus to the plasma membrane, decreasing ERK1/2 phosphorylation and prostatic epithelial cell proliferation. These findings provide a basis for physiological roles of oestrogen in the ventral prostate. Further studies with fulvestrant are necessary in benign prostate hyperplasia and prostatic cancer models. © 2010 The Authors. International Journal of Andrology © 2011 European Academy of Andrology.

ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer.

PubMed

Mahajan, Kiran; Malla, Pavani; Lawrence, Harshani R; Chen, Zhihua; Kumar-Sinha, Chandan; Malik, Rohit; Shukla, Sudhanshu; Kim, Jongphil; Coppola, Domenico; Lawrence, Nicholas J; Mahajan, Nupam P

2017-06-12

The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription. Reversal of the pY88-H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS-sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. Thus, a feedforward ACK1/pY88-H4/WDR5/MLL2/AR epigenetic circuit drives CRPC and is necessary for maintenance of the malignant state. Copyright © 2017 Elsevier Inc. All rights reserved.

The Histamine H1 Receptor Participates in the Increased Dorsal Telencephalic Neurogenesis in Embryos from Diabetic Rats

PubMed Central

Solís, Karina H.; Méndez, Laura I.; García-López, Guadalupe; Díaz, Néstor F.; Portillo, Wendy; De Nova-Ocampo, Mónica; Molina-Hernández, Anayansi

2017-01-01

Increased neuron telencephalic differentiation during deep cortical layer formation has been reported in embryos from diabetic mice. Transitory histaminergic neurons within the mesencephalon/rhombencephalon are responsible for fetal histamine synthesis during development, fibers from this system arrives to the frontal and parietal cortex at embryo day (E) 15. Histamine is a neurogenic factor for cortical neural stem cells in vitro through H1 receptor (H1R) which is highly expressed during corticogenesis in rats and mice. Furthermore, in utero administration of an H1R antagonist, chlorpheniramine, decreases the neuron markers microtubuline associated protein 2 (MAP2) and forkhead box protein 2. Interestingly, in the diabetic mouse model of diabetes induced with streptozotocin, an increase in fetal neurogenesis in terms of MAP2 expression in the telencephalon is reported at E11.5. Because of the reported effects on cortical neuron differentiation of maternal diabetes in one hand and of histamine in the other, here the participation of histamine and H1R on the increased dorsal telencephalic neurogenesis was explored. First, the increased neurogenesis in the dorsal telencephalon at E14 in diabetic rats was corroborated by immunohistochemistry and Western blot. Then, changes during corticogenesis in the level of histamine was analyzed by ELISA and in H1R expression by qRT-PCR and Western blot and, finally, we tested H1R participation in the increased dorsal telencephalic neurogenesis by the systemic administration of chlorpheniramine. Our results showed a significant increase of histamine at E14 and in the expression of the receptor at E12. The administration of chlorpheniramine to diabetic rats at E12 prevented the increased expression of βIII-tubulin and MAP2 mRNAs (neuron markers) and partially reverted the increased level of MAP2 protein at E14, concluding that H1R have an important role in the increased neurogenesis within the dorsal telencephalon of embryos from

Beef Tallow, but Not Perilla or Corn Oil, Promotion of Rat Prostate and Intestinal Carcinogenesis by 3,2‐Dimethyl‐4‐aminobiphenyl

PubMed Central

Mori, Toshio; Imaida, Katsumi; Tamano, Seiko; Sano, Masashi; Takahashi, Satoru; Asamoto, Makoto; Takeshita, Masazumi; Ueda, Hiroshi

2001-01-01

The modifying effects of three kinds of fat (corn oil, beef tallow or perilla oil, each at 20% in the diet) on F344 rat prostate carcinogenesis induced by 3,2‐dimethyl‐4‐aminobiphenyl (DMAB) were investigated. Non‐invasive carcinomas of the ventral prostate were induced by DMAB alone and invasive carcinomas of the other prostate lobes and seminal vesicles by DMAB and testosterone propionate (TP). Eight groups of F344 rats were initiated with 50 mg/kg body weight of DMAB at 2‐week intervals for the first 20 weeks, four also receiving TP, extended until week 60. The animals received basal chow powder diet or one of three high fat diets throughout the experiment (60 weeks). One further group served as a non‐carcinogen‐treated control maintained on basal chow powder diet. Beef tallow significantly increased the development of ventral prostate carcinomas with DMAB alone (from 15 to 45%, P<0.05), while perilla oil reduced the incidence of prostatic intraepithelial neoplasia (PIN) in the ventral lobe of rats given DMAB + TP (from 70 to 10%, P<0.01), but not in those given DMAB alone. No other effects of high fats were observed regarding PIN or invasive cancers of the dorsolateral and anterior prostate or seminal vesicles. A satellite experiment demonstrated that all high fat diets for 4 weeks increased the 5‐bromo‐2‐deoxyuridine (BrdU) labeling index of prostate epithelial cells, suggesting that a high fat intake, irrespective of the fatty acid composition, may accelerate cell kinetics in the prostate. Of the three high fat diets, beef tallow was also found to increase intestinal carcinogenesis. Thus, the present data revealed carcinogenesis in the prostate and intestine to be promoted by beef tallow. PMID:11676852

Preventive effect of ginsenoid on chronic bacterial prostatitis.

PubMed

Kim, Sang Hoon; Ha, U-Syn; Sohn, Dong Wan; Lee, Seung-Ju; Kim, Hyun Woo; Han, Chang Hee; Cho, Yong-Hyun

2012-10-01

Empirical antibiotic therapy is the preferred primary treatment modality for chronic bacterial prostatitis (CBP). However, this method of treatment has a low success rate and long-term therapy may result in complications and the appearance of resistant strains. Therefore a new alternative method for the prevention of CBP is necessary. There are several reports that ginsenoid has a preventive effect on urinary tract infection (UTI). To evaluate the preventive effect of ginsenoid on CBP compared to conventional antibiotics, we carried out an experiment in a rat model of the disease. Four groups of adult male Wistar rats were treated with the following medications: (1) control (no medication), (2) ciprofloxacin, (3) ginsenoid, and (4) ciprofloxacin/ginsenoid. All medications were given for 4 weeks, and then we created a CBP model in the animals by injecting an Escherichia coli Z17 (O2:K1;H(-)) suspension into the prostatic urethra. After 4 weeks, results of microbiological cultures of prostate and urine samples, as well as histological findings of the prostate in each group were analyzed. The microbiological cultures of the prostate samples demonstrated reduced bacterial growth in all experimental groups compared with the control group. Histopathological examination showed a significantly decreased rate of infiltration of inflammatory cells into prostatic tissue and decreased interstitial fibrosis in the ginsenoid group compared with the control group. Inhibition of prostate infection was greater in the group receiving both ginsenoid and antibiotic than in the single-medication groups. Although the findings of this study suggest a preventive effect of ginsenoid, preventive methods for CBP are still controversial.

Extracellular pH Modulates Neuroendocrine Prostate Cancer Cell Metabolism and Susceptibility to the Mitochondrial Inhibitor Niclosamide

PubMed Central

Ippolito, Joseph E.; Brandenburg, Matthew W.; Ge, Xia; Crowley, Jan R.; Kirmess, Kristopher M.; Som, Avik; D’Avignon, D. Andre; Arbeit, Jeffrey M.; Achilefu, Samuel; Yarasheski, Kevin E.; Milbrandt, Jeffrey

2016-01-01

Neuroendocrine prostate cancer is a lethal variant of prostate cancer that is associated with castrate-resistant growth, metastasis, and mortality. The tumor environment of neuroendocrine prostate cancer is heterogeneous and characterized by hypoxia, necrosis, and numerous mitoses. Although acidic extracellular pH has been implicated in aggressive cancer features including metastasis and therapeutic resistance, its role in neuroendocrine prostate cancer physiology and metabolism has not yet been explored. We used the well-characterized PNEC cell line as a model to establish the effects of extracellular pH (pH 6.5, 7.4, and 8.5) on neuroendocrine prostate cancer cell metabolism. We discovered that alkalinization of extracellular pH converted cellular metabolism to a nutrient consumption-dependent state that was susceptible to glucose deprivation, glutamine deprivation, and 2-deoxyglucose (2-DG) mediated inhibition of glycolysis. Conversely, acidic pH shifted cellular metabolism toward an oxidative phosphorylation (OXPHOS)-dependent state that was susceptible to OXPHOS inhibition. Based upon this mechanistic knowledge of pH-dependent metabolism, we identified that the FDA-approved anti-helminthic niclosamide depolarized mitochondrial potential and depleted ATP levels in PNEC cells whose effects were enhanced in acidic pH. To further establish relevance of these findings, we tested the effects of extracellular pH on susceptibility to nutrient deprivation and OXPHOS inhibition in a cohort of castrate-resistant prostate cancer cell lines C4-2B, PC-3, and PC-3M. We discovered similar pH-dependent toxicity profiles among all cell lines with these treatments. These findings underscore a potential importance to acidic extracellular pH in the modulation of cell metabolism in tumors and development of an emerging paradigm that exploits the synergy of environment and therapeutic efficacy in cancer. PMID:27438712

The histological and histometrical effects of Urtica dioica extract on rat's prostate hyperplasia.

PubMed

Moradi, Hamid Reza; Erfani Majd, Naeem; Esmaeilzadeh, Saleh; Fatemi Tabatabaei, Sayed Reza

2015-01-01

Benign prostatic hyperplasia (BPH) is a common disease in human that gradual overgrowth of the prostate gland leads to impinge on the urethra with impairment in urinary function. Numerous plants improve uncontrolled growth of the prostate gland and improve urinary tract symptoms associated with BPH. In this study, 25 healthy adult male Wistar rats were divided randomly in five groups: G1 (Control group) received ordinary feed without any treatment, G2 received 10 mg kg(-1) testosterone subcutaneously, G3 received 50 mg kg(-1) nettle root extract orally, G4 received 50 mg kg(-1) nettle root extract orally and 10 mg kg(-1) testosterone, G5 received 10 mg kg(-1) almond oil (Almond oil was used as testosterone solvent) subcutaneously. After six weeks, volume and weight of each lobe were measured and samples were taken. The 5 to 6 µm thickness sections were made using paraffin embedding method and stained by hematoxylin and eosin and periodic acid-Schiff. The results showed that prostate volume and ratio of prostate to body weight were increased significantly in the testosterone. Histological and histometrical results showed that dorsal and lateral type 1 and 2 lobes were not changed significantly but the ventral and anterior lobes have changed significantly. Over all, the nettle root could prevent from some of prostatic hyperplasia effects, so that percentage of folded alveoli in ventral lobe reduced insignificantly.

SYSTEMS MODELING OF PROSTATE REGULATION AND ...

EPA Pesticide Factsheets

The prostate is an androgen-dependent tissue that is an important site of disease in human males as well as an important indicator of androgen status in animals. The rat prostate is used for studying antiandrogenic drugs as well as for evaluation of endocrine disruption (e.g., Hershberger Assay). Pubertal changes in the prostate have been observed to be as sensitive to environmental antiandrogens as in utero effects. The goal of this research is to model the biology of prostate androgen function on a systems level to determine the factors responsible for the dose-response observable with androgens and antiandrogens in the male rat. This includes investigation of the roles of positive and negative feedback loops in prostatic response following castration and dosing with testosterone and/or antiandrogens. A biologically-based, systems-level model will be developed describing the regulation of the prostate by androgens. The model will extend an existing model for the male rat central axis, which describes feedback between luteinizing hormone and testosterone production in the testes, to include the prostate and conversion of testosterone to dihydrotestosterone (DHT). The prostate model will describe binding of androgens to the androgen receptor, 5α-reductase catalyzed production of DHT, and gene regulation affecting cell proliferation, apoptosis, and prostatic fluid production. The model will combine pharmacokinetic models for endogenous hormones (i.e., testost

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

PubMed Central

Özten, Nur; Schlicht, Michael; Diamond, Alan M.; Bosland, Maarten C.

2014-01-01

Previous animal studies examining dietary selenium effects on prostatic carcinogenesis did not show preventive benefit, including one 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 Nbl/Crl rats treated with T+E2 for 16 weeks. 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 and mRNA expression were induced by T+E2 (p<0.05–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. PMID:24773027

Identification of miR-133b and RB1CC1 as independent predictors for biochemical recurrence and potential therapeutic targets for prostate cancer.

PubMed

Li, Xia; Wan, Xuechao; Chen, Hongbing; Yang, Shu; Liu, Yiyang; Mo, Wenjuan; Meng, Delong; Du, Wenting; Huang, Yan; Wu, Hai; Wang, Jingqiang; Li, Tao; Li, Yao

2014-05-01

We aimed to investigate the contribution of microRNA-133b (miR-133b) in prostate cancer cell proliferation, cell cycle, and apoptosis. We also examined expression of miR-133b in prostate cancer tissues, and evaluated the prognostic significance of miR-133b, as well as its target gene RB1CC1 in patients with prostate cancer after radical prostatectomy. miR-133b mimics (miR-133bm) and anti-miR-133b were transfected into LNCaP and PC-3 cells. CCK-8 was used to look at cell proliferation, flow cytometric analysis was carried out to study cell cycle, and apoptosis was determined by caspase-3 activity. miR-133b expression was assessed by real-time reverse transcription PCR and in situ hybridization in prostatic cell lines and 178 prostate tissue samples, respectively. The protein level of RB1CC1 was examined by Western blot and immunohistochemistry in prostatic cell lines and prostate tissue samples, respectively. Overexpression of miR-133b in LNCaP cells boosted cell proliferation and cell-cycle progression, but inhibited apoptosis; in contrast, miR-133bm promoted cell apoptosis, but suppressed cell proliferation and cell-cycle progression in PC-3 cells. In LNCaP cells, silencing of RB1CC1, a target of miR-133b, inhibited cell apoptosis, and promoted cell-cycle progression. Moreover, miR-133b expression was significantly inversely correlated with RB1CC1 expression in prostate cancer tissues. Multivariate Cox analysis indicated that miR-133b and RB1CC1 might be two independent prognostic factors of biochemical recurrence. miR-133b might enhance tumor-promoting properties in less aggressive LNCaP cells, whereas this miR may act as a tumor suppressor in more aggressive PC-3 cells. miR-133b and RB1CC1 were independent prognostic indicators for prostate cancer. ©2014 AACR.

Estrogen Sensitivity of Target Genes and Expression of Nuclear Receptor Co-Regulators in Rat Prostate after Pre- and Postnatal Exposure to the Ultraviolet Filter 4-Methylbenzylidene Camphor

PubMed Central

Durrer, Stefan; Ehnes, Colin; Fuetsch, Michaela; Maerkel, Kirsten; Schlumpf, Margret; Lichtensteiger, Walter

2007-01-01

Background and objectives In previous studies, we found that the ultraviolet filter 4-methyl-benzylidene camphor (4-MBC) exhibits estrogenic activity, is a preferential estrogen receptor (ER)-β ligand, and interferes with development of female reproductive organs and brain of both sexes in rats. Here, we report effects on male development. Methods 4-MBC (0.7, 7, 24, 47 mg/kg/day) was administered in chow to the parent generation before mating, during gestation and lactation, and to offspring until adulthood. mRNA was determined in prostate lobes by real-time reverse transcription–polymerase chain reaction and protein was determined by Western blot analysis. Results 4-MBC delayed male puberty, decreased adult prostate weight, and slightly increased testis weight. Androgen receptor (AR), insulin-like growth factor-1 (IGF-1), ER-α, and ER-β expression in prostate were altered at mRNA and protein levels, with stronger effects in dorsolateral than ventral prostate. To assess sensitivity of target genes to estrogens, offspring were castrated on postnatal day 70, injected with 17β-estradiol (E2; 10 or 50 μg/kg, sc) or vehicle on postnatal day 84, and sacrificed 6 hr later. Acute repression of AR and IGF-1 mRNAs by E2, studied in ventral prostate, was reduced by 4-MBC exposure. This was accompanied by reduced co-repressor N-CoR (nuclear receptor co-repressor) protein in ventral and dorsolateral prostate, whereas steroid receptor coactivator-1 (SRC-1) protein levels were unaffected. Conclusions Our data indicate that 4-MBC affects development of male reproductive functions and organs, with a lowest observed adverse effect level of 0.7 mg/kg. Nuclear receptor coregulators were revealed as targets for endocrine disruptors, as shown for N-CoR in prostate and SRC-1 in uterus. This may have widespread effects on gene regulation. PMID:18174949

An integrated view of the role of miR-130b/301b miRNA cluster in prostate cancer.

PubMed

Fort, Rafael Sebastián; Mathó, Cecilia; Oliveira-Rizzo, Carolina; Garat, Beatriz; Sotelo-Silveira, José Roberto; Duhagon, María Ana

2018-01-01

Prostate cancer is a major health problem worldwide due to its high incidence morbidity and mortality. There is currently a need of improved biomarkers, capable to distinguish mild versus aggressive forms of the disease, and thus guide therapeutic decisions. Although miRNAs deregulated in cancer represent exciting candidates as biomarkers, its scientific literature is frequently fragmented in dispersed studies. This problem is aggravated for miRNAs belonging to miRNA gene clusters with shared target genes. The miRNA cluster composed by hsa-mir-130b and hsa-mir-301b precursors was recently involved in prostate cancer pathogenesis, yet different studies assigned it opposite effects on the disease. We sought to elucidate the role of the human miR-130b/301b miRNA cluster in prostate cancer through a comprehensive data analysis of most published clinical cohorts. We interrogated methylomes, transcriptomes and patient clinical data, unifying previous reports and adding original analysis using the largest available cohort (TCGA-PRAD). We found that hsa-miR-130b-3p and hsa-miR-301b-3p are upregulated in neoplastic vs normal prostate tissue, as well as in metastatic vs primary sites. However, this increase in expression is not due to a decrease of the global DNA methylation of the genes in prostate tissues, as the promoter of the gene remains lowly methylated in normal and neoplastic tissue. A comparison of the levels of human miR-130b/301b and all the clinical variables reported for the major available cohorts, yielded positive correlations with malignance, specifically significant for T-stage, residual tumor status and primary therapy outcome. The assessment of the correlations between the hsa-miR-130b-3p and hsa-miR-301b-3p and candidate target genes in clinical samples, supports their repression of tumor suppressor genes in prostate cancer. Altogether, these results favor an oncogenic role of miR-130b/301b cluster in prostate cancer.

Effects of Prenatal Exposure to a Low Dose Atrazine Metabolite Mixture on Pubertal Timing and Prostate Development of Male Long Evans Rats

PubMed Central

Stanko, Jason P.; Enoch, Rolondo R.; Rayner, Jennifer L.; Davis, Christine C.; Wolf, Douglas C.; Malarkey, David E.; Fenton, Suzanne E.

2010-01-01

The present study examines the postnatal reproductive development of male rats following prenatal exposure to an atrazine metabolite mixture (AMM) consisting of the herbicide atrazine and its environmental metabolites diaminochlorotriazine, hydroxyatrazine, deethylatrazine, and deisopropylatrazine. Pregnant Long Evans rats were treated by gavage with 0.09, 0.87, or 8.73 mg AMM/kg body weight (BW), vehicle, or 100 mg ATR/kg BW positive control, on gestation days 15-19. Preputial separation was significantly delayed in 0.87 mg and 8.73 mg AMM-exposed males. AMM-exposed males demonstrated a significant treatment-related increase in incidence and severity of inflammation in the prostate on postnatal day (PND) 120. A dose-dependent increase in epididymal fat masses and prostate foci were grossly visible in AMM-exposed offspring. These results indicate that a short, late prenatal exposure to mixture of chlorotriazine metabolites can cause chronic prostatitis in male LE rats. The mode of action for these effects is presently unclear. PMID:20727709

Effects of prenatal exposure to a low dose atrazine metabolite mixture on pubertal timing and prostate development of male Long-Evans rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stanko, Jason; Enoch, Rolondo; Rayner, Jennifer L

The present study examines the postnatal reproductive development of male rats following prenatal exposure to an atrazine metabolite mixture (AMM) consisting of the herbicide atrazine and its environmental metabolites diaminochlorotriazine, hydroxyatrazine, deethylatrazine, and deisopropylatrazine. Pregnant Long-Evans rats were treated by gavage with 0.09, 0.87, or 8.73 mg AMM/kg body weight (BW), vehicle, or 100 mg ATR/kg BW positive control, on gestation days 15 19. Preputial separation was significantly delayed in 0.87 mg and 8.73 mg AMM-exposed males. AMM-exposed males demonstrated a significant treatment-related increase in incidence and severity of inflammation in the prostate on postnatal day (PND) 120. A dose-dependentmore » increase in epididymal fat masses and prostate foci were grossly visible in AMM-exposed offspring. These results indicate that a short, late prenatal exposure to mixture of chlorotriazine metabolites can cause chronic prostatitis in male LE rats. The mode of action for these effects is presently unclear.« less

Molecularly Targeted Dose-Enhancement Radiotherapy Using Gold and Luminescent Nanoparticles in an Orthotopic Human Prostate Cancer Rat Model

DTIC Science & Technology

2013-10-01

cell lines, such as cervix cancer cell line (HeLa) and breast cancer cell line (MDA-MB-231), were also employed. The experiments with other cell lines...breast cancer cell line (MDA-MB- 231), and cervix cancer cell line (HeLa). Different from our hypothesis, prostate cancer cell lines did not present...Radiotherapy Using Gold and Luminescent Nanoparticles in an Orthotopic Human Prostate Cancer Rat Model PRINCIPAL INVESTIGATOR: Kwang Song

NEONATAL LOW- AND HIGH-DOSE EXPOSURE TO ESTRADIOL BENZOATE IN THE MALE RAT: I. EFFECTS ON THE PROSTATE GLAND

EPA Science Inventory

Neonatal Low- And High-Dose Exposure To Estradiol Benzoate In The Male Rat: 1. Effects On The Prostate Gland. Oliver Putz, Christian B. Schwartz, Steve Kim, Gerald A. LeBlanc Ralph L. Cooper, Gail S. Prins

ABSTRACT
Brief exposure of rats to high doses of natural estro...

Chronic toxic and carcinogenic effects of oral cadmium in the Noble (NBL/Cr) rat: induction of neoplastic and proliferative lesions of the adrenal, kidney, prostate, and testes.

PubMed

Waalkes, M P; Anver, M R; Diwan, B A

1999-10-29

Based on the occurrence of pulmonary cancers in exposed populations, cadmium is classified as a human carcinogen. More controversial target sites for cadmium in humans include the prostate and kidney, where some studies have shown a link between cadmium and cancer. In Wistar rats cadmium induces tumors in the ventral prostate. The relevance of such lesions to humans is debated since the rat ventral lobe, unlike the dorsolateral lobe, has no embryological homolog in the human prostate. Cadmium has not been linked with renal tumors in rodents but is a potent nephrotoxin. In this work we studied the effects of oral cadmium in the Noble (NBL/Cr) rat with particular attention to proliferative lesions of the prostate and kidneys. Cadmium (as CdCl2) was given ad libitum throughout the study in the drinking water at doses of 0, 25, 50, 100, and 200 ppm Cd to groups (initial n = 30) of male rats, which were observed for up to 102 wk. At the lower doses of cadmium (< or =50 ppm) a clear dose-related increase in total proliferative lesions of the prostate (ventral and dorsolateral lesions combined) occurred (0 ppm = 21% incidence, 25 ppm = 46%, 50 ppm = 50%; trend p < .03). These lesions were described as intraepithelial hyperplasia with occasional areas of atypical epithelial cells without stromal invasion. The lesions occurred primarily in the dorsolateral prostate with cadmium exposure and most frequently showed three or more foci within each specimen. At higher doses, prostatic proliferative lesions declined to control levels. The loss of prostatic response at the higher doses was likely due to diminished testicular function secondary to cadmium treatment. This was reflected in lesions indicative of testicular hypofunction at the highest cadmium dose, namely, interstitial cell hyperplasia, and a strong correlation between cadmium dose and total proliferative lesions of the testes (hyperplasias and tumors combined). Renal tumors (mainly mesenchymal and pelvic transitional

GENE ARRAY ANALYSIS OF THE VENTRAL PROSTATE IN RATS EXPOSED TO EITHER VINCLOZOLIN OR PROCYMIDONE

EPA Science Inventory

GENE ARRAY ANALYSIS OF THE VENTRAL PROSTATE IN RATS EXPOSED TO EITHER VINCLOZOLIN OR PROCYMIDONE. MB Rosen, VS Wilson, JE Schmid, and LE Gray Jr. US EPA, ORD, NHEERL, RTP, NC.

Vinclozolin (Vi) and procymidone (Pr) are antiandrogenic fungicides. While changes in gene expr...

PREPUBERTAL EXPOSURES TO COMPOUNDS THAT INCREASE PROLACTIN SECRETION IN THE MALE RAT: EFFECTS ON ADULT PROSTATE

EPA Science Inventory

Prepubertal exposure to compounds that increase prolactin secretion in the male rat: effects on the adult prostate.

Stoker TE, Robinette CL, Britt BH, Laws SC, Cooper RL.

Endocrinology Branch, Reproductive Toxicology Division, National Health and Environmental Effec...

Proton MRS detects Metabolic Changes in Hormone Sensitive and Resistant Human Prostate Cancer Model CWR22 and CWR22r

PubMed Central

Le, H. Carl; Lupu, Mihaela; Kotedia, Khushali; Rosen, Neal; Solit, David; Koutcher, Jason A.

