Testosterone regulates the intracellular bacterial community formation of uropathogenic Escherichia coli in prostate cells via STAT3.

BACKGROUND: UPEC can internalize clonally in prostate to form biofilm-like intracellular bacterial communities (IBCs) for recurrent or chronic infection. We previously indicated that the exposure of prostate cells to testosterone could suppress UPEC invasion and their persistent survival within cells by effectively inhibiting the JAK/STAT1 signaling pathway. However, the regulatory mechanism by which testosterone affects UPEC-induced prostatitis via STAT3, another latent transcription factor signaling pathway is still unclear. The present study aimed to clarify the role of STAT3 in the process of UPEC-induced inflammation and colonization in prostate epithelial cells. METHODS: The effects of testosterone-mediated inhibition were compared between the prostatitis by different UPEC strains (CFT073 and J96) through the specific GFP-UPEC-infected prostate cell model. Fluorescence microscopy was used for UPEC IBCs detection and quantifying, and Flow cytometry, RT-PCR and western blotting were used for analyzing related gene and protein expressions. Pretreatment of JAK and STAT3 inhibitors were also applied to verify the regulation of transduction pathway in testosterone-mediated anti-UPEC infection. RESULTS: This study revealed that testosterone effectively suppresses UPEC infection and IBC formation in prostate cells through the JAK/STAT3 pathway. The results show that CFT073 and J96 UPEC infection rates and colony numbers were dose-dependently reduced in RWPE-1 cells pretreated with 5 and 20 µg/mL testosterone at 0 and 24 h post-infection. Further, testosterone reduced the amounts of UPEC infecting and surviving within the prostate cells, as well as suppressed the size of IBCs formed. We demonstrated that pretreating testosterone effectively inhibited UPEC infection along with dose-dependent suppression of STAT3 and the phosphorylated-STAT3 expression in prostate cells, especially in 24 h J96 UPEC infected groups. The STAT inhibitor, SOCS3 also up-regulated at the same time. In addition, we pretreated the JAK1 or STAT3 inhibitor with testosterone to block the signaling transduction before CFT073 and J96 UPEC infection, and found the significant restoring in both the sizes of IBCs and bacterial numbers in RWPE-1 cells. Therefore, our results suggest that the suppression of STAT3 by testosterone treatment attenuate UPEC growing within IBCs and interfere with their infection to prostate cells. CONCLUSIONS: Overall, our study demonstrates that testosterone suppresses the initial infection of prostate epithelial cells by UPEC and reduces the survival of UPEC within IBCs after infection. These results indicate a critical role for STAT3 in facilitating UPEC infection and persistence, and its participation in driving testosterone-suppressive responses in prostate epithelial cells. In conclusion, this study suggests that testosterone may be beneficial in treating clinically recurrent UPEC infections and, thus, the persistent recurrence of prostatic inflammation.

l-Theanine inhibits proinflammatory PKC/ERK/ICAM-1/IL-33 signaling, apoptosis, and autophagy formation in substance P-induced hyperactive bladder in rats.