2010-01-01

17-Allylamino, 17-Demethoxygeldanamycin (17-AAG), an effective inhibitor of the heat shock protein hsp90, preferentially inhibiting tumor hsp90 compared to hsp90 from normal cells (1), has shown promising results against several cancers, including hormone resistant prostate cancer. Levels of several oncogenic proteins critical to tumor growth and progression, such as AR (androgen receptor) and HER2/neu, were reduced 4 hours post 17-AAG treatment. Post treatment metabolic changes have also been observed in several tumor cell lines. In this study total choline (t-cho) distributions in hormone sensitive CWR22 and hormone resistant CWR22r prostate cancer xenograft tumors in mice were measured before, 4 hours and 48 hours after a single bolus 17-AAG treatment at 100 mg/kg using proton MRS. Our results show that tumor t-cho levels declined 4 hours after the treatment for CWR22 (P = 0.001) and 48 hours post treatment for CWR22r (P=0.003). Metabolic changes, in particular of t-cho intensity detected by 1H MRSI, are consistent with the observed immunohistochemistry changes, tumor growth inhibition for CWR22r (P=0.01 at 14 days post treatment) and a constant PSA level versus increasing PSA for control CWR22 (P=0.01). Metabolic changes in t-cho by proton MRSI can be used as an early biomarker of response for advanced stage prostate cancer in targeted therapy such as 17-AAG. PMID:19780165

BDE47 induces rat CYP3A1 by targeting the transcriptional regulation of miR-23b

NASA Astrophysics Data System (ADS)

Sun, Zhenzhen; Zhang, Zhan; Ji, Minghui; Yang, Hongbao; Cromie, Meghan; Gu, Jun; Wang, Chao; Yang, Lu; Yu, Yongquan; Gao, Weimin; Wang, Shou-Lin

2016-08-01

Cytochrome P450 3A (CYP3A) is the most abundant CYP450 enzyme in the liver and is involved in the metabolism of over 50% of xenobiotics. Our previous studies revealed that 2,2‧,4,4‧-tetrabromodiphenyl ether (BDE47) could induce rat CYP3A1 expression, but the molecular basis remains unclear. Using in silico analysis, we identified a potential miR-23b recognition element (MRE23b) in the 3‧-UTR region of CYP3A1 mRNA, which was verified by the luciferase assay. The miR-23b mimic and inhibitor significantly down- and up-regulated the expression of CYP3A1, respectively. Additionally, BDE47 significantly down-regulated the expression of miR-23b in rats and in hepatic H4IIE cells. Induction or blockage of CYP3A1 by a miR-23b inhibitor or mimic could correspondingly alter BDE47-induced expression of CYP3A1 and cytotoxicity in H4IIE cells. Furthermore, LV-anti-miR-23b significantly decreased endogenous levels of miR-23b and increased the expression and activity of CYP3A1 in rat liver. LV-anti-miR-23b also significantly increased the hydroxylated metabolites of BDE47 (3-OH-BDE47, 4-OH-BDE42, and 4‧-OH-BDE49) in rat serum. In conclusion, we first found that BDE47 induced rat CYP3A1 expression by targeting the transcriptional regulation of miR-23b. This study helps provide a better understanding of CYP3A regulation and offers novel clues for the role of miRNAs in the metabolism and distribution of environmental pollutants.

Differential ontogenetic exposure to obesogenic environment induces hyperproliferative status and nuclear receptors imbalance in the rat prostate at adulthood.

PubMed

Pytlowanciv, Eloísa Zanin; Pinto-Fochi, Maria Etelvina; Reame, Vanessa; Gobbo, Marina Guimarães; Ribeiro, Daniele Lisboa; Taboga, Sebastião Roberto; Góes, Rejane Maira

2016-05-01

Experimental data indicate that high-fat diet (HFD) may alter proliferative activity and prostate health. However, the consequences of HFD exposure during different periods of ontogenetic development on prostate histophysiology remain to be elucidated. Herein, we compare the influence of obesogenic environment (OE) due to maternal obesity and HFD at different periods of life on proliferative activity and nuclear receptors frequency in the rat ventral prostate and a possible relationship with metabolic and hormonal alterations. Male Wistar rats (19 weeks old), treated with balanced chow (Control group-C; 3% high-fat, 3.5 Kcal/g), were compared with those exposed to HFD (20% high-fat, 4.9 kcal/g) during gestation (G-maternal obesity), gestation and lactation (GL), from post-weaning to adulthood (WA), from lactation to adulthood (LA) and from gestation to adulthood (GA). After the experimental period, the ventral prostate lobes were removed and analyzed with different methods. Metabolic data indicated that G and GL rats became insulin resistant and WA, LA, and GA became insulin resistant and obese. There was a strong inverse correlation between serum testosterone (∼133% lower) and leptin levels (∼467% higher) in WA, LA, and GA groups. Estrogen serum levels increased in GA, and insulin levels increased in all groups, especially in WA (64.8×). OE-groups exhibited prostatic hypertrophy, since prostate weight increased ∼40% in G, GL, LA, and GA and 31% in WA. As indicated by immunohistochemistry, all HFD-groups except G exhibited an increase in epithelial cell proliferation (PCNA-positive) and a decrease in frequency of AR- and ERβ-positive epithelial cells; there was also an increment of ERα-positive stromal cells in comparison with control. Cells containing PPARγ increased in both epithelium and stroma of all OE groups and those expressing LXRα decreased, particularly in groups OE-exposed during gestation (G, GL and GA). OE leads to prostate hypertrophy

Lack of Antidepressant Effects of (2R,6R)-Hydroxynorketamine in a Rat Learned Helplessness Model: Comparison with (R)-Ketamine.

PubMed

Shirayama, Yukihiko; Hashimoto, Kenji

2018-01-01

(R)-Ketamine exhibits rapid and sustained antidepressant effects in animal models of depression. It is stereoselectively metabolized to (R)-norketamine and subsequently to (2R,6R)-hydroxynorketamine in the liver. The metabolism of ketamine to hydroxynorketamine was recently demonstrated to be essential for ketamine's antidepressant actions. However, no study has compared the antidepressant effects of these 3 compounds in animal models of depression. The effects of a single i.p. injection of (R)-ketamine, (R)-norketamine, and (2R,6R)-hydroxynorketamine in a rat learned helplessness model were examined. A single dose of (R)-ketamine (20 mg/kg) showed an antidepressant effect in the rat learned helplessness model. In contrast, neither (R)-norketamine (20 mg/kg) nor (2R,6R)-hydroxynorketamine (20 and 40 mg/kg) did so. Unlike (R)-ketamine, its metabolite (2R,6R)-hydroxynorketamine did not show antidepressant actions in the rat learned helplessness model. Therefore, it is unlikely that the metabolism of ketamine to hydroxynorketamine is essential for ketamine's antidepressant actions. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Lack of Antidepressant Effects of (2R,6R)-Hydroxynorketamine in a Rat Learned Helplessness Model: Comparison with (R)-Ketamine

PubMed Central

Shirayama, Yukihiko

2018-01-01

Abstract Background (R)-Ketamine exhibits rapid and sustained antidepressant effects in animal models of depression. It is stereoselectively metabolized to (R)-norketamine and subsequently to (2R,6R)-hydroxynorketamine in the liver. The metabolism of ketamine to hydroxynorketamine was recently demonstrated to be essential for ketamine’s antidepressant actions. However, no study has compared the antidepressant effects of these 3 compounds in animal models of depression. Methods The effects of a single i.p. injection of (R)-ketamine, (R)-norketamine, and (2R,6R)-hydroxynorketamine in a rat learned helplessness model were examined. Results A single dose of (R)-ketamine (20 mg/kg) showed an antidepressant effect in the rat learned helplessness model. In contrast, neither (R)-norketamine (20 mg/kg) nor (2R,6R)-hydroxynorketamine (20 and 40 mg/kg) did so. Conclusions Unlike (R)-ketamine, its metabolite (2R,6R)-hydroxynorketamine did not show antidepressant actions in the rat learned helplessness model. Therefore, it is unlikely that the metabolism of ketamine to hydroxynorketamine is essential for ketamine’s antidepressant actions. PMID:29155993

Adamantanyl-Histone Deacetylase Inhibitor H6CAHA Exhibits Favorable Pharmacokinetics and Augments Prostate Cancer Radiation Sensitivity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Konsoula, Zacharoula; Cao Hong; Velena, Alfredo

2011-04-01

Purpose: To evaluate pharmacological properties of H6CAHA, an adamantyl-hydroxamate histone deacetylase inhibitor, and to investigate its effect on prostate cancer cells following exposure to {gamma}-radiation in vitro and in vivo. Methods and Materials: H6CAHA was assessed for in vitro solubility, lipophilicity and growth inhibition, and in vivo plasma pharmacokinetics. The effect of H6CAHA on radiation clonogenic survival and DNA damage repair was evaluated in human prostate cancer (PC3, DU145, LNCaP) and nonmalignant control epithelial (RWPE1 and 267B1) cell lines. The effect of this agent on the growth of prostate cancer xenografts was also assessed in mice. Results: H6CAHA demonstrated goodmore » solubility and permeability profiles and preferentially inhibited the growth of prostate cancer cells over nonmalignant cells. Plasma pharmacokinetics revealed that the area under the curve of H6CAHA was 8.08 {+-} 0.91 {mu}M x h, and its half-life was 11.17 {+-} 0.87 h. Radiation clonogenic assays revealed that H6CAHA decreased the survival of prostate cancer cells at the dose that exerted limited effect on normal cells. Concomitantly, delayed DNA damage repair following combination treatment was evident in cancer cells, indicated by the prolonged appearance of {gamma}H2AX and Rad51 foci and suppression of DNA damage repair genes (ATM, BRCA1, and BRCA2). Combined modality of H6CAHA (daily intraperitoneal injections for 10 days) with {gamma}-radiation (10 x 2 Gy) completely blocked the growth of PC3 tumor xenografts (p < 0.001) over 60 days. Conclusion: These results support the potential therapeutic value of H6CAHA in combination with radiation and support the rationale for further clinical investigation.« less

Differential expression of miR-34b and androgen receptor pathway regulate prostate cancer aggressiveness between African-Americans and Caucasians

PubMed Central

Kato, Taku; Yamamura, Soichiro; Tanaka, Yuichiro; Majid, Shahana; Saini, Sharanjot; Varahram, Shahryari; Kulkarni, Priyanka; Dasgupta, Pritha; Mitsui, Yozo; Sumida, Mitsuho; Tabatabai, Laura; Deng, Guoren; Kumar, Deepak; Dahiya, Rajvir

2017-01-01

African-Americans are diagnosed with more aggressive prostate cancers and have worse survival than Caucasians, however a comprehensive understanding of this health disparity remains unclear. To clarify the mechanisms leading to this disparity, we analyzed the potential involvement of miR-34b expression in African-Americans and Caucasians. miR-34b functions as a tumor suppressor and has a multi-functional role, through regulation of cell proliferation, cell cycle and apoptosis. We found that miR-34b expression is lower in human prostate cancer tissues from African-Americans compared to Caucasians. DNA hypermethylation of the miR-34b-3p promoter region showed significantly higher methylation in prostate cancer compared to normal samples. We then sequenced the promoter region of miR-34b-3p and found a chromosomal deletion in miR-34b in African-American prostate cancer cell line (MDA-PCA-2b) and not in Caucasian cell line (DU-145). We found that AR and ETV1 genes are differentially expressed in MDA-PCa-2b and DU-145 cells after overexpression of miR-34b. Direct interaction of miR-34b with the 3’ untranslated region of AR and ETV1 was validated by luciferase reporter assay. We found that miR-34b downregulation in African-Americans is inversely correlated with high AR levels that lead to increased cell proliferation. Overexpression of miR-34b in cell lines showed higher inhibition of cell proliferation, apoptosis and G1 arrest in the African-American cells (MDA-PCa-2b) compared to Caucasian cell line (DU-145). Taken together, our results show that differential expression of miR-34b and AR are associated with prostate cancer aggressiveness in African-Americans. PMID:28039468

Immunohistochemical expression of interleukin-2 receptor and interleukin-6 in patients with prostate cancer and benign prostatic hyperplasia: association with asymptomatic inflammatory prostatitis NIH category IV.

PubMed

Engelhardt, Paul Friedrich; Seklehner, Stephan; Brustmann, Hermann; Lusuardi, Lukas; Riedl, Claus R

2015-04-01

This study prospectively investigated the immunohistochemical expression of interleukin-2 receptor (IL-2R) and interleukin-6 (IL-6) in patients with prostate cancer and benign prostatic hyperplasia (BPH), and a possible association of these conditions with asymptomatic inflammatory prostatitis National Institutes of Health (NIH) category IV. The study included 139 consecutive patients who underwent transurethral resection of the prostate and transvesical enucleation of the prostate (n = 82) or radical prostatectomy (n = 57). To characterize inflammatory changes the criteria proposed by Irani et al. [J Urol 1997;157:1301-3] were used. IL-2R and IL-6 expression was studied by a standard immunohistochemical method. Results were correlated with tumour, node, metastasis stage, Gleason scores, total prostate-specific antigen, International Prostate Symptom Score and body mass index. IL-2R and IL-6 expression was significantly higher in neoplastic prostate cancer tissue than in normal tissue of prostate cancer patients (p < 0.001 and p < 0.04, respectively). Prostate cancer patients with prostatitis showed significantly higher IL-2R expression than those without inflammation (p < 0.03). In patients with BPH, expression of IL-2R as well as IL-6 was higher in patients with prostatitis than in those without (p < 0.01 and p < 0.02, respectively). IL-2R and IL-6 expression was significantly higher in prostate cancer tissue than in normal tissue. Patients with asymptomatic inflammatory prostatitis NIH category IV showed significantly greater activity.

Rat organic solute carrier protein 1 (rOscp1) mediated the transport of organic solutes in Xenopus laevis oocytes: isolation and pharmacological characterization of rOscp1.

PubMed

Izuno, Hisanori; Kobayashi, Yasuna; Sanada, Yutaka; Nihei, Daisuke; Suzuki, Masako; Kohyama, Noriko; Ohbayashi, Masayuki; Yamamoto, Toshinori

2007-09-22

Rat organic solute carrier protein 1 (rOscp1) was isolated from a rat testis cDNA library. Isolated rOscp1 cDNA consisted of 1089 base pairs that encoded a 363-amino acid protein, and the amino acid sequence was 88% and 93% identical to that of human OSCP1 (hOSCP1) and mouse Oscp1 (mOscp1), respectively. The message for rOscp1 is highly detected in rat testis. When expressed in X. oocytes, rOscp1 mediated the high affinity transport of p-aminohippurate (PAH) with a Km value of 15.7+/-1.9 microM, and rOscp1-mediated organic solutes were exhibited in time- and Na+-independent manners. rOscp1 also transported various structurally heterogenous compounds such as testosterone, dehydroepiandrosterone sulfate (DHEA-S), and taurocholate with some differences in substrate specificity compared with hOSCP1. Immunohistochemical analysis revealed that the rOscp1 protein is localized in the basal membrane side of Sertoli cells as observed in mouse testis [Kobayashi et al., 2007; Kobayashi, Y., Tsuchiya, A., Hayashi, T., Kohyama, N., Ohbayashi, M., Yamamoto, T., 2007. Isolation and characterization of polyspecific mouse organic solute carrier protein 1 (mOscp1). Drug Metabolism and Disposition 35 (7), 1239-1245]. Thus, the present results indicate that a newly isolated cDNA clone, rOscp1, is a polyspecific organic solute carrier protein with some differences in substrate specificity compared with human and mouse OSCP1.

Experimental autoimmune prostatitis induces microglial activation in the spinal cord.

PubMed

Wong, Larry; Done, Joseph D; Schaeffer, Anthony J; Thumbikat, Praveen

2015-01-01

The pathogenesis of chronic prostatitis/chronic pelvic pain syndrome is unknown and factors including the host's immune response and the nervous system have been attributed to the development of CP/CPPS. We previously demonstrated that mast cells and chemokines such as CCL2 and CCL3 play an important role in mediating prostatitis. Here, we examined the role of neuroinflammation and microglia in the CNS in the development of chronic pelvic pain. Experimental autoimmune prostatitis (EAP) was induced using a subcutaneous injection of rat prostate antigen. Sacral spinal cord tissue (segments S14-S5) was isolated and utilized for immunofluorescence or QRT-PCR analysis. Tactile allodynia was measured at baseline and at various points during EAP using Von Frey fibers as a function for pelvic pain. EAP mice were treated with minocycline after 30 days of prostatitis to test the efficacy of microglial inhibition on pelvic pain. Prostatitis induced the expansion and activation of microglia and the development of inflammation in the spinal cord as determined by increased expression levels of CCL3, IL-1β, Iba1, and ERK1/2 phosphorylation. Microglial activation in mice with prostatitis resulted in increased expression of P2X4R and elevated levels of BDNF, two molecular markers associated with chronic pain. Pharmacological inhibition of microglia alleviated pain in mice with prostatitis and resulted in decreased expression of IL-1β, P2X4R, and BDNF. Our data show that prostatitis leads to inflammation in the spinal cord and the activation and expansion of microglia, mechanisms that may contribute to the development and maintenance of chronic pelvic pain. © 2014 Wiley Periodicals, Inc.

Experimental autoimmune prostatitis induces microglial activation in the spinal cord

PubMed Central

Wong, Larry; Done, Joseph D.; Schaeffer, Anthony J.; Thumbikat, Praveen

2014-01-01

Background The pathogenesis of chronic prostatitis/chronic pelvic pain syndrome is unknown and factors including the host’s immune response and the nervous system have been attributed to the development of CP/CPPS. We previously demonstrated that mast cells and chemokines such as CCL2 and CCL3 play an important role in mediating prostatitis. Here, we examined the role of neuroinflammation and microglia in the CNS in the development of chronic pelvic pain. Methods Experimental autoimmune prostatitis (EAP) was induced using a subcutaneous injection of rat prostate antigen. Sacral spinal cord tissue (segments S4–S5) was isolated and utilized for immunofluorescence or QRT-PCR analysis. Tactile allodynia was measured at baseline and at various points during EAP using Von Frey fibers as a function for pelvic pain. EAP mice were treated with minocycline after 30 days of prostatitis to test the efficacy of microglial inhibition on pelvic pain. Results Prostatitis induced the expansion and activation of microglia and the development of inflammation in the spinal cord as determined by increased expression levels of CCL3, IL-1β, Iba1, and ERK1/2 phosphorylation. Microglial activation in mice with prostatitis resulted in increased expression of P2X4R and elevated levels of BDNF, two molecular markers associated with chronic pain. Pharmacological inhibition of microglia alleviated pain in mice with prostatitis and resulted in decreased expression of IL-1β, P2X4R, and BDNF. Conclusion Our data shows that prostatitis leads to inflammation in the spinal cord and the activation and expansion of microglia, mechanisms that may contribute to the development and maintenance of chronic pelvic pain. PMID:25263093

Highly potent analogues of luteinizing hormone-releasing hormone containing D-phenylalanine nitrogen mustard in position 6

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bajusz, S.; Janaky, T.; Csernus, V.J.

The nitrogen mustard derivatives of 4-phenylbutyric acid and L-phenylalanine, called chlorambucil (Chl) and melphalan (Mel), respectively, have been incorporated into several peptide hormones, including luteinizing hormone-releasing hormone (LH-RH). The alkylating analogues of LH-RH were prepared by linking Chl, as an N-acyl moiety, to the complete amino acid sequence of agonistic and antagonistic analogues. These compounds, in particular the antagonistic analogues, showed much lower potency than their congeners carrying other acyl groups. To obtain highly potent alkylating analogues of LH-RH, the D enantiomer of Mel was incorporated into position 6 of the native hormone and some of its antagonistic analogues. Ofmore » the peptides prepared, (D-Mel{sup 6})LH-RH (SB-05) and (Ac-D-Nal(2){sup 1},D-Phe(pCl){sup 2},D-Pal(3){sup 3},Arg{sup 5},D-Mel{sup 6},D-Ala{sup 10})LH-RH (SB-86, where Nal(2) is 3-(2-naphthyl)alanine and Pal(3) is 3-(3-pyridyl)alanine) possessed the expected high agonistic and antagonistic activities, respectively, and also showed high affinities for the membrane receptors of rat pituitary cells, human breast cancer cells, human prostate cancer cells, and rat Dunning R-3327 prostate tumor cells. These two analogues exerted cytotoxic effects on human and rat mammary cancer cells in vitro. Thus these two D-Mel{sup 6} analogues seem to be particularly suitable for the study of how alkylating analogues of LH-RH could interfere with intracellular events in certain cancer cells.« less

The prostate after castration and hormone replacement in a rat model: structural and ultrastructural analysis

PubMed Central

Felix-Patrício, Bruno; Miranda, Alexandre F.; Medeiros, Jorge L.; Gallo, Carla B. M.; Gregório, Bianca M.; de Souza, Diogo B.; Costa, Waldemar S.; Sampaio, Francisco J. B.

2017-01-01

ABSTRACT Purpose: To evaluate if late hormonal replacement is able to recover the prostatic tissue modified by androgenic deprivation. Materials and Methods: 24 rats were assigned into a Sham group; an androgen deficient group, submitted to bilateral orchiectomy (Orch); and a group submitted to bilateral orchiectomy followed by testosterone replacement therapy (Orch+T). After 60 days from surgery blood was collected for determination of testosterone levels and the ventral prostate was collected for quantitative and qualitative microscopic analysis. The acinar epithelium height, the number of mast cells per field, and the densities of collagen fibers and acinar lumen were analyzed by stereological methods under light microscopy. The muscle fibers and types of collagen fibers were qualitatively assessed by scanning electron microscopy and polarization microscopy. Results: Hormone depletion (in group Orch) and return to normal levels (in group Orch+T) were effective as verified by serum testosterone analysis. The androgen deprivation promoted several alterations in the prostate: the acinar epithelium height diminished from 16.58±0.47 to 11.48±0.29μm; the number of mast cells per field presented increased from 0.45±0.07 to 2.83±0.25; collagen fibers density increased from 5.83±0.92 to 24.70±1.56%; and acinar lumen density decreased from 36.78±2.14 to 16.47±1.31%. Smooth muscle was also increased in Orch animals, and type I collagen fibers became more predominant in these animals. With the exception of the densities of collagen fibers and acinar lumen, in animals receiving testosterone replacement therapy all parameters became statistically similar to Sham. Collagen fibers density became lower and acinar lumen density became higher in Orch+T animals, when compared to Sham. This is the first study to demonstrate a relation between mast cells and testosterone levels in the prostate. This cells have been implicated in prostatic cancer and benign hyperplasia

The prostate after castration and hormone replacement in a rat model: structural and ultrastructural analysis.

PubMed

Felix-Patrício, Bruno; Miranda, Alexandre F; Medeiros, Jorge L; Gallo, Carla B M; Gregório, Bianca M; Souza, Diogo B; Costa, Waldemar S; Sampaio, Francisco J B

2017-01-01

To evaluate if late hormonal replacement is able to recover the prostatic tissue modified by androgenic deprivation. 24 rats were assigned into a Sham group; an androgen deficient group, submitted to bilateral orchiectomy (Orch); and a group submitted to bilateral orchiectomy followed by testosterone replacement therapy (Orch+T). After 60 days from surgery blood was collected for determination of testosterone levels and the ventral prostate was collected for quantitative and qualitative microscopic analysis. The acinar epithelium height, the number of mast cells per field, and the densities of collagen fibers and acinar lumen were analyzed by stereological methods under light microscopy. The muscle fibers and types of collagen fibers were qualitatively assessed by scanning electron microscopy and polarization microscopy. Hormone depletion (in group Orch) and return to normal levels (in group Orch+T) were effective as verified by serum testosterone analysis. The androgen deprivation promoted several alterations in the prostate: the acinar epithelium height diminished from 16.58±0.47 to 11.48±0.29μm; the number of mast cells per field presented increased from 0.45±0.07 to 2.83±0.25; collagen fibers density increased from 5.83±0.92 to 24.70±1.56%; and acinar lumen density decreased from 36.78±2.14 to 16.47±1.31%. Smooth muscle was also increased in Orch animals, and type I collagen fibers became more predominant in these animals. With the exception of the densities of collagen fibers and acinar lumen, in animals receiving testosterone replacement therapy all parameters became statistically similar to Sham. Collagen fibers density became lower and acinar lumen density became higher in Orch+T animals, when compared to Sham. This is the first study to demonstrate a relation between mast cells and testosterone levels in the prostate. This cells have been implicated in prostatic cancer and benign hyperplasia, although its specific role is not understood

Procyanidin B2 ameliorates carrageenan-induced chronic nonbacterial prostatitis in rats via anti-inflammatory and activation of the Nrf2 pathway.

PubMed

Wang, Wei; Chen, Renzong; Wang, Jiye

2017-11-04

Prostatitis is one of the most prevalent problems in andriatry and urinary surgery. In the present study, we evaluated the effect of procyanidin B2 (PB) on carrageenan-induced chronic nonbacterial prostatitis in rats. Results showed that PB significantly decreased the prostatic index and enhanced the body weight inhibited by carrageenan. Biochemical results revealed that PB significantly lowered the prostatic specific antigen (PSA) and alleviated oxidative stress in serum. The levels of TNF-α, IL-6, and IL-10 in prostatic homogenate were also significantly decreased after PB treatment. We also found evidence that PB treatment reversed the suppression of Nrf2 nuclear translocation, and increased the expressions of NQO1 and HO-1 in the prostate glands. In conclusion, treatment with PB attenuates carrageenan-induced chronic nonbacterial prostatitis via anti-inflammatory and activation of the Nrf2 pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

Differential effects of 2-difluoromethylornithine and methylglyoxal bis(guanylhydrazone) on the testosterone-induced growth of ventral prostate and seminal vesicles of castrated rats.

PubMed Central

Käpyaho, K; Kallio, A; Jänne, J

1984-01-01

2-Difluoromethylornithine totally prevented any increases in putrescine and spermidine concentrations in the ventral prostate of castrated rats during a 6-day testosterone treatment. Prostatic ornithine decarboxylase activity was inhibited by 80%, whereas S-adenosylmethionine decarboxylase was stimulated by more than 9-fold. In seminal vesicle, the inhibition of putrescine and spermidine accumulation, as well as of ornithine decarboxylase activity, was only minimal, and no stimulation of S-adenosylmethionine decarboxylase was observed. Administration of methylglyoxal bis(guanylhydrazone) to castrated androgen-treated rats resulted in a marked increase in concentrations of all prostatic polyamines. Prostatic ornithine decarboxylase activity was nearly 2 times and adenosylmethionine decarboxylase activity 9 times higher than that of the testosterone-treated animals. In contrast with ventral prostate, methylglyoxal bis(guanylhydrazone) treatment inhibited moderately the accumulation of spermidine and spermine in seminal vesicle, although both ornithine decarboxylase and S-adenosylmethionine decarboxylase activities were stimulated. Difluoromethylornithine inhibited significantly the weight gain of ventral prostate, but methylglyoxal bis(guanylhydrazone) produced a substantial increase in prostatic weight. These changes were largely due to the fact that the volume of prostatic secretion was greatly decreased by difluoromethylornithine, whereas methylglyoxal bis(guanylhydrazone) increased the amount of secretion. Treatment with difluoromethylornithine strikingly increased the methylglyoxal bis(guanylhydrazone) content of both ventral prostate and seminal vesicle, but even under these conditions the drug concentration remained low in comparison with other tissues. The results indicate that a combined use of these two polyamine anti-metabolites does not necessarily result in a synergistic growth inhibition of the androgen-induced growth of male accessory sexual glands

Differential effects of 2-difluoromethylornithine and methylglyoxal bis(guanylhydrazone) on the testosterone-induced growth of ventral prostate and seminal vesicles of castrated rats.

PubMed

Käpyaho, K; Kallio, A; Jänne, J

1984-05-01

2-Difluoromethylornithine totally prevented any increases in putrescine and spermidine concentrations in the ventral prostate of castrated rats during a 6-day testosterone treatment. Prostatic ornithine decarboxylase activity was inhibited by 80%, whereas S-adenosylmethionine decarboxylase was stimulated by more than 9-fold. In seminal vesicle, the inhibition of putrescine and spermidine accumulation, as well as of ornithine decarboxylase activity, was only minimal, and no stimulation of S-adenosylmethionine decarboxylase was observed. Administration of methylglyoxal bis(guanylhydrazone) to castrated androgen-treated rats resulted in a marked increase in concentrations of all prostatic polyamines. Prostatic ornithine decarboxylase activity was nearly 2 times and adenosylmethionine decarboxylase activity 9 times higher than that of the testosterone-treated animals. In contrast with ventral prostate, methylglyoxal bis(guanylhydrazone) treatment inhibited moderately the accumulation of spermidine and spermine in seminal vesicle, although both ornithine decarboxylase and S-adenosylmethionine decarboxylase activities were stimulated. Difluoromethylornithine inhibited significantly the weight gain of ventral prostate, but methylglyoxal bis(guanylhydrazone) produced a substantial increase in prostatic weight. These changes were largely due to the fact that the volume of prostatic secretion was greatly decreased by difluoromethylornithine, whereas methylglyoxal bis(guanylhydrazone) increased the amount of secretion. Treatment with difluoromethylornithine strikingly increased the methylglyoxal bis(guanylhydrazone) content of both ventral prostate and seminal vesicle, but even under these conditions the drug concentration remained low in comparison with other tissues. The results indicate that a combined use of these two polyamine anti-metabolites does not necessarily result in a synergistic growth inhibition of the androgen-induced growth of male accessory sexual glands.

Comparison of the Pharmacological Effects of a Novel Selective Androgen Receptor Modulator, the 5α-Reductase Inhibitor Finasteride, and the Antiandrogen Hydroxyflutamide in Intact Rats: New Approach for Benign Prostate Hyperplasia

PubMed Central

Gao, Wenqing; Kearbey, Jeffrey D.; Nair, Vipin A.; Chung, Kiwon; Parlow, A. F.; Miller, Duane D.; Dalton, James T.

2007-01-01

Tissue-selective androgen receptor modulators (SARMs) demonstrate tissue selectivity in both castrated and intact male rats, behaving as partial agonists in androgenic tissues (i.e. prostate and seminal vesicle), but full agonists in anabolic tissues (i.e. levator ani muscle). The partial agonist activity of SARMs (compounds S-1 and S-4) in the prostate of intact rats suggested that SARM could be used for androgen suppression in the treatment of benign prostate hyperplasia (BPH). This study was designed to explore the mechanisms of action of SARM and to characterize the tissue selectivity of S-1 in intact male rats compared with that of hydroxyflutamide (antiandrogen) and finasteride (5α-reductase inhibitor), two major drugs used for androgen suppression treatment of BPH. In intact male rats, S-1 (5, 10, and 25 mg/kg) selectively decreased the prostate weight with similar efficacy to finasteride (5 mg/kg), without affecting the levator ani muscle or increasing the plasma levels of testosterone, LH, and FSH. Hydroxyflutamide (0.5, 1, 5, 10, and 25 mg/kg), however, decreased both the prostate and levator ani muscle weights without any selectivity and increased plasma hormone levels in a dose-dependent manner. Furthermore, S-1 and S-4 showed very weak inhibitory effects toward transiently expressed type I and II human 5α-reductase (Ki, >20 µM) during in vitro assays. Therefore, although S-1 and finasteride showed very similar suppressive effects in the prostate of intact male rats, they decreased prostate size via different mechanisms of action. S-1 simply worked as androgen receptor partial agonist, whereas finasteride inhibited prostatic 5α-reductase. These studies indicate that SARMs may demonstrate clinical utility as single agent or combination therapy for BPH. PMID:15308613

Induction at high incidence of ductal prostate adenocarcinomas in NBL/Cr and Sprague-Dawley Hsd:SD rats treated with a combination of testosterone and estradiol-17 beta or diethylstilbestrol.

PubMed

Bosland, M C; Ford, H; Horton, L

1995-06-01

This study determined the incidence of prostate adenocarcinoma following long-term treatment of NBL and Sprague-Dawley rats with estradiol-17 beta or diethylstilbestrol (DES) plus testosterone and it defined the origin of these tumors. NBL and Sprague-Dawley rats were treated with two Silastic tubing implants (i.d. 1.6 mm, o.d. 3.2 mm) containing a 2 cm long filling of testosterone and one implant containing a 1 cm long filling of estradiol-17 beta or DES. Control animals received empty implants. Treated animals were killed when moribund and controls were killed at 91 (NBL) or 75 (Sprague-Dawley) weeks after initiation of treatment and accessory sex glands were sampled for histopathological examination of multiple step sections. Prostatic adenocarcinoma occurred in 100% of NBL rats after treatment with estradiol-17 beta or DES plus testosterone for 44 and 59 weeks (group means) respectively. Adenocarcinoma incidences were lower in Sprague-Dawley rats. The adenocarcinomas were small, microscopic, invasive tumors and they were spatially closely associated with the periurethral ducts of the dorsal, lateral and/or anterior (= coagulating gland) prostate, but never with the ducts of the ventral lobe and seminal vesicles. One adenocarcinoma was of uncertain origin. Duct-acinar dysplastic lesions occurred in the periphery of the dorsal and lateral prostate of all hormone-treated NBL and many Sprague-Dawley rats, but did not appear to give rise to carcinoma. Although some adenocarcinomas were contiguous with dysplastic ducts of the peripheral dorsolateral prostate, the main mass of these neoplasms was located in the periurethral area. Also, most adenocarcinomas were only connected with the periurethral ducts, in which atypical hyperplasia occurred following hormone treatment for 36 weeks or longer. Thus atypical hyperplasia of the periurethral prostate ducts, but not peripheral duct-acinar dysplasia, appeared to be the likely precursor of the induced carcinomas

miR-503 suppresses tumor cell proliferation and metastasis by directly targeting RNF31 in prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guo, Jia; Liu, Xiuheng, E-mail: l_xiuheng@163.com; Wang, Min

2015-09-04

Microarray data analyses were performed to search for metastasis-associated oncogenes in prostate cancer (PCa). RNF31 mRNA expressions in tumor tissues and benign prostate tissues were evaluated. The RNF31 protein expression levels were also analyzed by western blot and immunohistochemistry. Luciferase reporter assays were used to identify miRNAs that can regulate RNF31. The effect of RNF31 on PCa progression was studied in vitro and in vivo. We found that RNF31 was significantly increased in PCa and its expression level was highly correlated with seminal vesicle invasion, clinical stage, prostate specific antigen (PSA) level, Gleason score, and BCR. Silence of RNF31 suppressed PCa cellmore » proliferation and metastasis in vitro and in vivo. miR-503 can directly regulate RNF31. Enforced expression of miR-503 inhibited the expression of RNF31 significantly and the restoration of RNF31 expression reversed the inhibitory effects of miR-503 on PCa cell proliferation and metastasis. These findings collectively indicated an oncogene role of RNF31 in PCa progression which can be regulated by miR-503, suggesting that RNF31 could serve as a potential prognostic biomarker and therapeutic target for PCa. - Highlights: • RNF31 is a potential metastasis associated gene and is associated with prostate cancer progression. • Silence of RNF31 inhibits PCa cell colony formation, migration and invasion. • RNF31 as a direct target of miR-503. • miR-503 can regulate cell proliferation, invasion and migration by targeting RNF31. • RNF31 plays an important role in PCa growth and metastasis in vivo.« less

Structural Variation of Prostate Urethra Reflected by the Ratio Between Prostate Volume and Prostatic Urethral Length is Associated with the Degrees of Lower Urinary Tract Symptoms.

PubMed

Ko, Young Hwii; Song, Phil Hyun

2016-05-01

Because it is well known that the prostate volume is not directly associated with the degrees of lower urinary tract symptom (LUTS), we hypothesized that change of the prostatic urethra led by prostatic enlargement as missing links between them. To provide an integral description, we determined the ratio between prostate volume and prostatic urethral length (RPVL), and investigated its clinical implication. Prostate volume, prostatic urethral length, RPVL was measured from transrectal ultrasonography for 213 consecutive patients. The degree of LUTS was investigated using the international prostate symptom score (IPSS) and uroflowmetry, then the correlations were analyzed. While no variables were significantly linked with total IPSS, obstructive symptoms (IPSS Q247) showed a negative association (r = -0.3, P < 0.001) and irritative symptoms (IPSS Q1356) showed a positive association solely with RPVL (r = 0.186, P = 0.007). These relevancies were enhanced (r = -0.471 [P = <0.001] and 0.3 [P = 0.004], respectively) in patients with a larger prostate (over 30 g, n = 93), but disappeared in their smaller counterparts (below 30 g, n = 120), (r = -0.133 [P = 0.143] and 0.75 [P = 0.410], respectively). In uroflowmetry, prostate urethral length showed positive correlation (r = 0.319 [P < 0.001]), and RPVL showed negative correlation (r = -0.195 [P = 0.004]) with post voiding residual amount, but these relationships similarly vanished in men with a smaller prostate. The structural variation of the prostatic urethra within the prostate reflected by RPVL showed correlation with the degree of LUTS, with a tendency toward increasing prostatic urethra in obstructive and decreasing prostatic urethra in irritative symptoms, in men with a relatively large prostate. © 2014 Wiley Publishing Asia Pty Ltd.

MicroRNAs Are Mediators of Androgen Action in Prostate and Muscle

PubMed Central

Narayanan, Ramesh; Jiang, Jinmai; Gusev, Yuriy; Jones, Amanda; Kearbey, Jeffrey D.; Miller, Duane D.; Schmittgen, Thomas D.; Dalton, James T.

2010-01-01

Androgen receptor (AR) function is critical for the development of male reproductive organs, muscle, bone and other tissues. Functionally impaired AR results in androgen insensitivity syndrome (AIS). The interaction between AR and microRNA (miR) signaling pathways was examined to understand the role of miRs in AR function. Reduction of androgen levels in Sprague-Dawley rats by castration inhibited the expression of a large set of miRs in prostate and muscle, which was reversed by treatment of castrated rats with 3 mg/day dihydrotestosterone (DHT) or selective androgen receptor modulators. Knockout of the miR processing enzyme, DICER, in LNCaP prostate cancer cells or tissue specifically in mice inhibited AR function leading to AIS. Since the only function of miRs is to bind to 3′ UTR and inhibit translation of target genes, androgens might induce miRs to inhibit repressors of AR function. In concordance, knock-down of DICER in LNCaP cells and in tissues in mice induced the expression of corepressors, NCoR and SMRT. These studies demonstrate a feedback loop between miRs, corepressors and AR and the imperative role of miRs in AR function in non-cancerous androgen-responsive tissues. PMID:21048966

Role of miR-452-5p in the tumorigenesis of prostate cancer: A study based on the Cancer Genome Atl(TCGA), Gene Expression Omnibus (GEO), and bioinformatics analysis.

PubMed

Gao, Li; Zhang, Li-Jie; Li, Sheng-Hua; Wei, Li-Li; Luo, Bin; He, Rong-Quan; Xia, Shuang

2018-03-06

MiR-452-5p has been reported to be down-regulated in prostate cancer, affecting the development of this type of cancer. However, the molecular mechanism of miR-452-5p in prostate cancer remains unclear. Therefore, we investigated the network of target genes of miR-452-5p in prostate cancer using bioinformatics analyses. We first analyzed the expression profiles and prognostic value of miR-452-5p in prostate cancer tissues from a public database. Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), PANTHER pathway analyses, and a disease ontology (DG) analysis were performed to find the molecular functions of the target genes from GSE datasets and miRWalk. Finally, we validated hub genes from the protein-protein interaction (PPI) networks of the target genes in the Human Protein Atlas (HPA) database and Gene Expression Profiling Interactive Analysis (GEPIA). Narrowing down the optimal target genes was conducted by seeking the common parts of up-regulated genes from GEPIA, down-regulated genes from GSE datasets, and predicted genes in miRWalk. Based on mining of GEO and ArrayExpress microarray chips and miRNA-Seq data in the TCGA database, which includes 1007 prostate cancer samples and 387 non-cancer samples, miR-452-5p is shown to be down-regulated in prostate cancer. GO, KEGG, and PANTHER pathway analyses suggested that the target genes might participate in important biological processes, such as transforming growth factor beta signaling and the positive regulation of brown fat cell differentiation and mesenchymal cell differentiation, as well as the Ras signaling pathway and pathways regulating the pluripotency of stem cells and arrhythmogenic right ventricular cardiomyopathy (ARVC). Nine genes-GABBR, PNISR, NTSR1, DOCK1, EREG, SFRP1, PTGS2, LEF1, and BMP2-were defined as hub genes in the PPI network. Three genes-FAM174B, SLC30A4, and SLIT1-were jointly shared by GEPIA, the GSE datasets, and miRWalk. Down-regulated miR-452-5p might play an

Plasma Exosomal miRNA-122-5p and miR-300-3p as Potential Markers for Transient Ischaemic Attack in Rats.

PubMed

Li, Dong-Bin; Liu, Jing-Li; Wang, Wei; Luo, Xiu-Mei; Zhou, Xia; Li, Jin-Pin; Cao, Xiao-Li; Long, Xiao-Hong; Chen, Jia-Gui; Qin, Chao

2018-01-01

Background: Differentiation of transient ischaemic attack (TIA) from ischaemic stroke within the thrombolysis time window is difficult. Although TIA may be diagnosed within this window, the latest imaging technologies are complex and costly. Serum markers, which are non-invasive, rapid and economic, are used for diagnosis and prognosis of various diseases. Exosome-derived miRNA markers for TIA are unknown. Methods: We examined focal brain ischaemia produced by occlusion of the middle cerebral artery (MCAo) for 5 min, 10 min, and 2 h in rats. Exosomal miRNAs with consistent trends in cerebrospinal fluid (CSF) and plasma were identified by deep sequencing and quantitative real-time polymerase chain reaction (qRT-PCR). The areas under the curve (AUC) of the receiver operating characteristic (ROC) curve were used to evaluate the diagnostic accuracy of these miRNAs for TIA in rats. Results: Rno-miR-122-5p and rno-miR-300-3p were selected. Plasma exosomal rno-miR-122-5p was significantly downregulated in 10 min ischaemic rats compared with control and 5 min plasma. Plasma exosomal rno-miR-300-3p was significantly upregulated in 5 min ischaemic rats compared with control, 10 min and 2 h rats. Plasma and CSF levels of these miRNAs were correlated. ROC analysis showed high AUC values for rno-miR-122-5p (0.960) and rno-miR-300-3p (0.970) in the 10 and 5 min rats, respectively, compared with controls. Conclusions: Plasma exosomal rno-miR-122-5p and rno-miR-300-3p may be blood-based TIA biomarkers.

Isolation and Growth of Prostate Stem Cells and Establishing Cancer Cell Lines from Human Prostate Tumors

DTIC Science & Technology

2009-05-01

contaminating rat UGSE cells ; and regions of host mouse glands were either from circulating pluripotent stem cells or local epithelial cells which were...CONTRACT NUMBER Isolation and Growth of Prostate Stem Cells and Establishing Cancer Cell Lines from Human Prostate Tumors 5b. GRANT NUMBER 81WXH...NOTES 14. ABSTRACT The objective of this proposal was to isolate, grow, and characterize normal prostate stem cells and establish new prostate

The Role of microRNA miR-101 in Prostate Cancer Progression

DTIC Science & Technology

2012-09-01

genome -wide mapping of PcG binding in human fibroblasts, human ES cells, mouse ES cells, and Drosophila 37-41 . All of the studies demonstrated that...development. Mamm Genome 2002; 13(9): 493-503. 15. Simon J, Chiang A, Bender W, Shimell MJ, O’Connor M. Elements of the Drosophila bithorax complex... sequencing analysis of the miR-203 genomic region revealed cancer-specific DNA methylation in a region proximal to miR-203 in prostate cancer tissues

The Role of Stromally Produced Cathepsin D in Promoting Prostate Tumorigenesis

DTIC Science & Technology

2013-09-01

estrogens in combination with androgen in the NBL rat model produced a 100% incidence of PCa. Treatment with androgen alone induced PCa with a 40% incidence...1996). 30. Bosland, M. C., Ford, H. & Horton, L. Induction at high incidence of ductal prostate adenocarcinomas in NBL /Cr and Sprague-Dawley Hsd:SD

Hypothalamic histamine H1 receptor-AMPK signaling time-dependently mediates olanzapine-induced hyperphagia and weight gain in female rats.

PubMed

He, Meng; Zhang, Qingsheng; Deng, Chao; Wang, Hongqin; Lian, Jiamei; Huang, Xu-Feng

2014-04-01

Although second-generation antipsychotics induce severe weight gain and obesity, there is a lack of detailed knowledge about the progressive development of antipsychotic-induced obesity. This study examined the hypothalamic histamine H1 receptor and AMP-activated protein kinase (H1R-AMPK) signaling at three distinctive stages of olanzapine-induced weight gain (day 1-12: early acceleration, day 13-28: middle new equilibrium, and day 29-36: late heavy weight maintenance). At the early acceleration stage, the rats were hyperphagic with an underlying mechanism of olanzapine-increased H1R mRNA expression and AMPK phosphorylation (pAMPK), in which pAMPK levels positively correlated with H1R mRNA expression and food intake. At the middle stage, when the rats were no longer hyperphagic, the changes in H1R-AMPK signaling vanished. At the late stage, olanzapine increased H1R mRNA expression but decreased pAMPK which were positively and negatively correlated with weight gain, respectively. These data suggest a time-dependent change of H1R-AMPK signaling, where olanzapine activates AMPK by blocking the H1Rs and causing hyperphagia in the acute phase. The chronic blockade of H1R may contribute to the late stage of olanzapine-induced heavy weight maintenance. However, pAMPK was no longer elevated and actually decreased. This indicates that AMPK acts as an energy sensor and negatively responds to the positive energy balance induced by olanzapine. Furthermore, we showed that an H1R agonist, 2-(3-trifluoromethylphenyl) histamine, can significantly inhibit olanzapine-induced hyperphagia and AMPK activation in the mediobasal hypothalamus in a dose dependent manner. Therefore, lowering H1R-AMPK signaling is an effective treatment for the olanzapine-induced hyperphagia associated with the development of obesity. Copyright © 2014 Elsevier Ltd. All rights reserved.

RLIP76-dependent suppression of PI3K/AKT/Bcl-2 pathway by miR-101 induces apoptosis in prostate cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Jing; Song, Qi; Cai, Yi

MicroRNA-101 (miR-101) participates in carcinogenesis and tumor progression in various cancers. However, its biological functions in prostate cancer are still unclear. Here, we demonstrate that miR-101 represents a critical role in regulating cell apoptosis in prostate cancer cells. We first demonstrated that miR-101 treatment promoted apoptosis in DU145 and PC3 cells by using flow cytometric analysis and transmission electron microscopy (TEM). To verify the mechanisms, we identified a novel miR-101 target, Ral binding protein 1 (RLIP76). We found miR-101 transfection significantly suppresses RLIP76 expression, which can transactivate phosphorylation of PI3K-Akt signaling, and resulted in an amplification of Bcl2-induced apoptosis. Furthermore,more » we demonstrated that RLIP76 overexpression could reverse the anti-tumor effects of miR-101 in DU145 and PC3 cells by using flow cytometry assay and MTT assay. Taken together, our results revealed that the effect of miR-101 on prostate cancer cell apoptosis was due to RLIP76 regulation of the PI3K/Akt/Bcl-2 signaling pathway. - Highlights: • miR-101 inhibited prostate cancer cell proliferation and enhanced apoptosis. • miR-101 directly targeted and regulated RLIP76 expression. • miR-101 suppressed PI3K/Akt/Bcl-2 signaling pathway by targeting RLIP76.« less

Computer-Assisted Quantitative Assessment of Prostatic Calcifications in Patients with Chronic Prostatitis.

PubMed

Boltri, Matteo; Magri, Vittorio; Montanari, Emanuele; Perletti, Gianpaolo; Trinchieri, Alberto

2018-04-26

The aim of this study was the development of quantitative assessment of prostatic calcifications at prostatic ultrasound examination by the use of an image analyzer. A group of 82 patients was evaluated by medical history, physical, and transrectal ultrasound examination. Patients had a urethral swab, a 4-specimen study and culture of the seminal fluid. Patients were classified according to National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health. Subjective symptoms were scored by Chronic Prostatitis Symptom Index (CPSI) questionnaire. Ultrasound images were analyzed by the digital processing software Image J to quantitatively assess the presence of calcifications. Computer-assessed calcified areas were significantly higher in chronic bacterial prostatitis (n = 18; group II; 6.76 ± 8.09%) than in the chronic pelvic pain syndrome group IIIa (n = 26; 2.07 ± 1.01%) and IIIb (n = 38; 2.31 ± 2.18%). The area of calcification of the prostate was significantly related to the CPSI score for domains of micturition (r = 0.278, p = 0.023), Prostatic Specific Antigen values (r = 0341, p = 0.005), postvoiding residual urine (r = 0.262, p = 0.032), total prostate volume (r = 0.592, p = 0.000), and adenoma volume (r = 0.593; p = 0.000). The presence of calcifications is more frequently observed in patients with chronic bacterial prostatitis and is related to urinary symptoms. © 2018 S. Karger AG, Basel.

Changes in proteomic profiles in different prostate lobes of male rats throughout growth and development and aging stages of the life span

PubMed Central

Das, Arunangshu; Bortner, James D.; Aliaga, Cesar A.; Baker, Aaron; Stanley, Anne; Stanley, Bruce A.; Kaag, Mathew; Richie, John P.; El-Bayoumy, Karam

2012-01-01

Background Aging-related changes in important cellular pathways in the prostate may promote a permissive environment for an increased risk for prostatic disease development such as prostate cancer. Our objectives were to examine for such changes, by systematically determining the effects of growth and development and aging on proteomic profiles in different lobes of the rat prostate. Methods Prostate lobes (dorsolateral lobe, DL and ventral lobe, VL) were obtained from male Fisher rats of various ages representing young (4 months), mature (12 months), old (18 months), and very old (24 months). Differentially expressed proteins between age groups in each lobe were identified using a proteomic approach, isobaric Tags for Relative and Absolute Quantitation (iTRAQ). Select changes in the DL and VL were verified by immunoblot analysis. Results iTRAQ identified 317 proteins with high confidence. iTRAQ discovered 12 and 6 proteins significantly modulated in response to growth and development in the DL and VL, respectively, and 42 and 29 proteins significantly modulated in response to aging in the DL and VL, respectively. Proteins modulated during growth and development in the DL and VL are involved in a variety of biological processes including cell communication and development, whereas proteins modulated during aging were predominantly related to antioxidant activity and immunity. Immunoblot analysis verified age-related changes for α-1 antitrypsin, annexin A1, hypoxia up-regulated protein 1, and 78 kDa glucose-regulated protein. Conclusions Aging results in changes in numerous prostatic proteins and pathways which are mainly linked to inflammation and may lead to prostatic disease development. PMID:22911278

Changes in proteomic profiles in different prostate lobes of male rats throughout growth and development and aging stages of the life span.

PubMed

Das, Arunangshu; Bortner, James D; Aliaga, Cesar A; Baker, Aaron; Stanley, Anne; Stanley, Bruce A; Kaag, Matthew; Richie, John P; El-Bayoumy, Karam

2013-03-01

Aging-related changes in important cellular pathways in the prostate may promote a permissive environment for an increased risk for prostatic disease development such as prostate cancer. Our objectives were to examine for such changes, by systematically determining the effects of growth and development and aging on proteomic profiles in different lobes of the rat prostate. Prostate lobes (dorsolateral lobe, DL and ventral lobe, VL) were obtained from male Fisher rats of various ages representing young (4 months), mature (12 months), old (18 months), and very old (24 months). Differentially expressed proteins between age groups in each lobe were identified using a proteomic approach, isobaric Tags for Relative and Absolute Quantitation (iTRAQ). Select changes in the DL and VL were verified by immunoblot analysis. iTRAQ identified 317 proteins with high confidence. iTRAQ discovered 12 and 6 proteins significantly modulated in response to growth and development in the DL and VL, respectively, and 42 and 29 proteins significantly modulated in response to aging in the DL and VL, respectively. Proteins modulated during growth and development in the DL and VL are involved in a variety of biological processes including cell communication and development, whereas proteins modulated during aging were predominantly related to antioxidant activity and immunity. Immunoblot analysis verified age-related changes for α-1 antitrypsin, annexin A1, hypoxia up-regulated protein 1, and 78 kDa glucose-regulated protein. Aging results in changes in numerous prostatic proteins and pathways which are mainly linked to inflammation and may lead to prostatic disease development. Copyright © 2012 Wiley Periodicals, Inc.

p53 adenoviral vector (Ad-CMV-p53) induced prostatic growth inhibition of primary cultures of human prostate and an experimental rat model.

PubMed

Shirakawa, T; Gotoh, A; Gardner, T A; Kao, C; Zhang, Z J; Matsubara, S; Wada, Y; Hinata, N; Fujisawa, M; Hanioka, K; Matsuo, M; Kamidono, S

2000-01-01

Benign prostatic hyperplasia (BPH) is the most common proliferative disease affecting men. Numerous minimally invasive technologies are being developed or are currently in use to obviate the need for transurethral surgery. The goal of the present study was to develop a novel molecular based approach for the treatment of BPH using recombinant p53 adenoviral vector. The over-expression of wt-p53 can cause cell apoptosis or cell growth arrest, thus preventing the uncontrolled cell proliferation underlying BPH pathophysiology. Ad-CMV-p53, a replication-deficient recombinant adenovirus containing cytomegalovirus promoter driving p53 gene, was used. Human prostate stromal (PS) cells were evaluated for apoptosis (TUNEL assay), mRNA levels of key cell cycle regulators influencing apoptosis (p-53, Bax and Bcl-2) using quantitative RT-PCR and cytotoxicity after Ad-CMV-p53. Ad-CMV-p53 was unilaterally injected into rat ventral prostates and growth inhibition was measured by prostate weight 3 weeks after injection. In vitro exposure to Ad-CMV-p53 significantly inhibited the proliferation of PS cells, induced mRNA over-expression of both wt-p53 and Bax, and increased the proportion of apoptotic cells. A 30% decrease in average prostate weight was demonstrated in rodents after Ad-CMV-p53 injection. The results suggest that further investigation of molecular gene therapy with recombinant wt-p53 adenovirus for the treatment of BPH is warranted.