AIMS: Upregulation of substance P (SP) and neurokinin-1 receptor (NK1R) activation induces pro-inflammatory bladder hyperactivity through the PKC/ERK/NF-κB/ICAM-1/IL-33 signaling pathways to increase the leukocyte infiltration and adhesion leading to reactive oxygen species (ROS) production, autophagy, and apoptosis. l-Theanine is a unique non-protein-forming amino acid present in tea (Camellia sinensis [L.] O. Kuntze) with its antioxidant, anti-inflammatory, and relaxation effects to improve cognition, mood, gastric ulcer injury, and cerebral ischemia/reperfusion injury, and posttraumatic stress disorder. We explored the protective effect of l-theanine on SP-induced bladder hyperactivity. METHODS: In urethane-anesthetized female Wistar rats, we explored the transcystometrogram, pelvic nerve activity, proinflammatory PKC/ERK/NF-κB/ICAM-1/IL-33 signaling, apoptosis-related Caspase 3/poly-(ADP-ribose)-polymerase (PARP), and autophagy-mediated LC3 II expression by Western blot, electrophoretic-mobility shift assay and immunohistochemistry, bladder ROS amount by a ultrasensitive chemiluminescence method, and possible ROS sources from the different leukocytes by specific stains in SP-evoked hyperactive bladder. RESULTS: l-Theanine dose-dependently depressed H2 O2 and HOCl activity in vitro. In urethane-anesthetized female Wistar rats, intra-arterial SP through NK1R activation increased voiding frequency (shortened intercontraction intervals) associated with the increase in bladder nerve activity, proinflammatory PKC/ERK/NF-κB/ICAM-1/IL-33 signaling, Caspase 3/PARP-mediated apoptosis, LC3 II-mediated autophagy, ROS amount, neutrophils adhesion, CD68 (monocyte/macrophage) infiltration, and mast cells degranulation in the hyperactive bladder. Intragastrical l-theanine (15 mg/kg) twice daily for 2 weeks efficiently ameliorated all the enhanced parameters in the SP-treated hyperactive bladder. CONCLUSIONS: In conclusion, l-theanine through antioxidant and anti-inflammatory actions ameliorates SP-induced bladder hyperactivity via the inhibition of proinflammatory PKC/ERK/NF-κB/ICAM-1/IL-33 signaling, oxidative stress, bladder nerve hyperactivity, apoptosis, and autophagy. Neurourol. Urodynam. 36:297-307, 2017. © 2016 Wiley Periodicals, Inc.

Testosterone Threshold for Increased Cardiovascular Risk in Middle-Aged and Elderly Men: A Locally Weighted Regression Analysis.

INTRODUCTION: Although testosterone deficiency has a well-known association with increased risk of cardiovascular disease (CVD), the threshold remains to be determined. AIM: To investigate whether there is a discriminatory testosterone level below which the CVD risk increases. METHODS: The study included 876 men 45 to 74 years old who underwent a general health checkup. The Framingham Risk Score was used to estimate the 10-year CVD risk; a high-sensitivity C-reactive protein (hsCRP) level of at least 1 mg/L was considered an indicator of increased CVD risk. Aging symptoms and sexual function were evaluated with the Aging Males' Symptom Scale. MAIN OUTCOME MEASURES: Locally weighted regression was performed to determine the testosterone threshold for Framingham CVD risk and increased hsCRP. RESULTS: The mean age was 56.6 ± 7.0 years. The mean total testosterone level was 394.3 ± 115.7 ng/dL. The mean 10-year Framingham CVD risk was 16.6 ± 10.7%, and 169 (19.3%) had increased hsCRP. The locally weighted regression showed that total testosterone levels of 440 and 480 ng/dL were associated with increased Framingham CVD risk and an increased probability of increased hsCRP, respectively. Men with sexual dysfunction (poor sexual performance, decreased morning erection, and loss of libido) had significantly greater CVD risk. Their risk appeared to increase at a relatively higher testosterone level, and it reached a plateau at a testosterone level of 300 to 350 ng/dL. In contrast, the risk in those with no or less sexual dysfunction remained low at a higher testosterone level, and a threshold level of 425 to 475 ng/dL was associated with increased CVD risk. A similar pattern and threshold were identified in the analyses of the relation between testosterone and hsCRP. CONCLUSION: These data showed that a testosterone threshold of 440 ng/dL was associated with increased Framingham 10-year CVD risk in middle-aged and elderly men. Poor sexual performance, decreased morning erection, and loss of libido had an impact on the testosterone threshold for CVD risk. The threshold level was higher in men with sexual dysfunction. Further study is required to evaluate the validity of these testosterone thresholds for CVD risk.

Erectile dysfunction, loss of libido and low sexual frequency increase the risk of cardiovascular disease in men with low testosterone.