Bioinformatics analysis for evaluation of the diagnostic potentialities of miR-19b, -125b and -205 as liquid biopsy markers of prostate cancer

NASA Astrophysics Data System (ADS)

Bryzgunova, O. E.; Lekchnov, E. A.; Zaripov, M. M.; Yurchenko, Yu. B.; Yarmoschuk, S. V.; Pashkovskaya, O. A.; Rykova, E. Yu.; Zheravin, A. A.; Laktionov, P. P.

2017-09-01

Presence of tumor-derived cell-free miRNA in biological fluids as well as simplicity and robustness of cell-free miRNA quantification makes them suitable markers for cancer diagnostics. Based on previously published data demonstrating diagnostic potentialities of miR-205 in blood and miR-19b as well as miR-125b in urine of prostate cancer patients, bioinformatics analysis was carried out to follow their involvement in prostate cancer development and select additional miRNA-markers for prostate cancer diagnostics. Studied miRNAs are involved in different signaling pathways and regulate a number of genes involved in cancer development. Five of their targets (CCND1, BRAF, CCNE1, CCNE2, RAF1), according to the STRING database, act as part of the same signaling pathway. RAF1 is regulated by miR-19b and miR-125b, and it was shown to be involved in prostate cancer development by DIANA and STRING databases. Thus, other microRNAs regulating RAF1 expression such as miR-16, -195, -497, and -7 (suggested by DIANA, TargetScan, MiRTarBase and miRDB databases) can potentially be regarded as prostate cancer markers.

Intake of water with high levels of dissolved hydrogen (H2) suppresses ischemia-induced cardio-renal injury in Dahl salt-sensitive rats.

PubMed

Zhu, Wan-Jun; Nakayama, Masaaki; Mori, Takefumi; Nakayama, Keisuke; Katoh, Junichiro; Murata, Yaeko; Sato, Toshinobu; Kabayama, Shigeru; Ito, Sadayoshi

2011-07-01

Hydrogen (H(2)) reportedly produces an antioxidative effect by quenching cytotoxic oxygen radicals. We studied the biological effects of water with dissolved H(2) on ischemia-induced cardio-renal injury in a rat model of chronic kidney disease (CKD). Dahl salt-sensitive rats (7 weeks old) were allowed ad libitum drinking of filtered water (FW: dissolved H(2), 0.00 ± 0.00 mg/L) or water with dissolved H(2) produced by electrolysis (EW: dissolved H(2), 0.35 ± 0.03 mg/L) for up to 6 weeks on a 0.5% salt diet. The rats then underwent ischemic reperfusion (I/R) of one kidney and were killed a week later for investigation of the contralateral kidney and the heart. In the rats given FW, unilateral kidney I/R induced significant increases in plasma monocyte chemoattractant protein-1, methylglyoxal and blood urea nitrogen. Histologically, significant increases were found in glomerular adhesion, cardiac fibrosis, number of ED-1 (CD68)-positive cells and nitrotyrosine staining in the contralateral kidney and the heart. In rats given EW, those findings were significantly ameliorated and there were significant histological differences between rats given FW and those given EW. Consumption of EW by ad libitum drinking has the potential to ameliorate ischemia-induced cardio-renal injury in CKD model rats. This indicates a novel strategy of applying H(2) produced by water electrolysis technology for the prevention of CKD cardio-renal syndrome.

Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer.

PubMed

Goto, Yusuke; Kurozumi, Akira; Arai, Takayuki; Nohata, Nijiro; Kojima, Satoko; Okato, Atsushi; Kato, Mayuko; Yamazaki, Kazuto; Ishida, Yasuo; Naya, Yukio; Ichikawa, Tomohiko; Seki, Naohiko

2017-07-25

Despite recent advancements, metastatic castration-resistant prostate cancer (CRPC) is not considered curative. Novel approaches for identification of therapeutic targets of CRPC are needed. Next-generation sequencing revealed 945-1248 miRNAs from each lethal mCRPC sample. We constructed miRNA expression signatures of CRPC by comparing the expression of miRNAs between CRPC and normal prostate tissue or hormone-sensitive prostate cancer (HSPC). Genome-wide gene expression studies and in silico analyses were carried out to predict miRNA regulation and investigate the functional significance and clinical utility of the novel oncogenic pathways regulated by these miRNAs in prostate cancer (PCa). Based on the novel miRNA expression signature of CRPC, miR-145-5p and miR-145-3p were downregulated in CRPC. By focusing on miR-145-3p, which is a passenger strand and has not been well studied in previous reports, we showed that miR-145-3p targeted 4 key molecules, i.e., MELK, NCAPG, BUB1, and CDK1, in CPRC. These 4 genes significantly predicted survival in patients with PCa. Small RNA sequencing for lethal CRPC and in silico analyses provided novel therapeutic targets for CRPC.

Integrating Molecular Imaging Approaches to Monitor Prostate Targeted Suicide and Anti-angiogenic Gene Therapy

DTIC Science & Technology

2005-02-01

tissue-specific expression of prostate-specific antigen. Cancer Res. 57: 495–499. 11. Schuur, E. R ., Henderson, G . A., Kmetec, L. A., Miller, J. D...Lamparski, H. G ., and Henderson, D. R . (1996). Prostate-specific antigen expression is regulated by an up- stream enhancer. J. Biol. Chem. 271: 7043...5: 223–232. 29. Blasberg, R . G ., and Tjuvajev, J. G . (1999). Herpes simplex virus thymidine kinase as a marker/reporter gene for PET imaging of gene

Targeted BikDD expression kills androgen-dependent and castration-resistant prostate cancer cells

PubMed Central

Xie, Xiaoming; Kong, Yanan; Tang, Hailin; Yang, Lu; Hsu, Jennifer L; Hung, Mien-Chie

2014-01-01

Targeted gene therapy is a promising approach for treating prostate cancer after the discovery of prostate cancer-specific promoters such as prostate-specific antigen, rat probasin, and human glandular kallikrein. However, these promoters are androgen-dependent, and after castration or androgen ablation therapy, they become much less active or sometimes inactive. Importantly, the disease will inevitably progress from androgen-dependent (ADPC) to castration-resistant prostate cancer (CRPC) at which treatments fail and high mortality ensues. Therefore, it is critical to develop a targeted gene therapy strategy that is effective in both ADPC and CRPC to eradicate recurrent prostate tumors. The human telomerase reverse transcriptase-VP16-Gal4-WPRE integrated systemic amplifier composite (T-VISA) vector we previously developed which targets transgene expression in ovarian and breast cancer is also active in prostate cancer. To further improve its effectiveness based on androgen response in ADPC progression, the ARR2 element (two copies of androgen response region from rat probasin promoter) was incorporated into T-VISA to produce AT-VISA. Under androgen analog (R1881) stimulation, the activity of AT-VISA was increased to a level greater than or comparable to the cytomegalovirus (CMV) promoter in ADPC and CRPC cells, respectively. Importantly, AT-VISA demonstrated little or no expression in normal cells. Systemic administration of AT-VISA-BikDD encapsulated in liposomes repressed prostate tumor growth and prolonged mouse survival in orthotopic animal models as well as in the transgenic adenocarcinoma mouse prostate model, indicating that AT-VISA-BikDD has therapeutic potential to treat ADPC and CRPC safely and effectively in preclinical setting. PMID:24785255

Resveratrol improves urinary dysfunction in rats with chronic prostatitis and suppresses the activity of the stem cell factor/c-Kit signaling pathway.

PubMed

Yu, Yang; Jiang, Jiang; He, Yi; Wang, Wei; Shen, Chen; Yang, Bo

2017-08-01

Chronic prostatitis (CP) is a common urological disorder, with bladder voiding dysfunction being the primary clinical manifestation. Resveratrol is polyphenolic compound isolated from numerous plants, with widely‑reported anti-inflammatory properties. The present study aimed to investigate whether resveratrol may improve overactive bladder in rats with CP and to investigate the underlying molecular mechanisms. Furthermore, the potential pharmacological synergy between resveratrol and solifenacin was also investigated as a potential treatment for CP. Following the successful establishment of a rat model of CP by subcutaneously injecting DPT vaccine, rats were treated with resveratrol or a combination of resveratrol + solifenacin. Bladder pressure and volume tests were performed to investigate the effect of resveratrol and solifenacin on urinary dysfunction in rats with chronic prostatitis. Western blot analysis and immunohistochemical staining were used to examine the expression of c‑Kit receptor, stem cell factor (SCF), AKT and phosphorylated‑AKT (p‑AKT) in the bladder tissue. The results of the bladder pressure and volume test indicated that the maximum capacity of the bladder, residual urine volume and maximum voiding pressure in the control group were 0.57 ml, 0.17 ml and 29.62 cm H2O, respectively. These values were increased by 71, 27 and 206% in rats in the CP group compared with the control group. Following treatment with resveratrol, the results in the resveratrol group were reduced by 25.77, 44.23 and 13.32% compared with the CP group. The results of western blot analysis, immunohistochemical staining and immunofluorescence labeling demonstrate that the protein expression of SCF, c‑Kit and p‑AKT in the bladder of rats in the CP group was 4.32, 6.13 and 6.31 times higher compared with the control group, respectively. Following treatment with resveratrol, protein expression was significantly reduced. However, no significant differences

Evaluation of miR-216a and miR-217 as Potential Biomarkers of Acute Exocrine Pancreatic Toxicity in Rats.

PubMed

Wang, Jianying; Huang, Wenhu; Thibault, Stephane; Brown, Thomas P; Bobrowski, Walter; Gukasyan, Hovhannes J; Evering, Winston; Hu, Wenyue; John-Baptiste, Annette; Vitsky, Allison

2017-02-01

Detecting and monitoring exocrine pancreatic damage during nonclinical and clinical testing is challenging because classical biomarkers amylase and lipase have limited sensitivity and specificity. Novel biomarkers for drug-induced pancreatic injury are needed to improve safety assessment and reduce late-stage attrition rates. In a series of studies, miR-216a and miR-217 were evaluated as potential biomarkers of acute exocrine pancreatic toxicity in rats. Our results revealed that miR-216a and miR-217 were almost exclusively expressed in rat pancreas and that circulating miR-216a and miR-217 were significantly increased in rats following administration of established exocrine pancreatic toxicants caerulein (CL) and 1-cyano-2-hydroxy-3-butene (CHB) as well as in rats administered a proprietary molecule known to primarily affect the exocrine pancreas. Conversely, neither microRNA was increased in rats administered a proprietary molecule known to cause a lesion at the pancreatic endocrine-exocrine interface (EEI) or in rats administered an established renal toxicant. Compared with amylase and lipase, increases in miR-216a and miR-217 were of greater magnitude, persisted longer, and/or correlated better with microscopic findings within the exocrine pancreas. Our findings demonstrate that in rats, miR-216a and miR-217 are sensitive and specific biomarkers of acute exocrine pancreatic toxicity that may add value to the measurement of classical pancreatic biomarkers.

Concepts of epigenetics in prostate cancer development.

PubMed

Cooper, C S; Foster, C S

2009-01-27

Substantial evidence now supports the view that epigenetic changes have a role in the development of human prostate cancer. Analyses of the patterns of epigenetic alteration are providing important insights into the origin of this disease and have identified specific alterations that may serve as useful diagnostic and prognostic biomarkers. Examination of cancer methylation patterns supports a stem cell origin of prostate cancer. It is well established that methylation of GSTpi is a marker of prostate cancer, and global patterns of histone marking appear to be linked to cancer prognosis with levels of acetylated histones H3K9, H3K18, and H4K12, and of dimethylated H4R3 and H3K4, dividing low-grade prostate cancer (Gleason 6 or less) into two prognostically separate groups. Elevated levels of several components of the polycomb group protein complex, EZH2, BMI1, and RING1, can also act as biomarkers of poor clinical outcome. Many components of the epigenetic machinery, including histone deacetylase (whose expression level is linked to the TMPRSS2:ERG translocation) and the histone methylase EZH2, are potential therapeutic targets. The recent discovery of the role of small RNAs in governing the epigenetic status of individual genes offers exciting new possibilities in therapeutics and chemoprevention.

Development and assessment of an evidence-based prostate cancer intervention programme for black men: the W.O.R.D. on prostate cancer video.

PubMed

Odedina, Folakemi; Oluwayemisi, Awoyemi O; Pressey, Shannon; Gaddy, Samuel; Egensteiner, Eva; Ojewale, Ezekiel O; Moline, Olivia Myra; Martin, Chloe Marie

2014-01-01

In spite of the numerous prostate cancer (CaP) intervention programmes that have been implemented to address the disparities experienced by black men, CaP prevention, risk reduction, and early detection behaviours remain low among black men. The lack of formal theoretical frameworks to guide the development and implementation of interventions has been recognised as one of the primary reasons for the failure of health interventions. Members of the Florida Prostate Cancer Health Disparity (CaPHD) group employed the Personal Model of Prostate Cancer Disparity (PIPCaD) model and the Health Communication Process Model to plan, implement, and evaluate an intervention programme, the 'Working through Outreach to Reduce Disparity (W.O.R.D. on Prostate Cancer)' video for black men. The location for the video was in a barbershop, a popular setting for the targeted group. The video starred CaP survivors, CaP advocates, a radio personality, and barbers. In addition, remarks were provided by a CaP scientist, a urologist, a CaP advocate, a former legislator, and a minister. The W.O.R.D. video was developed to assist black men in meeting the Healthy People 2020 goal for the United States of America. The efficacy of the W.O.R.D. video was successfully established among 143 black men in Florida. Exposure to the video was found to statistically increase CaP knowledge and intention to participate in CaP screening. Furthermore, exposure to the video statistically decreased participants' perception of the number of factors contributing to decision, uncertainty about CaP screening. Participants were highly satisfied with the video content and rated the quality of the video to be very good. Participants also rated the video as credible, informative, useful, relevant, understandable, not too time consuming, clear, and interesting.

Development and assessment of an evidence-based prostate cancer intervention programme for black men: the W.O.R.D. on prostate cancer video

PubMed Central

Odedina, Folakemi; Oluwayemisi, Awoyemi O; Pressey, Shannon; Gaddy, Samuel; Egensteiner, Eva; Ojewale, Ezekiel O; Moline, Olivia Myra; Martin, Chloe Marie

2014-01-01

In spite of the numerous prostate cancer (CaP) intervention programmes that have been implemented to address the disparities experienced by black men, CaP prevention, risk reduction, and early detection behaviours remain low among black men. The lack of formal theoretical frameworks to guide the development and implementation of interventions has been recognised as one of the primary reasons for the failure of health interventions. Members of the Florida Prostate Cancer Health Disparity (CaPHD) group employed the Personal Model of Prostate Cancer Disparity (PIPCaD) model and the Health Communication Process Model to plan, implement, and evaluate an intervention programme, the ‘Working through Outreach to Reduce Disparity (W.O.R.D. on Prostate Cancer)’ video for black men. The location for the video was in a barbershop, a popular setting for the targeted group. The video starred CaP survivors, CaP advocates, a radio personality, and barbers. In addition, remarks were provided by a CaP scientist, a urologist, a CaP advocate, a former legislator, and a minister. The W.O.R.D. video was developed to assist black men in meeting the Healthy People 2020 goal for the United States of America. The efficacy of the W.O.R.D. video was successfully established among 143 black men in Florida. Exposure to the video was found to statistically increase CaP knowledge and intention to participate in CaP screening. Furthermore, exposure to the video statistically decreased participants’ perception of the number of factors contributing to decision, uncertainty about CaP screening. Participants were highly satisfied with the video content and rated the quality of the video to be very good. Participants also rated the video as credible, informative, useful, relevant, understandable, not too time consuming, clear, and interesting. PMID:25228916

PEG-rHuMGDF ameliorates thrombocytopenia in carboplatin-treated rats without inducing myelofibrosis.

PubMed

Ide, Y; Harada, K; Imai, A; Yanagida, M

1999-08-01

We examined the effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) on carboplatin-induced thrombocytopenia in rats. The focus was on whether myelofibrosis is associated with the PEG-rHuMGDF treatment in this chemotherapy model. After a single injection of carboplatin, rats received subcutaneous PEG-rHuMGDF at pharmacologic doses (1,3, or 30 micrograms/kg) or a vehicle daily for 7 days. PEG-rHuMGDF at more than 3 micrograms/kg ameliorated the thrombocytopenia at day 10. Histologically, no myelofibrosis was detected in the rats treated with PEG-rHuMGDF or vehicle. Subsequently, PEG-rHuMGDF at a suprapharmacologic dose (100 micrograms/kg) was subcutaneously administered to normal and to carboplatin-treated rats daily for 7 days. Histological analysis revealed that the treatment with PEG-rHuMGDF induced myelofibrosis in the normal rats but not in the carboplatin-treated rats. Additionally, the transforming growth factor-beta 1 (TGF-beta 1) levels in the extracellular fluid and the whole extract of the bone marrow were increased to a much lesser degree in the carboplatin-treated rats compared to the normal rats. These findings suggest that PEG-rHuMGDF is effective for carboplatin-induced thrombocytopenia. Proper control of platelet counts and TGF-beta 1 levels is essential so that myelofibrosis is not induced in clinical use.

Protective Role of Acidic pH-Activated Chloride Channel in Severe Acidosis-Induced Contraction from the Aorta of Spontaneously Hypertensive Rats

PubMed Central

Ma, Zhiyong; Qi, Jia; Fu, Zhijie; Ling, Mingying; Li, Li; Zhang, Yun

2013-01-01

Severe acidic pH-activated chloride channel (ICl,acid) has been found in various mammalian cells. In the present study, we investigate whether this channel participates in reactions of the thoracic aorta to severe acidosis and whether it plays a role in hypertension. We measured isometric contraction in thoracic aorta rings from spontaneously hypertensive rats (SHRs) and normotensive Wistar rats. Severe acidosis induced contractions of both endothelium-intact and -denuded thoracic aorta rings. In Wistar rats, contractions did not differ at pH 6.4, 5.4 and 4.4. However, in SHRs, contractions were higher at pH 5.4 or 4.4 than pH 6.4, with no difference between contractions at pH 5.4 and 4.4. Nifedipine, ICl,acid blockers 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and 4,4′-diisothiocyanatostilbene-2, 2′-disulfonic acid (DIDS) inhibited severe acidosis-induced contraction of aortas at different pH levels. When blocking ICl,acid, the remnant contraction was greater at pH 4.4 than pH 5.4 and 6.4 for both SHRs and Wistar rats. With nifedipine, the remnant contraction was greatly reduced at pH 4.4 as compared with at pH 6.4 and 5.4. With NPPB or DIDS, the ratio of remnant contractions at pH 4.4 and 5.4 (R4.4/5.4) was lower for SHRs than Wistar rats (all <1). However, with nifedipine, the R4.4/5.4 was higher for SHRs than Wistar rats (both >1). Furthermore, patch clamp recordings of ICl,acid and intracellular Ca2+ measurements in smooth muscle cells confirmed these findings. ICl,acid may protect arteries against excess vasoconstriction under extremely acidic extracellular conditions. This protective effect may be decreased in hypertension. PMID:23580361

Are blood group isoantigens lost from malignant prostatic epithelium? Immunohistochemical support for the preservation of the H isoantigen.

PubMed Central

Vowden, P.; Lowe, A. D.; Lennox, E. S.; Bleehen, N. M.

1986-01-01

Previous studies while demonstrating the presence of blood group isoantigens on normal prostatic epithelium have failed to identify such antigens on malignant prostatic tissue. Using a series of blood group specific monoclonal antibodies directed towards the A, B, H and Y antigens we have reinvestigated blood group isoantigen expression in both benign prostatic hypertrophy and prostatic adenocarcinoma. Results obtained from areas of benign prostatic hypertrophy are in broad agreement with those published however though we were unable to detect either A or B blood group isoantigens Type 2H and Y isoantigens were identified in 10 of the 12 tumours. These findings, while differing from previously reported results, lend support to the suggested connection between ontogenesis, oncogenesis and blood group isoantigen expression and also support the proposed link between Type 2 structures and malignant transformation. Images Figure 1 Figure 2 PMID:2421753

Rubin H. Flocks and colloidal gold treatments for prostate cancer.

PubMed

Rosevear, Henry M; Lightfoot, Andrew J; O'Donnell, Michael A; Platz, Charles E; Loening, Stefan A; Hawtrey, Charles E

2011-01-01

In the early 1950s, Rubin H. Flocks of the University of Iowa began to treat prostate cancer patients with colloidal gold (Au(198)) therapy, evolving his technique over nearly 25 years in 1515 patients. We reviewed the long-term outcomes of Flocks' prostate cancer patients as compared to those patients treated by other methods at the University of Iowa before Flocks' chairmanship. We reviewed archived patient records, Flocks' published data, and long-term survival data from the Iowa Tumor Registry to determine short- and long-term outcomes of Flocks' work with colloidal gold. We also reviewed the literature of Flocks' time to compare his outcomes against those of his contemporaries. The use of colloidal gold, either as primary or adjunctive therapy, provided short- and long-term survival benefit for the majority of Flocks' patients as compared to historical treatment options (p < 0.001). Flocks' use of colloidal gold for the treatment of locally advanced prostate cancer offered short- and long-term survival benefits compared to other contemporary treatments.

Gene expression analysis in the ventral prostate of rats exposed to vinclozolin or procymidone.

PubMed

Rosen, Mitchell B; Wilson, Vickie S; Schmid, Judith E; Gray, L Earl

2005-01-01

Vinclozolin and procymidone are antiandrogens that are thought to share a common androgen receptor (AR) mediated mechanism of action. This assessment is based primarily on morphological, AR binding, and in vitro transcriptional activation studies. Studies designed to evaluate the gene expression profiles induced by these compounds have the potential to provide further information to test this hypothesis. We have used targeted gene arrays to examine gene expression in the ventral prostate (VP) of 100-day old Sprague Dawley male rats exposed to either vinclozolin or procymidone. Animals were castrated and administered silastic implants with or without testosterone. A subset of testosterone treated animals was then dosed with 200 mg/kg of either fungicide in corn oil. Four treatment groups were used: castrated (C), testosterone (T), testosterone+vinclozolin (V), and testosterone+procymidone (P). Tissue from the VP was collected from six animals per group (3 animals per block x 2 blocks) at 20 h and at 4 days after the start of treatment. Total RNA was then isolated and gene expression analyzed using Clontech Atlas Rat 1.2 Toxicology arrays. When compared to group T, similar changes in gene expression were observed in groups C, P and V at both the 20 h and 4 day time points. After 20 h of treatment, 20 genes were similarly affected across these three treatment groups. Down-regulated genes included various molecular chaperones, the 11-kDa diazepam binding inhibitor, cyclin D1, and mitochondrial aspartate aminotransferase. Genes such as the androgen receptor, PTEN, and ERK2 were up-regulated. Three of the down-regulated genes, GRP78 (BiP), Dad1, and mitochondrial aspartate aminotransferase have been previously shown to be directly androgen regulated. Fifty-four genes were affected at 20 h, whereas, 311 genes were altered 4 days after the start of treatment. These observations, in part, may reflect regression of the VP at the later time point. These results support the

Vatuximab(Trademark): Optimizing Therapeutic Strategies for Prostate Cancer Based on Dynamic MR Tumor Oximetry

DTIC Science & Technology

2007-01-01

diverse subcutaneous models will be translated to human tumor xenografts in intraosseous models of advanced metastatic prostate cancer (18). Here, PSA...representative MAT-LU, HI and H tumors growing on anesthetized rats breathing air with isoflurane anesthesia . Voxel dimension 1.25 mm in plane with 10

Effects of different natural extracts in an experimental model of benign prostatic hyperplasia (BPH).

PubMed

Paterniti, Irene; Campolo, Michela; Cordaro, Marika; Siracusa, Rosalba; Filippone, Antonio; Esposito, Emanuela; Cuzzocrea, Salvatore

2018-04-20

To characterize the impact of inflammatory process and oxidative stress in the degree of benign prostatic hyperplasia (BPH), a common condition in which chronic inflammation plays a crucial role, we investigated the effect of different plant extract preparations in an in vivo model of BPH as new therapeutic target. BPH was made in rats with daily administration of testosterone propionate (3 mg/kg) for 14 days. Rats were randomized into different groups to receive oral administration of plant extract preparations: Serenoa repens with selenium (SeR 28.5 mg/kg associated with Se 0.005 mg/kg), Teoside (2 mg/kg), and Puryprost (14 mg/kg containing Teoside 50% 2 mg/kg and Epilobium 12 mg/kg). After 14 days, rats were killed and histological changes, prostate weight and apoptotic pathways were assayed. The results obtained demonstrated that the association of treatments reduced prostate weight and hyperplasia, while treatment with Puryprost demonstrated a greater trend of protection compared to the other treatments. Thus, our results indicate that plant extract could be considered as new useful therapy in the treatment of BPH with particular attention on Puryprost that represents a rational approach to reduce BPH through modulation of inflammatory process and anti-oxidant process.

Exposure to leachate from municipal battery recycling site: implication as key inhibitor of steroidogenic enzymes and risk factor of prostate damage in rats.

PubMed

Akintunde, Jacob K; Oboh, G

2013-01-01

Few or no studies have measured the effect of short- and long-term exposure to industrial leachate. Mature male Wistar strain albino rats (175-220 g) underwent sub-chronic exposure to leachate from the Elewi Odo municipal battery recycling site (EOMABRL) via oral administration for a period of 60 days at different doses (20%, 40%, 60%, 80%, and 100%) per kilogram of body weight to evaluate the toxic effects of the leachate on male reproductive function using steroidogenic enzymes and biomarkers of prostate damage. Control groups were treated equally but were given distilled water instead of the leachate. After the treatment periods, results showed that the treatment induced systemic toxicity at the doses tested by causing a significant (p<0.05) loss in absolute body weight and decline in growth rate. There was a marked significant decrease (p<0.05) in testicular activities of Δ(5)-3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase. Conversely, the activity of prostatic acid phosphatase, a key marker enzyme for prostrate damage was significantly (p<0.05) elevated in the treated rats. Similarly, the administration of EOMABRL significantly (p<0.05) exacerbated the activity of total acid phosphatase with concomitant increase in the activity of prostatic alkaline phosphatase. These findings conclude that exposure to leachate from a battery recycling site induces sub-chronic testicular toxicity by inhibiting key steroidogenic enzymes and activating key markers linked with prostate damage/cancer in rats.