INTRODUCTION: Testosterone deficiency increases the cardiovascular disease (CVD) risk. AIM: To evaluate the effect of erectile dysfunction (ED), sexual frequency and hypogonadal symptoms on CVD risk. METHODS: A total of 395 hypogonadal men aged 45-74 years were surveyed using the Androgen Deficiency in the Aging Male and the International Index of Erectile Function. MAIN OUTCOME MEASURES: The 10-year CVD risk was measured with the Framingham Risk Score. Logistic regression was performed to obtain the odds ratios of sexual function and hypogonadal symptoms for a 10-year CVD risk ≥20% (high risk). RESULTS: The mean age was 56.1 ± 6.7 years. The mean 10-year CVD risk of the whole cohort was 18.1% ± 11.4%, while 131 subjects (33.2%) were classified as high risk. Logistic regression revealed that ED severity was associated with CVD risk [OR = 2.37 (CI 1.24-4.51) for mild-to-moderate ED, OR = 4.39 (1.78-8.43) for moderate ED and OR = 12.81 (4.65-26.11) for severe ED]. Compared to sexual frequency <1 per month, sexual frequency ≥4 decreased the risk of high CVD risk [OR = 0.35 (0.23-0.780)]. Loss of libido [OR = 2.95 (1.91-4.12)] and less strong erection [OR = 3.87 (CI 2.11-4.95)] increased the risk of high CVD risk. All remained significant after adjustment for age and testosterone. CONCLUSIONS: ED, decreased sexual frequency and loss of libido predict a high 10-year CVD risk in hypogonadal men.

The prevalence and the risk factors of testosterone deficiency in newly diagnosed and previously known type 2 diabetic men.

INTRODUCTION: While the epidemiology of testosterone deficiency has been well described in men with previously known type 2 diabetes mellitus (T2DM), it was less reported in those with untreated, newly diagnosed T2DM. AIM: The aim of this study was to investigate the prevalence and the risk factors of testosterone deficiency of men with newly diagnosed T2DM. METHODS: The cross-sectional study included 105 men (mean age: 61.2 ± 6.8 years) with previously known T2DM and another 81 (57.8 ± 8.8 years) with newly diagnosed T2DM. All received health checkup and sex hormone measurement at our institute in 2009. MAIN OUTCOME MEASURES: We calculated the prevalence and explored the risk factors of low total (<300 ng/dL) and free (<6 ng/dL) testosterone in men with newly diagnosed and previously known T2DM. RESULTS: Men with previously known T2DM were older and had higher diastolic pressure and greater fasting glucose. There was no significant difference in total (358.0 [155.0] ng/dL vs. 363.0 [154.0] ng/dL, P=0.68) and free (7.2 [2.5] ng/dL vs. 7.4 [2.4]ng/dL, P=0.84) testosterone and sex-hormone binding globulin (SHBG) (27.3 [22.3]nmol/L vs. 28.7 [14.9]nmol/L, P=0.46). The prevalence of low total and free testosterone was 28.4% and 21.0%, respectively, in men with newly diagnosed T2DM, and was 26.7% and 19.0% in those with previously known T2DM. In men with previously known T2DM, better glycemic control (HbA1c <7%) was associated with a higher level of total testosterone and a lower risk of low total testosterone. Men with newly diagnosed and previously known T2DM shared similar risk factors of low total testosterone, including high HbA1c (≥ 7%), low SHBG (<20 nmol/L), obesity, hyperuricemia, hypertriglycemia, and metabolic syndrome. Elevated prostate-specific antigen was a protective factor of low total testosterone. However, none of these factors was associated with low free testosterone. CONCLUSIONS: The prevalence and the risk factors of testosterone deficiency are similar between newly diagnosed and previously known type 2 diabetic men.

Alterations in peripheral purinergic and muscarinic signaling of rat bladder after long-term fructose-induced metabolic syndrome.