Lack of Humoral Immune Response to the Tetracycline (Tet) Activator in Rats Injected Intracranially with Tet-off rAAV Vectors

PubMed Central

Han, Ye; Chang, Qin A.; Virag, Tamas; West, Neva C.; George, David; Castro, Maria G.; Bohn, Martha C.

2010-01-01

The ability to safely control transgene expression from viral vectors is a long-term goal in the gene therapy field. We have previously reported tight regulation of GFP expression in rat brain using a self-regulating tet-off rAAV vector. The immune responses against tet regulatory elements observed by other groups in nonhuman primates after intramuscular injection of tet-on encoding vectors raise concerns about the clinical value of tet-regulated vectors. However, previous studies have not examined immune responses following injection of AAV vectors into brain. Therefore, rat striatum was injected with tet-off rAAV harboring a therapeutic gene for Parkinson's disease, either hAADC or hGDNF. The expression of each gene was tightly controlled by the tet-off regulatory system. Using an ELISA developed with purified GST-tTA protein, no detectable immunogenicity against tTA was observed in sera of rats that received an intrastriatal injection of either vector. In contrast, sera from rats intradermally injected with an adenovirus containing either tTA or rtTA, as positive controls, had readily detectable antibodies. These observations suggest that tet-off rAAV vectors do not elicit an immune response when injected into rat brain and that these may offer safer vectors for Parkinson's disease than vectors with constitutive expression. PMID:20164859

Inhibitory effect of rape pollen supercritical CO2 fluid extract against testosterone-induced benign prostatic hyperplasia in rats

PubMed Central

YANG, BI-CHENG; JIN, LI-LI; YANG, YI-FANG; LI, KUN; PENG, DAN-MING

2014-01-01

Benign prostatic hyperplasia (BPH) can lead to lower urinary tract symptoms. Rape pollen is an apicultural product that is composed of nutritionally valuable and biologically active substances. The aim of the present study was to investigate the protective effect of rape pollen supercritical CO2 fluid extract (SFE-CO2) in BPH development using a testosterone-induced BPH rat model. BPH was induced in the experimental groups by daily subcutaneous injections of testosterone for a period of 30 days. Rape pollen SFE-CO2 was administered daily by oral gavage concurrently with the testosterone injections. Animals were sacrificed at the scheduled termination and the prostates were weighed and subjected to histopathological examination. Testosterone, dihydrotestosterone (DHT), 5α-reductase and cyclooxygenase-2 (COX-2) levels were also measured. BPH-induced animals exhibited an increase in prostate weight with increased testosterone, DHT, 5α-reductase and COX-2 expression levels. However, rape pollen SFE-CO2 treatment resulted in significant reductions in the prostate index and testosterone, DHT, 5α-reductase and COX-2 levels compared with those in BPH-induced animals. Histopathological examination also demonstrated that rape pollen SFE-CO2 treatment suppressed testosterone-induced BPH. These observations indicate that rape pollen SFE-CO2 inhibits the development of BPH in rats and these effects are closely associated with reductions in DHT, 5α-reductase and COX-2 levels. Therefore, the results of the present study clearly indicate that rape pollen SFE-CO2 extract may be a useful agent in BPH treatment. PMID:24944593

Inhibitory effect of rape pollen supercritical CO2 fluid extract against testosterone-induced benign prostatic hyperplasia in rats.

PubMed

Yang, Bi-Cheng; Jin, Li-Li; Yang, Yi-Fang; Li, Kun; Peng, Dan-Ming

2014-07-01

Benign prostatic hyperplasia (BPH) can lead to lower urinary tract symptoms. Rape pollen is an apicultural product that is composed of nutritionally valuable and biologically active substances. The aim of the present study was to investigate the protective effect of rape pollen supercritical CO 2 fluid extract (SFE-CO 2 ) in BPH development using a testosterone-induced BPH rat model. BPH was induced in the experimental groups by daily subcutaneous injections of testosterone for a period of 30 days. Rape pollen SFE-CO 2 was administered daily by oral gavage concurrently with the testosterone injections. Animals were sacrificed at the scheduled termination and the prostates were weighed and subjected to histopathological examination. Testosterone, dihydrotestosterone (DHT), 5α-reductase and cyclooxygenase-2 (COX-2) levels were also measured. BPH-induced animals exhibited an increase in prostate weight with increased testosterone, DHT, 5α-reductase and COX-2 expression levels. However, rape pollen SFE-CO 2 treatment resulted in significant reductions in the prostate index and testosterone, DHT, 5α-reductase and COX-2 levels compared with those in BPH-induced animals. Histopathological examination also demonstrated that rape pollen SFE-CO 2 treatment suppressed testosterone-induced BPH. These observations indicate that rape pollen SFE-CO 2 inhibits the development of BPH in rats and these effects are closely associated with reductions in DHT, 5α-reductase and COX-2 levels. Therefore, the results of the present study clearly indicate that rape pollen SFE-CO 2 extract may be a useful agent in BPH treatment.

Dysregulation of miR-31 and miR-21 induced by zinc deficiency promotes esophageal cancer

PubMed Central

Croce, Carlo M; Fong, Louise Y.Y

2012-01-01

Zinc deficiency (ZD) increases the risk of esophageal squamous cell carcinoma (ESCC). In a rat model, chronic ZD induces an inflammatory gene signature that fuels ESCC development. microRNAs regulate gene expression and are aberrantly expressed in cancers. Here we investigated whether chronic ZD (23 weeks) also induces a protumorigenic microRNA signature. Using the nanoString technology, we evaluated microRNA profiles in ZD esophagus and six additional tissues (skin, lung, pancreas, liver, prostate and peripheral blood mononuclear cells [PBMC]). ZD caused overexpression of inflammation genes and altered microRNA expression across all tissues analyzed, predictive of disease development. Importantly, the inflammatory ZD esophagus had a distinct microRNA signature resembling human ESCC or tongue SCC miRNAomes with miR-31 and miR-21 as the top-up-regulated species. Circulating miR-31 was also the top-up-regulated species in PBMCs. In ZD esophagus and tongue, oncogenic miR-31 and miR-21 overexpression was accompanied by down-regulation of their respective tumor-suppressor targets PPP2R2A and PDCD4. Importantly, esophageal miR-31 and miR-21 levels were directly associated with the appearance of ESCC in ZD rats, as compared with their cancer-free Zn-sufficient or Zn-replenished counterparts. In situ hybridization analysis in rat and human tongue SCCs localized miR-31 to tumor cells and miR-21 to stromal cells. In regressing tongue SCCs from Zn-supplemented rats, miR-31 and miR-21 expression was concomitantly reduced, establishing their responsiveness to Zn therapy. A search for putative microRNA targets revealed a bias toward genes in inflammatory pathways. Our finding that ZD causes miR-31 and miR-21 dysregulation associated with inflammation provides insight into mechanisms whereby ZD promotes ESCC. PMID:22689922

Glial cells have heart: rH1 Na+ channel mRNA and protein in spinal cord astrocytes.

PubMed

Black, J A; Dib-Hajj, S; Cohen, S; Hinson, A W; Waxman, S G

1998-07-01

Astrocytes in vitro express several distinct voltage-sensitive sodium currents, including tetrodotoxin (TTX)-resistant in non-stellate astrocytes and TTX-sensitive currents in stellate astrocytes. However, the molecular identity of the underlying channels, and the mechanisms that regulate their expression, have yet to be identified. Since spinal cord astrocytes in vitro express sodium currents that are nearly ten-fold greater that those of astrocytes derived from other regions, we used reverse transcription polymerase chain reaction (RT-PCR), in situ hybridization, and immunocytochemistry to search for a sodium channel mRNA and protein corresponding to a TTX-resistant channel in these cells. RT-PCR did not detect transcripts for SNS, which is known to encode a TTX-resistant current in dorsal root ganglion neurons. However, RT-PCR demonstrated the presence of rH1 mRNA in cultured spinal cord astrocytes derived from postnatal day 0 (P0) Sprague Dawley rats at 7 days in vitro and in also intact spinal cords of P0 and P7 rats. Hybridization signal for rH1 mRNA was detected by in situ hybridization cytochemistry in most non-stellate and, at varying levels, in stellate astrocytes in these cultures. Immunocytochemical studies, utilizing a polyclonal antibody (R-12) generated against a conserved polypeptide sequence of sodium channels, demonstrated sodium channel immunoreactivity in non-stellate and stellate astrocytes in these cultures. Spinal cord cultures reacted with a rH1-specific polyclonal antibody also showed rH1 immunostaining in non-stellate and stellate astrocytes, although the intensity of the rH1 immunoreactivity in both astrocyte morphologies was attenuated compared to that observed with the R-12 generic sodium channel antibody. The presence of rH1 mRNA and protein in non-stellate astrocytes in vitro provides a possible correlate for the TTX-resistant current that has been recorded in these cells. Since TTX-resistant current is not present in stellate

Profile of cell proliferation and apoptosis activated by the intrinsic and extrinsic pathways in the prostate of aging rats.

PubMed

Gonzaga, Amanda C R; Campolina-Silva, Gabriel H; Werneck-Gomes, Hipácia; Moura-Cordeiro, Júnia D; Santos, Letícia C; Mahecha, Germán A B; Morais-Santos, Mônica; Oliveira, Cleida A

2017-06-01

Estrogens acting through the receptors ERα and ERβ participate in prostate normal growth and cancer. ERβ is highly expressed in the prostate epithelium, playing pro-apoptotic, anti-proliferative, and pro-differentiation roles. Apoptosis is activated by the intrinsic pathway after castration and by the extrinsic pathway after ERβ agonist treatment. This differential activation of apoptotic pathways is important since a major problem in the treatment of prostate cancer is the recurrence of tumors after androgen withdrawal. However, a comprehensive study about the pattern of apoptosis in the aging prostate is lacking, a knowledge gap that we aimed to address herein. Cellular age-related proliferative and apoptotic profiles of prostate tissue obtained from aging Wistar rats were evaluated. Cell death (caspase-3, -8, -9, TNFα) was assessed by immunohistochemistry, immunofluorescence, and TUNEL. Cell proliferation (MCM7) and cell survival factors (ERK1/2, p-ERK1/2, p-Akt, and NF-κB) were determined by immunohistochemistry. As the rats aged, the number of proliferating cells gradually reduced in the normal epithelium of all prostate lobes, while increasing in focal areas of intraepithelial proliferation. Interestingly, in areas of intraepithelial proliferation, we observed a reduction in the number of cells positive for caspase-3, -8, and -9. Regardless the animal's age, few prostate epithelial cells were positive for caspase-3, caspase-9, and TUNEL. In contrast, a progressive increase was seen in the positivity for caspase-8, especially in the atrophic epithelium of ventral prostate, which coincided with a reduction in TNFα immunoreaction. However, morphology of most caspase-8 positive cells suggests that they were not apoptotic. We also found reduced ERβ expression in the same areas. Possibly, low levels of the pro-apoptotic inductors TNFα and ERβ direct caspase-8 activity to an alternative pro-survival role in the atrophic epithelium. This hypothesis is

Imaging prostate cancer (PCa) with [99m Tc(CO)3 ]finasteride dithiocarbamate.

PubMed

Shah, Syed Qaiser; Gul-E-Raana; Uddin, Ghias

2018-06-15

This investigation aimed to modify finasteride (1) to finasteride dithiocarbamate (2) for subsequent synthesis of the rhenium analogue (3) and [ 99m Tc]tricarbonyl complexes (4), to assess its prostate cancer (PCa) targeting potential in a rat model. To validate the identity of (4), reference (3) has been synthesized by using fac-[Net 4 ] 2 [ReBr 3 (CO) 3 ] precursor and characterized by 1 H-NMR, 13 C-NMR, ESI-MS, and elemental analysis. The analogue (4) was synthesized by using fac-[ 99m Tc(H 2 O) 3 (CO) 3 ] + precursor, and its structure was confirmed by comparative HPLC by using (3) as a reference. Further, the suitability of (4) as a PCa imaging agent was investigated in vitro and in vivo. At room temperature, (4) had ≥99% radiochemical purity and remained ≥84% stable in serum. In preclinical studies, biodistribution of (4) in histopathologically established rat model showed adequately high in vivo uptake in the prostate attracting the possibility of using it for noninvasive imaging of PCa. Copyright © 2018 John Wiley & Sons, Ltd.

Continuous-wave vs. pulsed infrared laser stimulation of the rat prostate cavernous nerves

NASA Astrophysics Data System (ADS)

Tozburun, Serhat; Cilip, Christopher M.; Lagoda, Gwen A.; Burnett, Arthur L.; Fried, Nathaniel M.

2011-03-01

Optical nerve stimulation has recently been developed as an alternative to electrical nerve stimulation. However, recent studies have focused primarily on pulsed delivery of the laser radiation and at relatively low pulse rates. The objective of this study is to demonstrate faster optical stimulation of the prostate cavernous nerves using continuouswave (CW) infrared laser radiation, for potential diagnostic applications. A Thulium fiber laser (λ = 1870 nm) was used for non-contact optical stimulation of the rat prostate cavernous nerves, in vivo. Optical nerve stimulation, as measured by an intracavernous pressure (ICP) response in the penis, was achieved with the laser operating in either CW mode, or with a 5-ms pulse duration at 10, 20, 30, 40, 50, and 100 Hz. Successful optical stimulation was observed to be primarily dependent on a threshold nerve temperature (42-45 °C), not an incident fluence, as previously reported. CW optical nerve stimulation provides a significantly faster ICP response time using a laser with lower power output than pulsed stimulation. CW optical nerve stimulation may therefore represent an alternative mode of stimulation for intra-operative diagnostic applications where a rapid response is critical, such as identification of the cavernous nerves during prostate cancer surgery.

Daytime Blue Light Enhances the Nighttime Circadian Melatonin Inhibition of Human Prostate Cancer Growth.

PubMed

Dauchy, Robert T; Hoffman, Aaron E; Wren-Dail, Melissa A; Hanifin, John P; Warfield, Benjamin; Brainard, George C; Xiang, Shulin; Yuan, Lin; Hill, Steven M; Belancio, Victoria P; Dauchy, Erin M; Smith, Kara; Blask, David E

2015-12-01

Light controls pineal melatonin production and temporally coordinates circadian rhythms of metabolism and physiology in normal and neoplastic tissues. We previously showed that peak circulating nocturnal melatonin levels were 7-fold higher after daytime spectral transmittance of white light through blue-tinted (compared with clear) rodent cages. Here, we tested the hypothesis that daytime blue-light amplification of nocturnal melatonin enhances the inhibition of metabolism, signaling activity, and growth of prostate cancer xenografts. Compared with male nude rats housed in clear cages under a 12:12-h light:dark cycle, rats in blue-tinted cages (with increased transmittance of 462-484 nm and decreased red light greater than 640 nm) evinced over 6-fold higher peak plasma melatonin levels at middark phase (time, 2400), whereas midlight-phase levels (1200) were low (less than 3 pg/mL) in both groups. Circadian rhythms of arterial plasma levels of linoleic acid, glucose, lactic acid, pO2, pCO2, insulin, leptin, and corticosterone were disrupted in rats in blue cages as compared with the corresponding entrained rhythms in clear-caged rats. After implantation with tissue-isolated PC3 human prostate cancer xenografts, tumor latency-to-onset of growth and growth rates were markedly delayed, and tumor cAMP levels, uptake-metabolism of linoleic acid, aerobic glycolysis (Warburg effect), and growth signaling activities were reduced in rats in blue compared with clear cages. These data show that the amplification of nighttime melatonin levels by exposing nude rats to blue light during the daytime significantly reduces human prostate cancer metabolic, signaling, and proliferative activities.

Survival and Functionality of hESC-Derived Retinal Pigment Epithelium Cells Cultured as a Monolayer on Polymer Substrates Transplanted in RCS Rats.

PubMed

Thomas, Biju B; Zhu, Danhong; Zhang, Li; Thomas, Padmaja B; Hu, Yuntao; Nazari, Hossein; Stefanini, Francisco; Falabella, Paulo; Clegg, Dennis O; Hinton, David R; Humayun, Mark S

2016-05-01

To determine the safety, survival, and functionality of human embryonic stem cell-derived RPE (hESC-RPE) cells seeded on a polymeric substrate (rCPCB-RPE1 implant) and implanted into the subretinal (SR) space of Royal College of Surgeons (RCS) rats. Monolayers of hESC-RPE cells cultured on parylene membrane were transplanted into the SR space of 4-week-old RCS rats. Group 1 (n = 46) received vitronectin-coated parylene membrane without cells (rMSPM+VN), group 2 (n = 59) received rCPCB-RPE1 implants, and group 3 (n = 13) served as the control group. Animals that are selected based on optical coherence tomography screening were subjected to visual function assays using optokinetic (OKN) testing and superior colliculus (SC) electrophysiology. At approximately 25 weeks of age (21 weeks after surgery), the eyes were examined histologically for cell survival, phagocytosis, and local toxicity. Eighty-seven percent of the rCPCB-RPE1-implanted animals showed hESC-RPE survivability. Significant numbers of outer nuclear layer cells were rescued in both group 1 (rMSPM+VN) and group 2 (rCPCB-RPE1) animals. A significantly higher ratio of rod photoreceptor cells to cone photoreceptor cells was found in the rCPCB-RPE1-implanted group. Animals with rCPCB-RPE1 implant showed hESC-RPE cells containing rhodopsin-positive particles in immunohistochemistry, suggesting phagocytic function. Superior colliculus mapping data demonstrated that a significantly higher number of SC sites responded to light stimulus at a lower luminance threshold level in the rCPCB-RPE1-implanted group. Optokinetic data suggested both implantation groups showed improved visual acuity. These results demonstrate the safety, survival, and functionality of the hESC-RPE monolayer transplantation in an RPE dysfunction rat model.

R-modafinil attenuates nicotine-taking and nicotine-seeking behavior in alcohol-preferring rats.

PubMed

Wang, Xiao-Fei; Bi, Guo-Hua; He, Yi; Yang, Hong-Ju; Gao, Jun-Tao; Okunola-Bakare, Oluyomi M; Slack, Rachel D; Gardner, Eliot L; Xi, Zheng-Xiong; Newman, Amy Hauck

2015-06-01

(±)-Modafinil (MOD) is used clinically for the treatment of sleep disorders and has been investigated as a potential medication for the treatment of psychostimulant addiction. However, the therapeutic efficacy of (±)-MOD for addiction is inconclusive. Herein we used animal models of self-administration and in vivo microdialysis to study the pharmacological actions of R-modafinil (R-MOD) and S-modafinil (S-MOD) on nicotine-taking and nicotine-seeking behavior, and mechanisms underlying such actions. We found that R-MOD is more potent and effective than S-MOD in attenuating nicotine self-administration in Long-Evans rats. As Long-Evans rats did not show a robust reinstatement response to nicotine, we used alcohol-preferring rats (P-rats) that display much higher reinstatement responses to nicotine than Long-Evans rats. We found that R-MOD significantly inhibited intravenous nicotine self-administration, nicotine-induced reinstatement, and nicotine-associated cue-induced drug-seeking behavior in P-rats. R-MOD alone neither sustained self-administration in P-rats previously self-administering nicotine nor reinstated extinguished nicotine-seeking behavior. The in vivo brain microdialysis assays demonstrated that R-MOD alone produced a slow-onset moderate increase in extracellular DA. Pretreatment with R-MOD dose-dependently blocked nicotine-induced dopamine (DA) release in the nucleus accumbens (NAc) in both naive and nicotine self-administrating rats, suggesting a DA-dependent mechanism underlying mitigation of nicotine's effects. In conclusion, the present findings support further investigation of R-MOD for treatment of nicotine dependence in humans.

R-Modafinil Attenuates Nicotine-Taking and Nicotine-Seeking Behavior in Alcohol-Preferring Rats

PubMed Central

Wang, Xiao-Fei; Bi, Guo-Hua; He, Yi; Yang, Hong-Ju; Gao, Jun-Tao; Okunola-Bakare, Oluyomi M; Slack, Rachel D; Gardner, Eliot L; Xi, Zheng-Xiong; Newman, Amy Hauck

2015-01-01

(±)-Modafinil (MOD) is used clinically for the treatment of sleep disorders and has been investigated as a potential medication for the treatment of psychostimulant addiction. However, the therapeutic efficacy of (±)-MOD for addiction is inconclusive. Herein we used animal models of self-administration and in vivo microdialysis to study the pharmacological actions of R-modafinil (R-MOD) and S-modafinil (S-MOD) on nicotine-taking and nicotine-seeking behavior, and mechanisms underlying such actions. We found that R-MOD is more potent and effective than S-MOD in attenuating nicotine self-administration in Long–Evans rats. As Long–Evans rats did not show a robust reinstatement response to nicotine, we used alcohol-preferring rats (P-rats) that display much higher reinstatement responses to nicotine than Long–Evans rats. We found that R-MOD significantly inhibited intravenous nicotine self-administration, nicotine-induced reinstatement, and nicotine-associated cue-induced drug-seeking behavior in P-rats. R-MOD alone neither sustained self-administration in P-rats previously self-administering nicotine nor reinstated extinguished nicotine-seeking behavior. The in vivo brain microdialysis assays demonstrated that R-MOD alone produced a slow-onset moderate increase in extracellular DA. Pretreatment with R-MOD dose-dependently blocked nicotine-induced dopamine (DA) release in the nucleus accumbens (NAc) in both naive and nicotine self-administrating rats, suggesting a DA-dependent mechanism underlying mitigation of nicotine's effects. In conclusion, the present findings support further investigation of R-MOD for treatment of nicotine dependence in humans. PMID:25613829

Resveratrol improves prostate fibrosis during progression of urinary dysfunction in chronic prostatitis.

PubMed

He, Yi; Zeng, Hui-Zhi; Yu, Yang; Zhang, Jia-Shu; Duan, Xingping; Zeng, Xiao-Na; Gong, Feng-Tao; Liu, Qi; Yang, Bo

2017-09-01

We investigated whether prostate fibrosis was associated with urinary dysfunction in chronic prostatitis (CP) and whether resveratrol improved urinary dysfunction and the underlying molecular mechanism. Rat model of CP was established via subcutaneous injections of DPT vaccine and subsequently treated with resveratrol. Bladder pressure and volume tests investigated the effect of resveratrol on urinary dysfunction in CP rats. Western blotting and immunohistochemical staining examined the expression level of C-kit/SCF and TGF-β/Wnt/β-catenin. Compared to the control group, the maximum capacity of the bladder, residual urine volume and maximum voiding pressure, the activity of C-kit/SCF and TGF-β/Wnt/β-catenin pathways were increased significantly in the CP group. Resveratrol treatment significantly improved these factors. CP induced significantly prostate fibrosis, which exhibits a close relationship with urinary dysfunction. Resveratrol improved fibrosis, which may be associated with the suppression of C-kit/SCF and TGF-β/Wnt/β-catenin pathway. Copyright © 2017 Elsevier B.V. All rights reserved.

Possible protective effect of royal jelly against cyclophosphamide induced prostatic damage in male albino rats; a biochemical, histological and immuno-histo-chemical study.

PubMed

Abdel-Hafez, Sara Mohammed Naguib; Rifaai, Rehab Ahmed; Abdelzaher, Walaa Yehia

2017-06-01

Almost all the chemotherapy treat many cancer types effectively, but it leads to severe side effects. Chemotherapy like cyclophosphamide (CP) not works only on the active cells, such as cancer cells, but also acts on the healthy cells. Royal jelly (RJ) was reported to have a lot of therapeutic effects besides being an anti-oxidant and anti-cancer agent. The purpose of this study was to assess the possible protective role of RJ in ameliorating the toxic effects of CP overdose in the rat prostatic tissue. The rats were separated into 4 groups; control group, RJ group, CP group and RJ with CP group. Prostatic specimens were processed for biochemical, histological and immune-histo-chemical studies. The mean area fractions of eNOS and Bax expression were measured in all groups, and statistical analysis was carried out. The results showed that in CP treated group, there were marked biological changes in the form of significant increase in prostatic malondialdehyde (MDA) and C - reactive protein (CRP). Additionally there was a significant decrease in glutathione peroxidase (GPx) in prostatic tissue if compared with the control group. Furthermore, the histological changes showed marked acinar and stromal prostatic degeneration. Most prostatic acini showed less PAS reaction and more (eNOS and Bax) expression if compared with the control group. Concomitant administration of RJ with CP revealed a noticeable amelioration of these biochemical and histological changes. In conclusion, RJ provided biochemical and histo-pathological improvement in CP induced prostatic tissue toxicity. These findings revealed that this improvement was associated with a decrease in the tissue oxidative damage and apoptosis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Structure-based Virtual Screening and Identification of a Novel Androgen Receptor Antagonist*

PubMed Central

Song, Chin-Hee; Yang, Su Hui; Park, Eunsook; Cho, Suk Hee; Gong, Eun-Yeung; Khadka, Daulat Bikram; Cho, Won-Jea; Lee, Keesook

2012-01-01

Hormonal therapies, mainly combinations of anti-androgens and androgen deprivation, have been the mainstay treatment for advanced prostate cancer because the androgen-androgen receptor (AR) system plays a pivotal role in the development and progression of prostate cancers. However, the emergence of androgen resistance, largely due to inefficient anti-hormone action, limits the therapeutic usefulness of these therapies. Here, we report that 6-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(6-methylpyridin-2-yl)nicotinamide (DIMN) acts as a novel anti-androgenic compound that may be effective in the treatment of both androgen-dependent and androgen-independent prostate cancers. Through AR structure-based virtual screening using the FlexX docking model, fifty-four compounds were selected and further screened for AR antagonism via cell-based tests. One compound, DIMN, showed an antagonistic effect specific to AR with comparable potency to that of the classical AR antagonists, hydroxyflutamide and bicalutamide. Consistent with their anti-androgenic activity, DIMN inhibited the growth of androgen-dependent LNCaP prostate cancer cells. Interestingly, the compound also suppressed the growth of androgen-independent C4–2 and CWR22rv prostate cancer cells, which express a functional AR, but did not suppress the growth of the AR-negative prostate cancer cells PPC-1, DU145, and R3327-AT3.1. Taken together, the results suggest that the synthetic compound DIMN is a novel anti-androgen and strong candidate for useful therapeutic agent against early stage to advanced prostate cancer. PMID:22798067

Immunomodulatory Effect of Red Onion (Allium cepa Linn) Scale Extract on Experimentally Induced Atypical Prostatic Hyperplasia in Wistar Rats

PubMed Central

Elberry, Ahmed A.; Al-Maghrabi, Jaudah; Abdel Sattar, Essam; Ghareib, Salah A.; Mosli, Hisham A.; Gabr, Salah A.

2014-01-01

Red onion scales (ROS) contain large amounts of flavonoids that are responsible for the reported antioxidant activity, immune enhancement, and anticancer property. Atypical prostatic hyperplasia (APH) was induced in adult castrated Wistar rats by both s.c. injection of testosterone (0.5 mg/rat/day) and by smearing citral on shaved skin once every 3 days for 30 days. Saw palmetto (100 mg/kg) as a positive control and ROS suspension at doses of 75, 150, and 300 mg/kg/day were given orally every day for 30 days. All medications were started 7 days after castration and along with testosterone and citral. The HPLC profile of ROS methanolic extract displayed two major peaks identified as quercetin and quercetin-4′-β-O-D-glucoside. Histopathological examination of APH-induced prostatic rats revealed evidence of hyperplasia and inflammation with cellular proliferation and reduced apoptosis Immunohistochemistry showed increased tissue expressions of IL-6, IL-8, TNF-α, IGF-1, and clusterin, while TGF-β1 was decreased, which correlates with the presence of inflammation. Both saw palmetto and RO scale treatment have ameliorated these changes. These ameliorative effects were more evident in RO scale groups and were dose dependent. In conclusion, methanolic extract of ROS showed a protective effect against APH induced rats that may be attributed to potential anti-inflammatory and immunomodulatory effects. PMID:24829522

Serum ferritin in combination with prostate-specific antigen improves predictive accuracy for prostate cancer.

PubMed

Wang, Xijuan; An, Peng; Zeng, Jiling; Liu, Xiaoyan; Wang, Bo; Fang, Xuexian; Wang, Fudi; Ren, Guoping; Min, Junxia

2017-03-14

Ferritin is highly expressed in many cancer types. Although a few studies have reported an association between high serum ferritin levels and an increased risk of prostate cancer, the results are inconsistent. Therefore, we performed a large case-control study consisting of 2002 prostate cancer patients and 951 control patients with benign prostatic hyperplasia (BPH). We found that high ferritin levels were positively associated with increased serum prostate-specific antigen (PSA) levels and prostate cancer risk; each 100 ng/ml increase in serum ferritin increased the odds ratio (OR) by 1.20 (95% CI: 1.13-1.36). In the prostate cancer group, increased serum ferritin levels were significantly correlated with higher Gleason scores (p < 0.001). Notably, serum PSA values had even higher predictive accuracy among prostate cancer patients with serum ferritin levels > 400 ng/ml (Gleason score + total PSA correlation: r = 0.38; Gleason score + free PSA correlation: r = 0.49). Moreover, using immunohistochemistry, we found that prostate tissue ferritin levels were significantly higher (p < 0.001) in prostate cancer patients (n = 129) compared to BPH controls (n = 31). Prostate tissue ferritin levels were also highly correlated with serum ferritin when patients were classified by cancer severity (r = 0.81). Importantly, we found no correlation between serum ferritin levels and the inflammation marker C-reactive protein (CRP) in prostate cancer patients. In conclusion, serum ferritin is significantly associated with prostate cancer and may serve as a non-invasive biomarker to complement the PSA test in the diagnosis and prognostic evaluation of prostate cancer.

Screening of allergic components mediated by H(1)R in homoharringtonine injection through H(1)R/CMC-HPLC/MS.

PubMed

Guo, Ying; Han, Shengli; Cao, Jingjing; Liu, Qi; Zhang, Tao

2014-12-01

It has been reported that the histamine H1 receptor (H(1)R) gene is up-regulated in patients with allergic rhinitis and H(1)R expression level strongly correlates with the severity of allergy symptoms. Drugs for therapy should avoid allergy symptoms, especially for patients with over-expressed H(1)R. Therefore, screening of the components which could induce H(1)R activation is urgently needed for drug safety evaluation. Homoharringtonine injection is a preparation for acute nonlymphocytic leukemia, which is approved by China Food and Drug Administration (CFDA) and US Food and Drug Administration. However, severely adverse reactions often occur with intravenous injection of the preparation. In present study, an H(1)R/CMC model was applied for capturing membrane retained components which could induce H(1)R activation. Retention components were enriched and analyzed by H(1)R/CMC-HPLC/MS. Homoharringtonine was recognized, separated and identified in homoharringtonine injection. Ca(2+) flux assay and p-IP3R expression founded that homoharringtonine retained by the H1 R/CMC model increased phosphorylation of IP3R and promoted cytosolic free Ca(2+) elevation in a dose-dependent manner which further verified the activity of homoharringtonine in activating the H1 R. In conclusion, homoharringtonine was screened and identified as a potential allergic factor. This provides an indication that a patient with over-expressed H1 R should be aware of possible allergic reaction when applying homoharringtonine injection. Copyright © 2014 John Wiley & Sons, Ltd.

Identification and Characterization of Small-Molecule Inhibitors of the R132H/R132H Mutant Isocitrate Dehydrogenase 1 Homodimer and R132H/Wild-Type Heterodimer.

PubMed

Brooks, Eric; Wu, Xiang; Hanel, Art; Nguyen, Shaun; Wang, Jing; Zhang, Jeffrey H; Harrison, Amanda; Zhang, Wentao

2014-09-01

Recurrent genetic mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) have been identified in multiple tumor types. The most frequent mutation, IDH1 R132H, is a gain-of-function mutation resulting in an enzyme-catalyzing conversion of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). A high-throughput assay quantifying consumption of NADPH by IDH1 R132H has been optimized and implemented to screen 3 million compounds in 1536-well formats. The primary high-throughput screening hits were further characterized by RapidFire-mass spectrometry measuring 2-HG directly. Multiple distinct chemotypes were identified with nanomolar potencies (6-300 nM). All inhibitors were found to be inactive against the wild-type IDH1 homodimers. An IDH1 heterodimer between wild-type and R132H mutant is capable of catalyzing conversion of α-KG to 2-HG and isocitrate to α-KG. Interestingly, one of the inhibitors, EXEL-9324, was found to inhibit both conversions by the IDH1 heterodimer. This indicates the R132H/WT heterodimer may adopt conformations distinct from that of the R132H/R132H homodimer. Further enzymatic studies support this conclusion as the heterodimer exhibited a significantly lower apparent Michaelis-Menten constant for α-KG (K(m)=110 µM) compared with the R132H homodimer (K(m)= 1200 µM). The enhanced apparent affinity for α-KG suggests R132H/WT heterodimeric IDH1 can produce 2-HG more efficiently at normal intracellular levels of α-KG (approximately 100 µM). © 2014 Society for Laboratory Automation and Screening.

ENP11, a potential CB1R antagonist, induces anorexia in rats.

PubMed

Méndez-Díaz, Mónica; Amancio-Belmont, Octavio; Hernández-Vázquez, Eduardo; Ruiz-Contreras, Alejandra E; Hernández-Luis, Francisco; Prospéro-García, Oscar

2015-08-01

Over the past decade, pharmacological manipulation of cannabinoid 1 receptor (CB1R) has become an interesting approach for the management of food ingestion disorders, among other physiological functions. Searching for new substances with similar desirable effects, but fewer side-effects we have synthesized a SR141716A (a cannabinoid receptor inverse agonist also called Rimonabant) analog, 1-(2,4-Difluorophenyl)-4-methyl-N-(1-piperidinyl)-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide, ENP11, that so far, as we have previously shown, has induced changes in glucose availability, i.e. hypoglycemia, in rats. In this study we tested the effects, if any, of ENP11 (0.5, 1.0, and 3.0mg/kg) in food ingestion, core temperature, pain perception and motor control in adult Wistar rats. Results showed that ENP11 reduced food ingestion during the first hour immediately after administration. Likewise, ENP11 (1.0mg/kg) blocked anandamide (AEA)-induced hyperphagia during the first 4h of the dark phase of the light-dark cycle, and it also blocked AEA-induced hypothermia. However, none of the ENP11 doses used affected pain perception or motor control. We believe that ENP11 is a potential useful CB1R antagonist that reduces food ingestion and regulates core temperature. Copyright © 2015 Elsevier Inc. All rights reserved.

Diagnostic performance of expression of PCA3, Hepsin and miR biomarkers inejaculate in combination with serum PSA for the detection of prostate cancer.

PubMed

Roberts, Matthew J; Chow, Clement W K; Schirra, Horst Joachim; Richards, Renee; Buck, Marion; Selth, Luke A; Doi, Suhail A R; Samaratunga, Hema; Perry-Keene, Joanna; Payton, Diane; Yaxley, John; Lavin, Martin F; Gardiner, Robert A

2015-04-01

Here, we report on the evaluation of the diagnostic performance of ejaculate-derived PCA3, Hepsin, and miRNAs to complement serum PSA to detect prostate cancer. cDNA was prepared from 152 candidate specimens following RNA isolation and amplification for PSA, PCA3 and Hepsin qPCR, with 66 having adequate RNA for all three assays. Small RNA sequencing and examination of PCa-associated miRNAs miR-200b, miR-200c, miR-375 and miR-125b was performed on 20 specimens. We compared findings from prostate biopsies using D'Amico and PRIAS classifications and in relation to whole gland histopathology following radical prostatectomy. Multivariate logistic regression modeling and clinical risk (incorporating standard clinicopathological variables) were performed for all ejaculate-based markers. While Hepsin alone was not of predictive value, the Hepsin:PCA3 ratio together with serum PSA, expressed as a univariate composite score based on multivariate logistic regression, was shown to be a better predictor than PSA alone of prostate cancer status (AUC 0.724 vs. 0.676) and risk, using D'Amico (AUC 0.701 vs. 0.680) and PRIAS (AUC 0.679 vs. 0.659) risk stratification criteria as classified using prostate biopsies. It was also possible to analyse a subgroup of patients for miRNA expression with miR-200c (AUC 0.788) and miR-375 (AUC 0.758) showing best single marker performance, while a combination of serum PSA, miR-200c, and miR-125b further improved prediction for prostate cancer status when compared to PSA alone determined by biopsy (AUC 0.869 vs. 0.672; P < 0.05), and risk (D'Amico/PRIAS) as well as by radical prostatectomy histology (AUC 0.809 vs. 0.690). For prostate cancer status by biopsy, at a sensitivity of 90%, the specificity of the test increased from 11% for PSA alone to 67% for a combination of PSA, miR-200c, and miR-125b. These results show that use of a combination of different types of genetic markers in ejaculate together with serum PSA are at least as sensitive as

Daytime Blue Light Enhances the Nighttime Circadian Melatonin Inhibition of Human Prostate Cancer Growth

PubMed Central

Dauchy, Robert T; Hoffman, Aaron E; Wren-Dail, Melissa A; Hanifin, John P; Warfield, Benjamin; Brainard, George C; Xiang, Shulin; Yuan, Lin; Hill, Steven M; Belancio, Victoria P; Dauchy, Erin M; Smith, Kara; Blask, David E

2015-01-01

Light controls pineal melatonin production and temporally coordinates circadian rhythms of metabolism and physiology in normal and neoplastic tissues. We previously showed that peak circulating nocturnal melatonin levels were 7-fold higher after daytime spectral transmittance of white light through blue-tinted (compared with clear) rodent cages. Here, we tested the hypothesis that daytime blue-light amplification of nocturnal melatonin enhances the inhibition of metabolism, signaling activity, and growth of prostate cancer xenografts. Compared with male nude rats housed in clear cages under a 12:12-h light:dark cycle, rats in blue-tinted cages (with increased transmittance of 462–484 nm and decreased red light greater than 640 nm) evinced over 6-fold higher peak plasma melatonin levels at middark phase (time, 2400), whereas midlight-phase levels (1200) were low (less than 3 pg/mL) in both groups. Circadian rhythms of arterial plasma levels of linoleic acid, glucose, lactic acid, pO2, pCO2, insulin, leptin, and corticosterone were disrupted in rats in blue cages as compared with the corresponding entrained rhythms in clear-caged rats. After implantation with tissue-isolated PC3 human prostate cancer xenografts, tumor latency-to-onset of growth and growth rates were markedly delayed, and tumor cAMP levels, uptake–metabolism of linoleic acid, aerobic glycolysis (Warburg effect), and growth signaling activities were reduced in rats in blue compared with clear cages. These data show that the amplification of nighttime melatonin levels by exposing nude rats to blue light during the daytime significantly reduces human prostate cancer metabolic, signaling, and proliferative activities. PMID:26678364

Puerarin offsets the anticoagulation effect of warfarin in rats by inducing rCyps, upregulating vitamin K epoxide reductase and inhibiting thrombomodulin.

PubMed

Ge, Beikang; Zhang, Zhen; Lam, Teddy Taining; Zuo, Zhong

2017-01-01

The current study was conducted to investigate the potential pharmacokinetic and pharmacodynamic interactions between warfarin and puerarin which is the most abundant component in Pueraria lobata (Gegen). In vivo and ex vivo rat models were used to reveal the underlying mechanisms of such interactions. Apart from one control group, five groups of Sprague-Dawley rats were treated with warfarin, oral puerarin, oral puerarin with warfarin, intravenous puerarin, intravenous puerarin with warfarin. The treatment lasted for 5 consecutive days. Thereafter, the levels of warfarin, warfarin metabolites and puerarin in plasma of these rats were monitored and compared. The rCyps activity and expression in rat livers of different treatment groups were assessed. The prothrombin time was observed. The vitamin K epoxide reductase (VKOR) activity and expression in rat livers were evaluated. Thrombomodulin activity and expression in the rat lung and rat plasma were assessed. The soluble thrombomodulin (sTM) concentrations of different treatment groups were examined. Intravenously administered puerarin altered the pharmacokinetics of warfarin significantly by shortening t 1/2 , decreasing AUC 0-96 h and increasing the clearance of warfarin. Further mechanistic studies suggested that both oral and intravenous administration of puerarin significantly induced the activities and expressions of rCyp2b1, rCyp2c6 and rCyp1a1. In addition, co-administration of puerarin reduced the prothrombin time of rat plasma by enhancing VKOR and inhibiting thrombomodulin. Puerarin increased warfarin metabolism and offset warfarin anticoagulation by inducing rCyps, upregulating VKOR and inhibiting thrombomodulin in rats. The clinical impact of such potential interactions warrants further verification. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

A pharmacological investigation of Hippophae salicifolia (HS) and Hippophae rhamnoides turkestanica (HRT) against multiple stress (C-H-R): an experimental study using rat model.

PubMed

Rathor, Richa; Sharma, Priyanka; Suryakumar, Geetha; Ganju, Lilly

2015-09-01

Hippophae salicifolia (HS) and Hippophae rhamnoides turkestanica (HRT) are abundantly found species of Hippophae in Himalayan region of India. As these plants thrive under extreme climatic conditions, it is suspected that these plants must have a unique adaptogenic property against high-altitude stress. To keeping these views in our mind, the present study was planned to evaluate the mechanism of action of aqueous extract of HS and aqueous extract of HRT against multiple stress [cold-hypoxia-restraint (C-H-R)] for their adaptogenic activity. The present study reported the adaptogenic activity of HS in facilitating tolerance to multiple stress, CHR in rats. Pre-treatment with aqueous extract of HS significantly attenuated reactive oxygen species (ROS) production, protein oxidation, and lipid peroxidation and also showed role in maintaining antioxidant status as similar to control rats. Since protein oxidation was decreased by pre-treatment of HS, protein homeostasis was also sustained by regulation of heat shock proteins (HSP70 and HSP60). Interestingly, heme oxygenase-1 (HO-1), Vascular Endothelial Growth Factor (VEGF), and nitric oxide (NO) level was also increased in HS pre-treated rats depicted its adaptogenic activity against multiple stress, CHR. Conclusively, aqueous extract of HS could use an adaptogen for high altitude-associated multiple stress (CHR).

Presence of PSA auto-antibodies in men with prostate abnormalities (prostate cancer/benign prostatic hyperplasia/prostatitis).

PubMed

Lokant, M T; Naz, R K

2015-04-01

Prostate-specific antigen (PSA), produced by the prostate, liquefies post-ejaculate semen. PSA is detected in semen and blood. Increased circulating PSA levels indicate prostate abnormality [prostate cancer (PC), benign prostatic hyperplasia (BPH), prostatitis (PTIS)], with variance among individuals. As the prostate has been proposed as an immune organ, we hypothesise that variation in PSA levels among men may be due to presence of auto-antibodies against PSA. Sera from healthy men (n = 28) and men having prostatitis (n = 25), BPH (n = 30) or PC (n = 29) were tested for PSA antibody presence using enzyme-linked immunosorbent assay (ELISA) values converted to standard deviation (SD) units, and Western blotting. Taking ≥2 SD units as cut-off for positive immunoreactivity, 0% of normal men, 0% with prostatitis, 33% with BPH and 3.45% with PC demonstrated PSA antibodies. One-way analysis of variance (anova) performed on the mean absorbance values and SD units of each group showed BPH as significantly different (P < 0.01) compared with PC and prostatitis. All others were nonsignificant (P < 0.05). Men (33%) with BPH had PSA antibodies by ELISA and Western blot. These discoveries may find clinical application in differential diagnosis among prostate abnormalities, especially differentiating BPH from prostate cancer and prostatitis. © 2014 Blackwell Verlag GmbH.

Novel revertants of H-ras oncogene-transformed R6-PKC3 cells.

PubMed Central

Krauss, R S; Guadagno, S N; Weinstein, I B

1992-01-01

Rat 6 fibroblasts that overproduce protein kinase C beta 1 (R6-PKC3 cells) are hypersensitive to complete transformation by the T24 H-ras oncogene; yet T24 H-ras-transformed R6-PKC3 cells are killed when exposed to 12-O-tetradecanoylphorbol-13-acetate (TPA) (W.-L. W. Hsiao, G. M. Housey, M. D. Johnson, and I. B. Weinstein, Mol. Cell. Biol. 9:2641-2647, 1989). Treatment of an R6-PKC3 subclone that harbors a T24 H-ras gene under the control of an inducible mouse metallothionein I promoter with ZnSO4 and TPA is extremely cytocidal. This procedure was used to isolate rare revertants that are resistant to this toxicity. Two revertant lines, R-1a and ER-1-2, continue to express very high levels of protein kinase C enzyme activity but, unlike the parental cells, do not grow in soft agar. Furthermore, these revertants are resistant to the induction of anchorage-independent growth by the v-src, v-H-ras, v-raf, and, in the case of the R-1a line, v-fos oncogenes. Both revertant lines, however, retain the ability to undergo morphological alterations when either treated with TPA or infected with a v-H-ras virus, thus dissociating anchorage independence from morphological transformation. The revertant phenotype of both R-1a and ER-1-2 cells is dominant over the transformed phenotype in somatic cell hybridizations. Interestingly, the revertant lines no longer induce the metallothionein I-T24 H-ras construct or the endogenous metallothionein I and II genes in response to three distinct agents: ZnSO4, TPA, and dexamethasone. The reduction in activity of metallothionein promoters seen in these revertants may reflect defects in signal transduction pathways that control the expression of genes mediating specific effects of protein kinase C and certain oncogenes in cell transformation. Images PMID:1535685

Long noncoding RNA SNHG7 accelerates prostate cancer proliferation and cycle progression through cyclin D1 by sponging miR-503.

PubMed

Qi, Honggang; Wen, Bifeng; Wu, Qihang; Cheng, Wei; Lou, Jiangyong; Wei, Junjun; Huang, Jianjun; Yao, Xuping; Weng, Guobin

2018-06-01

Increasing evidence has indicated the important roles of long non-coding RNAs (lncRNAs) in tumorigenesis and cellular progression, including prostate cancer. In this study, we aim to investigate the expression level of SNHG7 and its biological functions on prostate cancer cells. Results indicated that SNHG7 expression was significantly up-regulated in prostate cancer tissue and cell lines. Besides, the overexpression of SNHG7 was closely correlated with the poor prognosis. In vitro and in vivo, experiments demonstrated that SNHG7 knockdown markedly inhibited prostate cancer proliferation and cycle-related protein (CDK4, CDK6, Cyclin D1), induced cell cycle arrest at G0/G1 phase and suppressed tumor growth. Moreover, miR-503 was predicted by bioinformatics tools and validated using luciferase reporter assay to both directly inhibited SNHG7 and Cyclin D1 expression by targeting their RNA 3'-UTR. In conclusion, results present that SNHG7 regulates the cycle progression and acts as an oncogenic gene in the prostate cancer tumorigenesis via miR-503/Cyclin D1 pathway, revealing the vital role of lncRNA/miRNA/mRNA axis in prostate cancer carcinogenesis. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Safety and efficacy of a novel Prunus domestica extract (Sitoprin, CR002) on testosterone-induced benign prostatic hyperplasia (BPH) in male Wistar rats.

PubMed

Swaroop, Anand; Bagchi, Manashi; Kumar, Pawan; Preuss, Harry G; Bagchi, Debasis

2015-01-01

The efficacy of a novel Prunus domestica bark extract (Sitoprin, CR002) was investigated on testosterone propionate (TP)-induced benign prostatic hyperplasia (BPH) in male Wistar rats. BPH was induced by daily subcutaneous administration of TP (3.0 mg/kg) over a period of 15 days (interim sacrifice group) and for an additional 21 days (terminal sacrifice group). We evaluated the dose-dependent efficacy (0, 50, 100 and 200 mg/kg body weight/day) of CR002 and a control group against BPH, and compared with a reference standard Prunus africana extract (CR001). Extensive clinical examinations were carried out on days 1, 7, 14, 21, 28 and 35 of treatment period to determine the onset, duration and severity of clinical signs. Clinical pathology, hematology, biochemistry and histopathology were performed on days 15 and 35, prior to necropsy. Animals were fasted overnight prior to blood collection. Prostate glands and tissues were examined. On day 36, histopathology of ventral prostrate of control rats demonstrates single layer of columnar mucin secreting epithelial cells along with a lumen occupied with eosinophilic secretion. In contrast, CR002 and CR001 groups (100 and 200 mg/kg/day) exhibited no hyperplasia and proliferation of epithelial cells. Prostate histopathology of these treated groups was comparable with control rats. The hyperplasia and hypertrophy of prostrate was reduced to single-layered cell indicating the efficacy of CR002 and CR001. Overall, results demonstrate that CR002 exhibits therapeutic efficacy/activity in TP-induced BPH in rats, which is comparable to CR001.

Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene.

PubMed Central

Maroulakou, I G; Anver, M; Garrett, L; Green, J E

1994-01-01

A transgenic mouse model for prostate and mammary cancer has been developed in mice containing a recombinant gene expressing the simian virus 40 early-region transforming sequences under the regulatory control of the rat prostatic steroid binding protein [C3(1)] gene. Male transgenic mice develop prostatic hyperplasia in early life that progresses to adenoma or adenocarcinoma in most animals surviving to longer than 7 months of age. Prostate cancer metastases to lung have been observed. Female animals from the same founder lines generally develop mammary hyperplasia by 3 months of age with subsequent development of mammary adenocarcinoma by 6 months of age in 100% of the animals. The development of tumors correlates with the expression of the transgene as determined by Northern blot and immunohistochemical analyses. The results of these experiments demonstrate that the C3(1) regulatory region used in these experiments is useful for targeting expression to the prostate and mammary gland. To our knowledge, this experimental system is the first reported transgenic mouse model for prostate cancer. These transgenic animals offer the opportunity to study hormone response elements in vivo and the multistage progression from normal tissue to carcinoma in the prostate and mammary glands. Images PMID:7972041

Vasculature-Specific Adenovirus Vectors for Gene Therapy of Prostate Cancer

DTIC Science & Technology

2008-02-01

Renata Pasqualini (University of Texas M.D. Anderson Cancer Center). This assay showed excellent binding of the wt fiber to sCAR and no binding...Bernasconi, R. Kain, D. Rajotte, S. Krajewski, H. M. Ellerby, D. E. Bredesen, R. Pasqualini , and E. Ruoslahti. 2002. Targeting the prostate for...D. Bucana, E. Koivunen, D. Cahill, P. Troncoso, K. A. Baggerly, R. D. Pentz, K. A. Do, C. J. Logothetis, and R. Pasqualini . 2002. Steps toward

Differential expression of androgen, estrogen, and progesterone receptors in benign prostatic hyperplasia

PubMed Central

Song, Lingmin; Shen, Wenhao; Zhang, Heng; Wang, Qiwu; Wang, Yongquan; Zhou, Zhansong

2016-01-01

This study aimed to identify the differential expression levels of androgen receptor (AR), estrogen receptors (ERα, ERβ), and progesterone receptor (PGR) between normal prostate and benign prostatic hyperplasia (BPH). The combination of immunohistochemistry, quantitative real-time reverse transcription polymerase chain reaction, and Western blotting assay was used to identify the distribution and differential expression of these receptors at the immunoactive biomarker, transcriptional, and protein levels between 5 normal human prostate tissues and 40 BPH tissues. The results were then validated in a rat model of BPH induced by testosterone propionate and estradiol benzoate. In both human and rat prostate tissues, AR was localized mainly to epithelial and stromal cell nuclei; ERα was distributed mainly to stromal cells, but not exclusively; ERβ was interspersed in the basal layer of epithelium, but sporadically in epithelial and stromal cells; PGR was expressed abundantly in cytoplasm of epithelial and stromal cells. There were decreased expression of ERα and increased expression of PGR, but no difference in the expression of ERβ in the BPH compared to the normal prostate of both human and rat. Increased expression of AR in the BPH compared to the normal prostate of human was observed, however, the expression of AR in the rat prostate tissue was decreased. This study identified the activation of AR and PGR and repression of ERα in BPH, which indicate a promoting role of AR and PGR and an inhibitory role of ERα in the pathogenesis of BPH. PMID:27294569

Expression differences of circulating microRNAs in metastatic castration resistant prostate cancer and low-risk, localized prostate cancer.

PubMed

Nguyen, Han Christine Ngoc; Xie, Wanling; Yang, Ming; Hsieh, Chen-Lin; Drouin, Sarah; Lee, Gwo-Shu Mary; Kantoff, Philip W

2013-03-01

Recent studies show that microRNAs (miRNAs), small non-coding RNAs that negatively regulate gene expression, may have potential for monitoring cancer status. We investigated circulating miRNAs in prostate cancer that may be associated with the progression of hormone-sensitive primary tumors to metastatic castration resistant prostate cancer (CRPC) after androgen deprivation therapy. Using genome-wide expression profiling by TaqMan Human MicroRNA Arrays (Applied Biosystems) and/or quantitative real-time polymerase chain reaction, we compared the expression levels of miRNAs in serum samples from 28 patients of low-risk localized disease, 30 of high-risk localized disease and 26 of metastatic CRPC. We demonstrated that serum samples from patients of low risk, localized prostate cancer and metastatic CRPC patients exhibit distinct circulating miRNA signatures. MiR-375, miR-378*, and miR-141 were significantly over-expressed in serum from CRPC patients compared with serum from low-risk localized patients, while miR-409-3p was significantly under-expressed. In prostate primary tumor samples, miR-375 and miR-141 also had significantly higher expression levels compared with those in normal prostate tissue. Circulating miRNAs, particularly miR-375, miR-141, miR-378*, and miR-409-3p, are differentially expressed in serum samples from prostate cancer patients. In the search for improved minimally invasive methods to follow cancer pathogenesis, the correlation of disease status with the expression patterns of circulating miRNAs may indicate the potential importance of circulating miRNAs as prognostic markers for prostate cancer progression. Copyright © 2012 Wiley Periodicals, Inc.

MiR-139-5p is Increased in the Peripheral Blood of Patients with Prostate Cancer.

PubMed

Pang, Cheng; Liu, Ming; Fang, Weiwei; Guo, Jun; Zhang, Zhipeng; Wu, Pengjie; Zhang, Yaoguang; Wang, Jianye

2016-01-01

Emerging evidence suggested that microRNAs (miRNAs) play a causal role in cancer tumorigenesis. Aberrant expression of miRNA (miR)-139-5p has been observed in various types of cancers. The present study evaluated the relationship between miR-139-5p expression levels and prostate cancer (PCa), to assess the feasibility of using peripheral blood miR-139-5p as a potential non-invasive biomarker for PCa. Total RNA was extracted from peripheral whole blood samples from 45 PCa patients, 45 benign prostatic hyperplasia (BPH) patients and 50 healthy controls (HC). The expression of miR-139-5p was assessed by reverse transcription quantitative polymerase chain reaction. MiR-139-5p in peripheral blood was significantly higher in PCa patients than in patients with BPH and HC individuals (P<0.001). Higher miR-139-5p expression was observed to be associated with certain clinicopathological parameters, including PSA>20ng/ml (P<0.05), pathological tumor stage 3/4 (P<0.05) and Gleason score >7 (P<0.01). A receiver operating characteristic (ROC) curve analysis revealed that miR-139-5p distinguished PCa patients from BPH patients [area under the curve (AUC), 0.936; 95% CI, 0.878-0.993; P<0.001]. Peripheral blood miR-139-5p may be utilized as a potential novel non-invasive biomarker for PCa screening. © 2016 The Author(s) Published by S. Karger AG, Basel.

Feasibility Study of a Novel Diet-Based Intervention for Prostate Cancer

DTIC Science & Technology

2009-09-01

Vegetables Cruciferous vegetables include broccoli , broccoli sprouts, cauliflower, radishes, cabbage, brussels sprouts, kale, collard greens, and... broccoli sprout extract containing isothiocyanates increases phase 2 enzyme activity in the prostate. [28] Interestingly, a recent study indicated...that rats fed a combination tomato and broccoli diet had greater suppression of prostate tumors than rats fed either tomato or broccoli alone

Prostate cancer, benign prostatic hyperplasia and physical activity in Shanghai, China.

PubMed

Lacey, J V; Deng, J; Dosemeci, M; Gao, Y T; Mostofi, F K; Sesterhenn, I A; Xie, T; Hsing, A W

2001-04-01

Studies suggest that increased levels of physical activity might decrease the risk of prostate cancer. We ascertained lifetime measures of activity in a population-based case-control study of prostate cancer in Shanghai, China to investigate physical activity in a population where the incidence of prostate cancer is low but rising. In all, 238 men with prostate cancer, diagnosed 1993-1995, were identified through a rapid reporting system. A second group of 206 men with benign prostatic hyperplasia (BPH) was matched to prostate cancer cases, and 471 age-matched and population-based controls were identified from urban Shanghai. Through personal interviews, we ascertained all daily, occupational, and recreational activities at ages 20-29, ages 40-49, and in 1988 to generate hours spent sleeping, sitting, in moderate activity, and in vigorous activity. Time spent per week in different activities was converted to metabolic equivalents (MET-h) and energy expended. Time spent in, MET-h of, and energy expended in physical activities were not consistently related to either prostate cancer or BPH when compared to controls. Few men reported regular vigorous activity. Occupational activity, based on an energy expenditure index using job titles, was suggestively associated with a decreased risk of BPH, but not associated with prostate cancer. Associations did not vary according to age or stage of prostate cancer at diagnosis. Our results, based on regular physical activity, occupational activity, hours in activities, MET-h, and energy expended, did not support a protective role of physical activity in prostate cancer or BPH for men in a low-risk population.

Potential ameliorative effects of grape seed-derived polyphenols against cadmium induced prostatic deficits.

PubMed

Lei, Yongfang; Chen, Qian; Chen, Jinglou; Liu, Dong

2017-07-01

Grape (Vitis vinifera) is consumed as fruit and wine for people. In this study, rat model of prostatic deficits was induced by orally receiving 60mg/L cadmium chlorine (CdCl 2 ) through drinking water for 20 weeks. Grape seed-derived polyphenols extract (GSP) was orally given for 20 weeks. Finally, the prostatic levels of E-cadherin, fibronectin, and α-smooth muscle actin were measured by immunohistochemical and qPCR analysis. The oxidative stress was measured by detecting the levels of malondialdehyde, nitric oxide, reduced glutathione/oxidized glutathione and enzymatic antioxidant status. Additionally, the prostatic expressions of transforming growth factor-β1 (TGF-β1), type I TGF-β receptor (TGF-βRI), Smad3, phosphorylation-Smad3 (p-Smad3), Smad7, nuclear related factor-2 (Nrf-2), heme oxygenase-1 (HO-1) and γ-glutamate cysteine ligase catalytic subunit (γ-GCLC) were measured by western blot. The levels of microRNA (miR)-133a/b were measured by qPCR. It was observed that GSP ameliorated the prostatic oxidative stress and fibrosis induced by CdCl 2 . GSP also inhibited the over-generation of TGF-β1 and p-Smad3, as well as enhanced the levels of Smad7, Nrf-2, HO-1, γ-GCLC and miR-133a/b. These results showed that GSP could attenuate Cd-induced prostatic deficits. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Expression and role of the angiotensin II AT2 receptor in human prostate tissue: in search of a new therapeutic option for prostate cancer.

PubMed

Guimond, Marie-Odile; Battista, Marie-Claude; Nikjouitavabi, Fatemeh; Carmel, Maude; Barres, Véronique; Doueik, Alexandre A; Fazli, Ladan; Gleave, Martin; Sabbagh, Robert; Gallo-Payet, Nicole

2013-07-01

Evidence shows that angiotensin II type 1 receptor (AT1R) blockers may be associated with improved outcome in prostate cancer patients. It has been proposed that part of this effect could be due to angiotensin II type 2 receptor (AT2R) activation, the only active angiotensin II receptor in this situation. This study aimed to characterize the localization and expression of AT2R in prostate tissues and to assess its role on cell morphology and number in prostatic epithelial cells in primary culture. AT2R and its AT2R-interacting protein (ATIP) expression were assessed on non-tumoral and tumoral human prostate using tissue microarray immunohistochemistry, binding assay, and Western blotting. AT2R effect on cell number was measured in primary cultures of epithelial cells from non-tumoral human prostate. AT2R was localized at the level of the acinar epithelial layer and its expression decreased in cancers with a Gleason score 6 or higher. In contrast, ATIP expression increased with cancer progression. Treatment of primary cell cultures from non-tumoral prostate tissues with C21/M024, a selective AT2R agonist, alone or in co-incubation with losartan, an AT1R antagonist, significantly decreased cell number compared to untreated cells. AT2R and ATIP are present in non-tumoral human prostate tissues and differentially regulated according to Gleason score. The decrease in non-tumoral prostate cell number upon selective AT2R stimulation suggests that AT2R may have a protective role against prostate cancer development. Treatment with a selective AT2R agonist could represent a new approach for prostate cancer prevention or for patients on active surveillance. Copyright © 2013 Wiley Periodicals, Inc.

Effects of saw palmetto extract on micturition reflex of rats and its autonomic receptor binding activity.

PubMed

Oki, Tomomi; Suzuki, Mayumi; Nishioka, Yasuhiko; Yasuda, Akio; Umegaki, Keizo; Yamada, Shizuo

2005-04-01

We examined the effects of saw palmetto extract (SPE) on the rat micturition reflex and on autonomic receptors in the lower urinary tract. The effect of SPE was examined on cystometrograms of anesthetized rats induced by intravesical infusion of saline or 0.1% acetic acid. SHR/NDmc-cp (cp/cp) rats received repeat oral administration of SPE and nighttime urodynamic function was determined. The autonomic receptor binding activity of SPE in the rat bladder and prostate was examined by radioligand binding assay. Intraduodenal administration of SPE (60 mg/kg) in anesthetized rat cystometry caused a significant increase in the micturition interval, micturition volume and bladder capacity during intravesical saline infusion. Also, similar administration of SPE at doses of 12 and 20 mg/kg significantly reversed the shortened micturition interval as well as the decreased micturition volume and bladder capacity due to 0.1% acetic acid infusion in a dose dependent manner. In conscious SHR/NDmc-cp (cp/cp) rats repeat oral administration of SPE (6 mg/kg daily) constantly increased the micturition interval and concomitantly decreased voiding frequency. SPE inhibited specific binding of [H]NMS ([N-methyl-H]scopolamine methyl chloride) (bladder) and [H]prazosin (prostate) with IC50 values of 46.1 and 183 microg/ml, respectively. SPE significantly alleviates urodynamic symptoms in hyperactive rat bladders by increasing bladder capacity and subsequently prolonging the micturition interval. Our data may support the clinical efficacy of SPE for the treatment of lower urinary tract symptoms.

Polyphenois and Prostate Cancer Chemoprevention

DTIC Science & Technology

2006-03-01

The goal of this research is to investigate the potential of resveratrol genistein and (-) epigallocatechin -3- gallate ( EGCG ), alone in combination...to protect against prostate cancer in a transgenic rat model (TRAMP). The specific aims are 1) to investigate the potential of genistein, EGCG and...we have demonstrated that pure resveratrol in the diet, but not EGCG in the water, suppressed spontaneously developing prostate tumors in TRAMPs

Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects.

PubMed

Messaoudi, Michaël; Lalonde, Robert; Violle, Nicolas; Javelot, Hervé; Desor, Didier; Nejdi, Amine; Bisson, Jean-François; Rougeot, Catherine; Pichelin, Matthieu; Cazaubiel, Murielle; Cazaubiel, Jean-Marc

2011-03-01

In a previous clinical study, a probiotic formulation (PF) consisting of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) decreased stress-induced gastrointestinal discomfort. Emerging evidence of a role for gut microbiota on central nervous system functions therefore suggests that oral intake of probiotics may have beneficial consequences on mood and psychological distress. The aim of the present study was to investigate the anxiolytic-like activity of PF in rats, and its possible effects on anxiety, depression, stress and coping strategies in healthy human volunteers. In the preclinical study, rats were daily administered PF for 2 weeks and subsequently tested in the conditioned defensive burying test, a screening model for anti-anxiety agents. In the clinical trial, volunteers participated in a double-blind, placebo-controlled, randomised parallel group study with PF administered for 30 d and assessed with the Hopkins Symptom Checklist (HSCL-90), the Hospital Anxiety and Depression Scale (HADS), the Perceived Stress Scale, the Coping Checklist (CCL) and 24 h urinary free cortisol (UFC). Daily subchronic administration of PF significantly reduced anxiety-like behaviour in rats (P < 0·05) and alleviated psychological distress in volunteers, as measured particularly by the HSCL-90 scale (global severity index, P < 0·05; somatisation, P < 0·05; depression, P < 0·05; and anger-hostility, P < 0·05), the HADS (HADS global score, P < 0·05; and HADS-anxiety, P < 0·06), and by the CCL (problem solving, P < 0·05) and the UFC level (P < 0·05). L. helveticus R0052 and B. longum R0175 taken in combination display anxiolytic-like activity in rats and beneficial psychological effects in healthy human volunteers.

[Relationship between the changes in ischemia/reperfusion cerebro-microvessel basement membrane injury and gelatinase system in senile rat].

PubMed

Li, Jian-sheng; Liu, Ke; Liu, Jing-xia; Wang, Ming-hang; Zhao, Yue-wu; Liu, Zheng-guo

2008-11-01

To study the relationship of cerebro-microvessel basement membrane injury and gelatinase system after cerebral ischemia/reperfusion (I/R) in aged rats. Cerebral I/R injury model was reproduced by intraluminal silk ligature thrombosis of the middle cerebral artery occlusion (MCAO). Rats were divided randomly into sham control and I/R groups in young rats [ischemia 3 hours (I 3 h) and reperfusion 6 hours (I/R 6 h), 12 hours (I/R 12 h), 24 hours (I/R 24 h), 3 days (I/R 3 d), 6 days (I/R 6 d)], and sham control group and I/R group in aged rats (I 3 h and I/R 6 h, I/R 12 h, I/R 24 h , I/R 3 d, I/R 6 d). The change in cerebro-cortex microvessel basement membrane structure, basement membrane type IV collagen (Col IV) and laminin (LN) contents, matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) expression in every group were determined with immunohistochemical method and zymogram analysis. With the increase in age, Col IV and LN contents of the microvessel basement membrane were increased, and MMP-2 and MMP-9 expressions were stronger. With prolongation of I/R, the degradation of microvessel basement membrane components (Col IV and LN) was positively correlated with the duration of cerebral I/R. MMP-2 expression was increased gradually, and MMP-9 and TIMP-1 expression increased at the beginning and decreased subsequently. Col IV(I 3 h, I/R 6 h , I/R 12 h), LN (I 3 h, I/R 6-24 h), MMP-2 (I 3 h, I/R 6 h-6 d) and MMP-9 (I 3 h, I/R 6-24 h) expression level in aged rats with I/R injury were higher, and TIMP-1 (I/R 24 h) expression was lower than those in young rats (P<0.05 or P<0.01). In addition, changes in MMP-2 and MMP-9 contents as determined by zymogram analysis method coincided with their immunoexpression. With the increase of age, alteration in membrane components of cerebro-microvessel basement membrane in rats is related with MMPs and TIMP. Cerebro-microvessel basement membrane injury is more serious in aged rats than that of young rats

Inflammasomes are important mediators of prostatic inflammation associated with BPH.

PubMed

Kashyap, Mahendra; Pore, Subrata; Wang, Zhou; Gingrich, Jeffrey; Yoshimura, Naoki; Tyagi, Pradeep

2015-01-01

There is mounting evidence to support the role of inflammation in benign prostate hyperplasia (BPH), and a recent study reported expression of inflammasome derived cytokine IL-18 in prostate biopsy of BPH patients. Here we examined the expression of inflammasome-derived cytokines and activation of nucleotide-binding oligomerization domain-like receptor with pyrin domain protein 1 (NLRP) 1 inflammasome in a rat model of prostatic inflammation relevant to BPH. Prostatic inflammation was experimentally induced in three-month-old male Sprague-Dawley rats by intraprostatic injection (50 μL) of either 5 % formalin or saline (sham) into the ventral lobes of prostate. 7 days later, prostate and bladder tissue was harvested for analysis of inflammasome by Western blot, immunohistochemistry and downstream cytokine production by Milliplex. Expression of interleukins, CXC and CC chemokines were elevated 2-15 fold in formalin injected prostate relative to sham. Significant expression of NLRP1 inflammasome components and caspase-1 in prostate were associated with significant elevation of pro and cleaved forms of IL-1β (25.50 ± 1.16 vs 3.05 ± 0.65 pg/mg of protein) and IL-18 (1646.15 ± 182.61 vs 304.67 ± 103.95 pg/mg of protein). Relative to prostate tissue, the cytokine expression in bladder tissue was much lower and did not involve inflammasome activation. Significant upregulation of NLRP1, caspase-1 and downstream cytokines (IL-18 and IL-1β) suggests that a NLRP1 inflammasome is assembled and activated in prostate tissue of this rat model . Recapitulation of findings from human BPH specimens suggests that the inflammasome may perpetuate the inflammatory state associated with BPH. Further clarification of these pathways may offer innovative therapeutic targets for BPH-related inflammation.

OCT image segmentation of the prostate nerves

NASA Astrophysics Data System (ADS)

Chitchian, Shahab; Weldon, Thomas P.; Fried, Nathaniel M.

2009-08-01

The cavernous nerves course along the surface of the prostate and are responsible for erectile function. Improvements in identification, imaging, and visualization of the cavernous nerves during prostate cancer surgery may improve nerve preservation and postoperative sexual potency. In this study, 2-D OCT images of the rat prostate were segmented to differentiate the cavernous nerves from the prostate gland. Three image features were employed: Gabor filter, Daubechies wavelet, and Laws filter. The features were segmented using a nearestneighbor classifier. N-ary morphological post-processing was used to remove small voids. The cavernous nerves were differentiated from the prostate gland with a segmentation error rate of only 0.058 +/- 0.019.

Bone Marrow-derived Mesenchymal Stem Cells (MSCs) as a Selective Delivery Vehicle for a PSA-Activated Protoxin for Advanced Prostate Cancer

DTIC Science & Technology

2014-04-01

other groups are seeking to develop MSCs as vectors to deliver prostate - specific antigen (PSA)-activated prodrugs (Denmeade et al. 2003) and protoxins...Denmeade SR, Jakobsen CM, Janssen S, Khan SR, Garrett ES, Lilja H, Christensen SB & Isaacs JT 2003 Prostate - specific antigen -activated thapsigargin...cells derived from benign prostatic hyperplasia specimens possess stem cell like property. Prostate 67 1265–1276. (doi:10.1002/ pros .20599) Lin G, Yang R

N-Cadherin in Prostate Cancer: Downstream Pathways and Their Translational Application for Castrate-Resistant Prostate Cancer

DTIC Science & Technology

2012-09-01

with properties of stem cells. Cell 133, 704–715 (2008). 22. Mason , M.J., Fan, G ., Plath, K., Zhou, Q. & Horvath , S. Signed weighted gene co...An J, Horvath S, Gleave M, Rettig MB, Wainberg ZA, Reiter RE. Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis...N at u re A m er ic a, In c. A ll ri g h ts r es er ve d . A r t i c l e s nAture medicine VOLUME 16 | NUMBER 12 | DECEMBER 2010 1415 of in

ePCR: an R-package for survival and time-to-event prediction in advanced prostate cancer, applied to real-world patient cohorts.

PubMed

Laajala, Teemu D; Murtojärvi, Mika; Virkki, Arho; Aittokallio, Tero

2018-06-15

Prognostic models are widely used in clinical decision-making, such as risk stratification and tailoring treatment strategies, with the aim to improve patient outcomes while reducing overall healthcare costs. While prognostic models have been adopted into clinical use, benchmarking their performance has been difficult due to lack of open clinical datasets. The recent DREAM 9.5 Prostate Cancer Challenge carried out an extensive benchmarking of prognostic models for metastatic Castration-Resistant Prostate Cancer (mCRPC), based on multiple cohorts of open clinical trial data. We make available an open-source implementation of the top-performing model, ePCR, along with an extended toolbox for its further re-use and development, and demonstrate how to best apply the implemented model to real-world data cohorts of advanced prostate cancer patients. The open-source R-package ePCR and its reference documentation are available at the Central R Archive Network (CRAN): https://CRAN.R-project.org/package=ePCR. R-vignette provides step-by-step examples for the ePCR usage. Supplementary data are available at Bioinformatics online.

A Cancer-Indicative microRNA Pattern in Normal Prostate Tissue

PubMed Central

Hellwinkel, Olaf J. C.; Sellier, Christina; Sylvester, Yu-Mi Jessica; Brase, Jan C.; Isbarn, Hendrik; Erbersdobler, Andreas; Steuber, Thomas; Sültmann, Holger; Schlomm, Thorsten; Wagner, Christina

2013-01-01

We analyzed the levels of selected micro-RNAs in normal prostate tissue to assess their potential to indicate tumor foci elsewhere in the prostate. Histologically normal prostate tissue samples from 31 prostate cancer patients and two cancer negative control groups with either unsuspicious or elevated prostate specific antigen (PSA) levels (14 and 17 individuals, respectively) were analyzed. Based on the expression analysis of 157 microRNAs in a pool of prostate tissue samples and information from data bases/literature, we selected eight microRNAs for quantification by real-time polymerase chain reactions (RT-PCRs). Selected miRNAs were analyzed in histologically tumor-free biopsy samples from patients and healthy controls. We identified seven microRNAs (miR-124a, miR-146a & b, miR-185, miR-16 and let-7a & b), which displayed significant differential expression in normal prostate tissue from men with prostate cancer compared to both cancer negative control groups. Four microRNAs (miR-185, miR-16 and let-7a and let-7b) remained to significantly discriminate normal tissues from prostate cancer patients from those of the cancer negative control group with elevated PSA levels. The transcript levels of these microRNAs were highly indicative for the presence of cancer in the prostates, independently of the PSA level. Our results suggest a microRNA-pattern in histologically normal prostate tissue, indicating prostate cancer elsewhere in the organ. PMID:23459235

Impact of maternal and postnatal zinc dietary status on the prostate of pubescent and adult rats.

PubMed

Camora, Lucas F; Silva, Ana Priscila G; Santos, Sérgio A A; Justulin, Luis A; Perobelli, Juliana E; Barbisan, Luis Fernando; Scarano, Wellerson R

2017-11-01

Zinc is important for cell physiology and alteration of its levels during development can modulate a series of biological events. The aim of this study was to investigate whether dietary zinc deficiency or supplementation during morphogenesis and early postnatal development could interfere in prostate maturation. Pregnant rats were exposed to a standard diet (NZ:35 mg Zn/kg chow), low-zinc diet (LZ:3 mg of Zn/kg chow) and zinc-supplemented diet (HZ:180 mg/Kg chow) from gestational day 10 (GD10) through postnatal day 21 (PND21). After weaning, male offspring were divided into three groups that were submitted to the same food conditions as their mothers until PND53. The animals were euthanized at PND53 and PND115. The ventral prostate was removed, weighed and its fragments were subjected to histological, western blot and zymography analysis. PND53: body and prostate weight were lower in LZ compared to NZ; the epithelial compartment was reduced while the stromal compartment was increased in LZ compared to NZ; there was an increase in the amount of collagen and reduction in AR and SIRT1 expression in LZ compared to NZ. PND115: body weight was lower in LZ compared to NZ and prostate weight was similar among the groups; peripheral physiological hyperplasia was observed, as well as an increased epithelial proliferation index and reduced PAR4 expression in LZ and HZ compared to NZ. Zinc deficiency during prostate morphogenesis and differentiation is potentially harmful to its morphology, however, by restoring the standard dietary environment, the gland responds to the new microenvironment independent of the previous dietary condition. © 2017 International Federation for Cell Biology.

miR-130a activates apoptotic signaling through activation of caspase-8 in taxane-resistant prostate cancer cells.

PubMed

Fujita, Yasunori; Kojima, Toshio; Kawakami, Kyojiro; Mizutani, Kosuke; Kato, Taku; Deguchi, Takashi; Ito, Masafumi

2015-10-01

The acquisition of drug resistance is one of the most malignant phenotypes of cancer and identification of its therapeutic target is a prerequisite for the development of novel therapy. MicroRNAs (miRNAs) have been implicated in various types of cancer and proposed as potential therapeutic targets for patients. In the present study, we aimed to identify miRNA that could serve as a therapeutic target for taxane-resistant prostate cancer. In order to identify miRNAs related to taxane-resistance, miRNA profiling was performed using prostate cancer PC-3 cells and paclitaxel-resistant PC-3 cell lines established from PC-3 cells. Microarray analysis of mRNA expression was also conducted to search for potential target genes of miRNA. Luciferase reporter assay was performed to examine miRNA binding to the 3'-UTR of target genes. The effects of ectopic expression of miRNA on cell growth, tubulin polymerization, drug sensitivity, and apoptotic signaling pathway were investigated in a paclitaxel-resistant PC-3 cell line. The expression of miR-130a was down-regulated in all paclitaxel-resistant cell lines compared with parental PC-3 cells. Based on mRNA microarray analysis and luciferase reporter assay, we identified SLAIN1 as a direct target gene for miR-130a. Transfection of a miR-130a precursor into a paclitaxel-resistant cell line suppressed cell growth and increased the sensitivity to paclitaxel. Lastly, ectopic expression of miR-130a did not affect the polymerized tubulin level, but activated apoptotic signaling through activation of caspase-8. Our results suggested that reduced expression of miR-130a may be involved in the paclitaxel-resistance and that miR-130a could be a therapeutic target for taxane-resistant prostate cancer patients. © 2015 Wiley Periodicals, Inc.

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

PubMed

Joshi, Sangeeta; Nair, Neena; Bedwal, R S

2014-10-01

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.

Histamine H3 receptor antagonists display antischizophrenic activities in rats treated with MK-801.

PubMed

Mahmood, Danish; Akhtar, Mohd; Jahan, Kausar; Goswami, Dipanjan

2016-09-01

Animal models based on N-methyl-d-aspartate receptor blockade have been extensively used for schizophrenia. Ketamine and MK-801 produce behaviors related to schizophrenia and exacerbated symptoms in patients with schizophrenia, which led to the use of PCP (phencyclidine)- and MK-801 (dizocilpine)-treated animals as models for schizophrenia. The study investigated the effect of subchronic dosing (once daily, 7 days) of histamine H3 receptor (H3R) antagonists, ciproxifan (CPX) (3 mg/kg, i.p.), and clobenpropit (CBP) (15 mg/kg, i.p.) on MK-801 (0.2 mg/kg, i.p.)-induced locomotor activity and also measured dopamine and histamine levels in rat's brain homogenates. The study also included clozapine (CLZ) (3.0 mg/kg, i.p.) and chlorpromazine (CPZ) (3.0 mg/kg, i.p.), the atypical and typical antipsychotic, respectively. Atypical and typical antipsychotic was used to serve as clinically relevant reference agents to compare the effects of the H3R antagonists. MK-801 significantly increased horizontal locomotor activity, which was reduced with CPX and CBP. MK-801-induced locomotor hyperactivity attenuated by CPX and CBP was comparable to CLZ and CPZ. MK-801 raised striatal dopamine level, which was reduced in rats pretreated with CPX and CBP. CPZ also significantly lowered striatal dopamine levels, although the decrease was less robust compared to CLZ, CPX, and CBP. MK-801 increased histamine content although to a lesser degree. Subchronic treatment with CPX and CBP exhibited further increased histamine levels in the hypothalamus compared to MK-801 treatment alone. Histamine H3 receptor agonist, R-α methylhistamine (10 mg/kg, i.p.), counteracted the effect of CPX and CBP. The present study shows the positive effects of CPX and CBP on MK-801-induced schizophrenia-like behaviors in rodents.

miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1.

PubMed

Galardi, Silvia; Mercatelli, Neri; Giorda, Ezio; Massalini, Simone; Frajese, Giovanni Vanni; Ciafrè, Silvia Anna; Farace, Maria Giulia

2007-08-10

MicroRNAs are short regulatory RNAs that negatively modulate protein expression at a post-transcriptional level and are deeply involved in the pathogenesis of several types of cancers. Here we show that miR-221 and miR-222, encoded in tandem on chromosome X, are overexpressed in the PC3 cellular model of aggressive prostate carcinoma, as compared with LNCaP and 22Rv1 cell line models of slowly growing carcinomas. In all cell lines tested, we show an inverse relationship between the expression of miR-221 and miR-222 and the cell cycle inhibitor p27(Kip1). We recognize two target sites for the microRNAs in the 3' untranslated region of p27 mRNA, and we show that miR-221/222 ectopic overexpression directly results in p27 down-regulation in LNCaP cells. In those cells, we demonstrate that the ectopic overexpression of miR-221/222 strongly affects their growth potential by inducing a G(1) to S shift in the cell cycle and is sufficient to induce a powerful enhancement of their colony-forming potential in soft agar. Consistently, miR-221 and miR-222 knock-down through antisense LNA oligonucleotides increases p27(Kip1) in PC3 cells and strongly reduces their clonogenicity in vitro. Our results suggest that miR-221/222 can be regarded as a new family of oncogenes, directly targeting the tumor suppressor p27(Kip1), and that their overexpression might be one of the factors contributing to the oncogenesis and progression of prostate carcinoma through p27(Kip1) down-regulation.

miR-22 and miR-29a Are Members of the Androgen Receptor Cistrome Modulating LAMC1 and Mcl-1 in Prostate Cancer.

PubMed

Pasqualini, Lorenza; Bu, Huajie; Puhr, Martin; Narisu, Narisu; Rainer, Johannes; Schlick, Bettina; Schäfer, Georg; Angelova, Mihaela; Trajanoski, Zlatko; Börno, Stefan T; Schweiger, Michal R; Fuchsberger, Christian; Klocker, Helmut

2015-07-01

The normal prostate as well as early stages and advanced prostate cancer (PCa) require a functional androgen receptor (AR) for growth and survival. The recent discovery of microRNAs (miRNAs) as novel effector molecules of AR disclosed the existence of an intricate network between AR, miRNAs and downstream target genes. In this study DUCaP cells, characterized by high content of wild-type AR and robust AR transcriptional activity, were chosen as the main experimental model. By integrative analysis of chromatin immunoprecipitation-sequencing (ChIP-seq) and microarray expression profiling data, miRNAs putatively bound and significantly regulated by AR were identified. A direct AR regulation of miR-22, miR-29a, and miR-17-92 cluster along with their host genes was confirmed. Interestingly, endogenous levels of miR-22 and miR-29a were found to be reduced in PCa cells expressing AR. In primary tumor samples, miR-22 and miR-29a were less abundant in the cancerous tissue compared with the benign counterpart. This specific expression pattern was associated with a differential DNA methylation of the genomic AR binding sites. The identification of laminin gamma 1 (LAMC1) and myeloid cell leukemia 1 (MCL1) as direct targets of miR-22 and miR-29a, respectively, suggested a tumor-suppressive role of these miRNAs. Indeed, transfection of miRNA mimics in PCa cells induced apoptosis and diminished cell migration and viability. Collectively, these data provide additional information regarding the complex regulatory machinery that guides miRNAs activity in PCa, highlighting an important contribution of miRNAs in the AR signaling.

Intracellular pH regulation in rat round spermatids.

PubMed

Osses, N; Pancetti, F; Benos, D J; Reyes, J G

1997-07-01

Intracellular pH has been shown to be an important physiological parameter in cell cycle control and differentiation, aspects that are central to the spermatogenic process. However, the pH regulatory mechanisms in spermatogenic cells have not been systematically explored. In this work, measuring intracellular pH (pHi) with a fluorescent probe (BCECF), membrane potential with a fluorescent lipophilic anion (bisoxonol), and net movement of acid using a pH-stat system, we have found that rat round spermatids regulate pHi by means of a V-type H(+)-ATPase, a HCO3- entry pathway, a Na+/HCO3- dependent transport system, and a putative proton conductive pathway. Rat spermatids do not have functional base extruder transport systems. These pH regulatory characteristics seem specially designed to withstand acid challenges, and can generate sustained alkalinization upon acid exit stimulation.

Protein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth.

PubMed

Deng, X; Shao, G; Zhang, H-T; Li, C; Zhang, D; Cheng, L; Elzey, B D; Pili, R; Ratliff, T L; Huang, J; Hu, C-D

2017-03-02

Protein arginine methyltransferase 5 (PRMT5) is an emerging epigenetic enzyme that mainly represses transcription of target genes via symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3. Accumulating evidence suggests that PRMT5 may function as an oncogene to drive cancer cell growth by epigenetic inactivation of several tumor suppressors. Here, we provide evidence that PRMT5 promotes prostate cancer cell growth by epigenetically activating transcription of the androgen receptor (AR) in prostate cancer cells. Knockdown of PRMT5 or inhibition of PRMT5 by a specific inhibitor reduces the expression of AR and suppresses the growth of multiple AR-positive, but not AR-negative, prostate cancer cells. Significantly, knockdown of PRMT5 in AR-positive LNCaP cells completely suppresses the growth of xenograft tumors in mice. Molecular analysis reveals that PRMT5 binds to the proximal promoter region of the AR gene and contributes mainly to the enriched symmetric dimethylation of H4R3 in the same region. Mechanistically, PRMT5 is recruited to the AR promoter by its interaction with Sp1, the major transcription factor responsible for AR transcription, and forms a complex with Brg1, an ATP-dependent chromatin remodeler, on the proximal promoter region of the AR gene. Furthermore, PRMT5 expression in prostate cancer tissues is significantly higher than that in benign prostatic hyperplasia tissues, and PRMT5 expression correlates positively with AR expression at both the protein and mRNA levels. Taken together, our results identify PRMT5 as a novel epigenetic activator of AR in prostate cancer. Given that inhibiting AR transcriptional activity or androgen synthesis remains the major mechanism of action for most existing anti-androgen agents, our findings also raise an interesting possibility that targeting PRMT5 may represent a novel approach for prostate cancer treatment by eliminating AR expression.

The selective 5-hydroxytryptamine 1A antagonist, AZD7371 [3(R)-(N,N-dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide (R,R)-tartrate monohydrate] (robalzotan tartrate monohydrate), inhibits visceral pain-related visceromotor, but not autonomic cardiovascular, responses to colorectal distension in rats.

PubMed

Lindström, E; Ravnefjord, A; Brusberg, M; Hjorth, S; Larsson, H; Martinez, V

2009-06-01

5-Hydroxytryptamine 1A (5-HT(1A)) receptors have been suggested as a target for the treatment of irritable bowel syndrome (IBS). A recent clinical trial investigating the efficacy of the selective 5-HT(1A) antagonist AZD7371 [3(R)-(N,N-dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide (R,R)-tartrate monohydrate] showed no symptomatic improvement in IBS patients. We characterized the mechanisms mediating potential analgesic effects of AZD7371 in a model of colorectal distension (CRD)-induced visceral pain in rats to understand its mechanism of action and the lack of clinical efficacy. Visceromotor and cardiovascular responses (telemetry) were assessed in conscious rats during noxious CRD (80 mm Hg). Effects of AZD7371 (3-300 nmol/kg i.v.; 1-30 micromol/kg p.o.) and a reference 5-HT(1A) antagonist, WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide maleate salt; 3-300 nmol/kg i.v.), were assessed. Effects of intracerebroventricular AZD7371 were also evaluated. Intravenous AZD7371 or WAY-100635 and oral AZD7371 dose-dependently inhibited visceromotor responses to CRD (ED(50), 203, 231, and 14 micromol/kg, respectively). In telemetrized rats, oral AZD7371 inhibited visceromotor responses to CRD without affecting the concomitant hypertensive and tachycardic responses. Intracerebroventricular AZD7371 did not affect visceromotor responses, whereas it inhibited micturition. None of the doses tested induced visible gross side effects. AZD7371, likely acting at a spinal site, inhibited the visceromotor but not the cardiovascular responses to visceral pain in the CRD model in rats. Although agents effective on multiple pain-related readouts in the CRD model (e.g., pregabalin or clonidine) alleviate IBS symptoms, AZD7371, which is effective on only one pain-related pseudoaffective readout, does not. Data from preclinical CRD models of visceral pain need to be interpreted cautiously as it relates to their clinical

Deregulation of an imprinted gene network in prostate cancer

PubMed Central

Ribarska, Teodora; Goering, Wolfgang; Droop, Johanna; Bastian, Klaus-Marius; Ingenwerth, Marc; Schulz, Wolfgang A

2014-01-01

Multiple epigenetic alterations contribute to prostate cancer progression by deregulating gene expression. Epigenetic mechanisms, especially differential DNA methylation at imprinting control regions (termed DMRs), normally ensure the exclusive expression of imprinted genes from one specific parental allele. We therefore wondered to which extent imprinted genes become deregulated in prostate cancer and, if so, whether deregulation is due to altered DNA methylation at DMRs. Therefore, we selected presumptive deregulated imprinted genes from a previously conducted in silico analysis and from the literature and analyzed their expression in prostate cancer tissues by qRT-PCR. We found significantly diminished expression of PLAGL1/ZAC1, MEG3, NDN, CDKN1C, IGF2, and H19, while LIT1 was significantly overexpressed. The PPP1R9A gene, which is imprinted in selected tissues only, was strongly overexpressed, but was expressed biallelically in benign and cancerous prostatic tissues. Expression of many of these genes was strongly correlated, suggesting co-regulation, as in an imprinted gene network (IGN) reported in mice. Deregulation of the network genes also correlated with EZH2 and HOXC6 overexpression. Pyrosequencing analysis of all relevant DMRs revealed generally stable DNA methylation between benign and cancerous prostatic tissues, but frequent hypo- and hyper-methylation was observed at the H19 DMR in both benign and cancerous tissues. Re-expression of the ZAC1 transcription factor induced H19, CDKN1C and IGF2, supporting its function as a nodal regulator of the IGN. Our results indicate that a group of imprinted genes are coordinately deregulated in prostate cancers, independently of DNA methylation changes. PMID:24513574

Deregulation of an imprinted gene network in prostate cancer.

PubMed

Ribarska, Teodora; Goering, Wolfgang; Droop, Johanna; Bastian, Klaus-Marius; Ingenwerth, Marc; Schulz, Wolfgang A

2014-05-01

Multiple epigenetic alterations contribute to prostate cancer progression by deregulating gene expression. Epigenetic mechanisms, especially differential DNA methylation at imprinting control regions (termed DMRs), normally ensure the exclusive expression of imprinted genes from one specific parental allele. We therefore wondered to which extent imprinted genes become deregulated in prostate cancer and, if so, whether deregulation is due to altered DNA methylation at DMRs. Therefore, we selected presumptive deregulated imprinted genes from a previously conducted in silico analysis and from the literature and analyzed their expression in prostate cancer tissues by qRT-PCR. We found significantly diminished expression of PLAGL1/ZAC1, MEG3, NDN, CDKN1C, IGF2, and H19, while LIT1 was significantly overexpressed. The PPP1R9A gene, which is imprinted in selected tissues only, was strongly overexpressed, but was expressed biallelically in benign and cancerous prostatic tissues. Expression of many of these genes was strongly correlated, suggesting co-regulation, as in an imprinted gene network (IGN) reported in mice. Deregulation of the network genes also correlated with EZH2 and HOXC6 overexpression. Pyrosequencing analysis of all relevant DMRs revealed generally stable DNA methylation between benign and cancerous prostatic tissues, but frequent hypo- and hyper-methylation was observed at the H19 DMR in both benign and cancerous tissues. Re-expression of the ZAC1 transcription factor induced H19, CDKN1C and IGF2, supporting its function as a nodal regulator of the IGN. Our results indicate that a group of imprinted genes are coordinately deregulated in prostate cancers, independently of DNA methylation changes.

Extra-prostatic Transgene-associated Neoplastic Lesions in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) Mice

PubMed Central

Berman-Booty, Lisa D.; Thomas-Ahner, Jennifer M.; Bolon, Brad; Oglesbee, Michael J.; Clinton, Steven K.; Kulp, Samuel K.; Chen, Ching-Shih; La Perle, Krista

2014-01-01

Male transgenic adenocarcinoma of the mouse prostate (TRAMP) mice are frequently used in prostate cancer research because their prostates consistently develop a series of pre-neoplastic and neoplastic lesions. Disease progression in TRAMP mouse prostates culminates in metastatic, poorly differentiated carcinomas with neuroendocrine features. The androgen dependence of the rat probasin promoter largely limits transgene expression to the prostatic epithelium. However, extra-prostatic transgene-positive lesions have been described in TRAMP mice, including renal tubulo-acinar carcinomas, neuroendocrine carcinomas of the urethra, and phyllodes-like tumors of the seminal vesicle. Here we describe the histologic and immunohistochemical features of two novel extra-prostatic lesions in TRAMP mice: primary anaplastic tumors of uncertain cell origin in the midbrain, and poorly differentiated adenocarcinomas of the submandibular salivary gland. These newly characterized tumors apparently result from transgene expression in extra-prostatic locations rather than representing metastatic prostate neoplasms because lesions were identified in both male and female mice as well as in male TRAMP mice without histologically apparent prostate tumors. In this paper we also calculate the incidences of the urethral carcinomas and renal tubulo-acinar carcinomas, further elucidate the biological behavior of the urethral carcinomas, and demonstrate the critical importance of complete necropsies even when evaluating presumably well characterized phenotypes in genetically engineered mice. PMID:24742627

Extra-prostatic transgene-associated neoplastic lesions in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice.

PubMed

Berman-Booty, Lisa D; Thomas-Ahner, Jennifer M; Bolon, Brad; Oglesbee, Michael J; Clinton, Steven K; Kulp, Samuel K; Chen, Ching-Shih; La Perle, Krista M D

2015-02-01

Male transgenic adenocarcinoma of the mouse prostate (TRAMP) mice are frequently used in prostate cancer research because their prostates consistently develop a series of preneoplastic and neoplastic lesions. Disease progression in TRAMP mouse prostates culminates in metastatic, poorly differentiated carcinomas with neuroendocrine features. The androgen dependence of the rat probasin promoter largely limits transgene expression to the prostatic epithelium. However, extra-prostatic transgene-positive lesions have been described in TRAMP mice, including renal tubuloacinar carcinomas, neuroendocrine carcinomas of the urethra, and phyllodes-like tumors of the seminal vesicle. Here, we describe the histologic and immunohistochemical features of 2 novel extra-prostatic lesions in TRAMP mice: primary anaplastic tumors of uncertain cell origin in the midbrain and poorly differentiated adenocarcinomas of the submandibular salivary gland. These newly characterized tumors apparently result from transgene expression in extra-prostatic locations rather than representing metastatic prostate neoplasms because lesions were identified in both male and female mice and in male TRAMP mice without histologically apparent prostate tumors. In this article, we also calculate the incidences of the urethral carcinomas and renal tubuloacinar carcinomas, further elucidate the biological behavior of the urethral carcinomas, and demonstrate the critical importance of complete necropsies even when evaluating presumably well characterized phenotypes in genetically engineered mice. © 2014 by The Author(s).

Elevated insulin and reduced insulin like growth factor binding protein-3/prostate specific antigen ratio with increase in prostate size in Benign Prostatic Hyperplasia.

PubMed

Sreenivasulu, Karli; Nandeesha, Hanumanthappa; Dorairajan, Lalgudi Narayanan; Rajappa, Medha; Vinayagam, Vickneshwaran

2017-06-01

Insulin and insulin like growth factor-1 (IGF-1) have growth promoting effects, while insulin like growth factor binding protein-3 (IGFBP-3) has growth inhibitory effects. The present study was designed to assess the concentrations of insulin, IGF-1, IGFBP-3 and their association with prostate size in patients with BPH. Ninety 90 BPH cases and 90 controls were enrolled in the study. Insulin, IGF-1, IGFBP-3, PSA, testosterone and estradiol were estimated in both the groups. Insulin, IGF-1 and estradiol were increased and IGFBP-3/PSA was decreased in BPH cases when compared with controls. Insulin (r=0.64, p=0.001) and IGF-1 (r=0.22, p=0.03) were positively correlated and IGFBP-3/PSA (r=-0.316, p=0.002) were negatively correlated with prostate size in BPH. Multivariate analysis showed that insulin (p=0.001) and IGFBP-3/PSA (p=0.004) predicts the prostate size in patients with BPH. Insulin was increased and IGFBP-3/PSA was reduced in BPH patients with increased prostate size. At a cutoff concentration of 527.52, IGFBP-3/PSA ratio was found to differentiate benign growth of prostate from normal prostate with 96% sensitivity and 96% specificity. Insulin is elevated and IGFBP-3/PSA is reduced with increase prostate size in BPH cases. Copyright © 2017 Elsevier B.V. All rights reserved.

The anti-hyperplasia, anti-oxidative and anti-inflammatory properties of Qing Ye Dan and swertiamarin in testosterone-induced benign prostatic hyperplasia in rats.

PubMed

Wu, Xinying; Gu, Ye; Li, Lun

2017-01-04

Qing Ye Dan (QYD) is the whole plant of Swertia mileensis and used in Chinese folk medicine for the treatment of prostatitis, benign prostatic hyperplasia (BPH) and so on. This study was to investigate the effects of QYD and its main component swertiamarin on BPH induced by testosterone in rats. The prostatic expressions of vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), basic fibroblast growth factor (βFGF) and proliferating cell nuclear antigen (PCNA) were detected by immunohistochemistry assay. Prostatic levels of oxidative stress and inflammatory-related factors were also analyzed. Additionally, the prostatic expressions of androgen receptor (AR), estrogen receptor (ER)-α, ER-β, hypoxia-inducible factor (HIF)-1α, B-cell CLL/lymphoma (Bcl)-2 and Bcl-2-associated X protein (Bax) were measured by western blot. The epithelial-mesenchymal transition (EMT) associated factors were evaluated by quantitative RT-PCR. It showed that QYD and swertiamarin ameliorated the testosterone-induced prostatic hyperplasia and collagen deposition, attenuated the over-expressions of HIF-1α, VEGF, EGF, βFGF, PCNA, AR and ER-α, reduced the ratio of Bcl-2/Bax, enhanced the expression of ER-β, inhibited the oxidative stress and local inflammation, as well as relieved prostatic EMT. It suggested that QYD and swertiamarin had prostatic protective potential against BPH. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Visualization of prostatic nerves by polarization-sensitive optical coherence tomography

PubMed Central

Yoon, Yeoreum; Jeon, Seung Hwan; Park, Yong Hyun; Jang, Won Hyuk; Lee, Ji Youl; Kim, Ki Hean

2016-01-01

Preservation of prostatic nerves is critical to recovery of a man’s sexual potency after radical prostatectomy. A real-time imaging method of prostatic nerves will be helpful for nerve-sparing radical prostatectomy (NSRP). Polarization-sensitive optical coherence tomography (PS-OCT), which provides both structural and birefringent information of tissue, was applied for detection of prostatic nerves in both rat and human prostate specimens, ex vivo. PS-OCT imaging of rat prostate specimens visualized highly scattering and birefringent fibrous structures superficially, and these birefringent structures were confirmed to be nerves by histology or multiphoton microscopy (MPM). PS-OCT could easily distinguish these birefringent structures from surrounding other tissue compartments such as prostatic glands and fats. PS-OCT imaging of human prostatectomy specimens visualized two different birefringent structures, appearing fibrous and sheet-like. The fibrous ones were confirmed to be nerves by histology, and the sheet-like ones were considered to be fascias surrounding the human prostate. PS-OCT imaging of human prostatectomy specimens along the perimeter showed spatial variation in the amount of birefringent fibrous structures which was consistent with anatomy. These results demonstrate the feasibility of PS-OCT for detection of prostatic nerves, and this study will provide a basis for intraoperative use of PS-OCT. PMID:27699090

NPS R-568 halts or reverses osteitis fibrosa in uremic rats.

PubMed

Wada, M; Ishii, H; Furuya, Y; Fox, J; Nemeth, E F; Nagano, N

1998-02-01

Osteitis fibrosa is a common bone injury associated with secondary hyperparathyroidism (2(o)HPT). NPS R-568 is a phenylalkylamine derivative that acts as an agonist at the cell-surface Ca2+ receptor ("calcimimetic") and inhibits parathyroid hormone (PTH) secretion. In the present study, we tested whether NPS R-568 could ameliorate osteitis fibrosa in partially nephrectomized (Nx) rats with 2(o)HPT. Six months after surgery, Nx rats had developed mild but progressive 2(o)HPT and osteitis fibrosa. Two groups of Nx rats received NPS R-568 (3 and 30 mg/kg body wt x day) by daily gavage for 30 days, which led to a dose-related decrease in serum PTH levels and to a marked reduction in peritrabecular fibrosis (0.96 +/- 0.49% to < 0.1%). Furthermore, 2(o)HPT was associated with decreases in volumetric cortical bone mineral density (vCtBMD) and in cortical bone stiffness at the femoral midshaft. NPS R-568 significantly restored the deficits in vCtBMD and stiffness. These results indicate that NPS R-568 has beneficial effects on bones with osteitis fibrosa by normalizing serum PTH levels.

Aberrant expression of miR-141 and nuclear receptor small heterodimer partner in clinical samples of prostate cancer.

PubMed

Khorasani, Maryam; Teimoori-Toolabi, Ladan; Farivar, Taghi Naserpour; Asgari, Mojgan; Abolhasani, Maryam; Shahrokh, Hossein; Afgar, Ali; Kalantari, Elham; Peymani, Amir; Mahdian, Reza

2018-01-01

Prostate cancer (PCa) is the second most common cancer in men worldwide. Currently, prostate-specific antigen (PSA) test and digital rectal exam are the main screening tests used for PCa diagnosis. However, due to the low specificity of these tests, new alternative biomarkers such as deregulated RNAs and microRNAs have been implemented. Aberrant expressions of small heterodimer partner gene (SHP, NR0B2) and mir-141 are reported in various cancers. The aim of this study was to investigate the SHP and miR-141 expression level in tissue samples of prostate cancer. The expression level of SHP gene and miR-141 was assessed by real time PCR and their relative amounts were calculated by the Δ⁢ΔCT method. Also, IHC technique was used to determine the expression level of SHP protein. The miR-141 was significantly up-regulated in the samples of metastatic tumors compared to localized tumor samples (P< 0.001, 31.17-fold change). Tumor samples showed lower SHP mRNA expression levels than BPH samples (p= 0.014, 4.7-fold change). The results of paired t-test analysis showed there was no significant difference between the SHP gene expression in PCa samples and their matched tumor-adjacent normal tissue (p= 0.5). The data obtained in our study confirm the involvement of miR-141 in PCa progression and metastasis. These effects could be mediated by AR via down-regulation of its co-repressor protein, i.e., SHP.

Gene Expression in Single Cells Isolated from the CWR-R1 Prostate Cancer Cell Line and Human Prostate Tissue Based on the Side Population Phenotype.

PubMed

Gangavarapu, Kalyan J; Miller, Austin; Huss, Wendy J

2016-09-01

Defining biological signals at the single cell level can identify cancer initiating driver mutations. Techniques to isolate single cells such as microfluidics sorting and magnetic capturing systems have limitations such as: high cost, labor intense, and the requirement of a large number of cells. Therefore, the goal of our current study is to identify a cost and labor effective, reliable, and reproducible technique that allows single cell isolation for analysis to promote regular laboratory use, including standard reverse transcription PCR (RT-PCR). In the current study, we utilized single prostate cells isolated from the CWR-R1 prostate cancer cell line and human prostate clinical specimens, based on the ATP binding cassette (ABC) transporter efflux of dye cycle violet (DCV), side population assay. Expression of four genes: ABCG2; Aldehyde dehydrogenase1A1 (ALDH1A1); androgen receptor (AR); and embryonic stem cell marker, Oct-4, were determined. Results from the current study in the CWR-R1 cell line showed ABCG2 and ALDH1A1 gene expression in 67% of single side population cells and in 17% or 100% of non-side population cells respectively. Studies using single cells isolated from clinical specimens showed that the Oct-4 gene is detected in only 22% of single side population cells and in 78% of single non-side population cells. Whereas, AR gene expression is in 100% single side population and non-side population cells isolated from the same human prostate clinical specimen. These studies show that performing RT-PCR on single cells isolated by FACS can be successfully conducted to determine gene expression in single cells from cell lines and enzymatically digested tissue. While these studies provide a simple yes/no expression readout, the more sensitive quantitative RT-PCR would be able to provide even more information if necessary.

Gene Expression in Single Cells Isolated from the CWR-R1 Prostate Cancer Cell Line and Human Prostate Tissue Based on the Side Population Phenotype

PubMed Central

Gangavarapu, Kalyan J; Miller, Austin; Huss, Wendy J