PURPOSE: We explored the pathophysiologic mechanisms of long-term fructose-induced lower urinary tract symptoms (LUTS) in rats. METHODS: Male Wistar rats were fed with fructose for 3 or 6 months. Biochemical and transcystometric parameters were compared between fructose-fed and age-matched normal-diet rats. Pelvic nerve and external urethral sphincter-electromyogram activity recordings were performed to investigate fructose effects on neural control of bladders. Mitochondrial structure, ATP and acetylcholine content and purinergic and muscarinic cholinergic receptors were examined. Cytosolic cytochrome C staining by Western blot and immunocytochemistry for mitochondrial injury and PGP 9.5 stain for nerve density were also determined. RESULTS: The fructose-fed rats with higher plasma triglyceride, LDL and fasting glucose levels displayed LUTS with increased frequency and suppressed voiding contractile amplitude in phase 1 and phase 2 duration versus normal-diet control. Fructose feeding altered the firing types in pelvic afferent and efferent nerves and external urethral sphincter-electromyogram activity. Increased mast cell number, disrupted and swollen mitochondria, increased cytosolic cytochrome C stain and expression and decreased nerve density in bladder smooth muscle layers appeared in the fructose-fed rats. Fructose feeding also significantly reduced ATP and acetylcholine content and enhanced protein expression of postsynaptic P(2)X(1), P(2)X(2) and P(2)X(3) purinergic receptors and M(2) and M(3) muscarinic cholinergic receptors expression in the smooth muscles of urinary bladder. CONCLUSION: Long-term fructose feeding induced neuropathy and myopathy in the urinary bladders. Impaired mitochondrial integrity, reduced nerve density, ATP and acetylcholine content and upregulation of purinergic and muscarinic cholinergic receptors expression may contribute to the bladder dysfunction of fructose-fed animals.

Clear cell carcinoma of female urethral diverticulum--a case report.

Primary malignancies of female urethral diverticulum are rare. A well-documented female patient with primary clear cell carcinoma of the urethral diverticulum is presented here. A 65-year-old woman presented with frequency and voiding difficulty for 2 months. Physical examination showed a 4-cm mass protruding from anterior vaginal wall. Intravenous urography, magnetic resonance imaging, and cystoscopy showed a polypoid mass in urethral diverticulum. She then underwent anterior exenteration with ileal conduit diversion and urethrectomy. Pathology confirmed the diagnosis of clear cell adenocarcinoma with bladder neck invasion. She had no disease recurrence at 2-year follow-up. Careful clinical examination and image studies are helpful in making the preoperative diagnosis for the rare disease. Early radical surgery can achieve better survival.

Quinolone prophylaxis in transrectal ultrasound guided prostate biopsy: an eight-year single center experience.

We retrospectively evaluated the efficacy of prophylaxis with pipemidic acid and levofloxacin in transrectal ultrasound guided prostate biopsy (TRUSP-Bx). From January 2002 to December 2004, patients receiving oral pipemidic acid 500 mg twice daily for three days with or without a preoperative intravenous cefazolin 1 gm injection comprised group A. Between January 2005 and December 2009, patients receiving oral levofloxacin 500 mg one hour before biopsy comprised group B. We calculated the annual febrile urinary tract infection (fUTI) rates. Patients' characteristics, including age, prophylactic antibiotics, biopsy core numbers, pathologic results, PSA, and the spectrums and susceptibility of pathogens, were also evaluated. A total of 1313 (35.5%) patients belonged to group A, while 2381 (64.5%) patients belonged to group B. Seventy-three patients experienced postoperative infectious complications. There was a significant difference in the fUTI rate between groups A and B (3.7% versus 1.0%, P < 0.001). The yearly fUTI rates varied from 0.6 to 3.9% between 2002 and 2009. Of the 73 patients with fUTI, those receiving levofloxacin prophylaxis were more likely to harbor fluoroquinolone-resistant pathogens (P < 0.001). E. coli was the most common pathogen in both groups. Levofloxacin remains effective and appears superior to pipemidic acid based prophylaxis.

Laparo-endoscopic single-site (LESS) bilateral nephroureterectomy for patients with end-stage renal disease.

We present the first report of LESS bilateral nephroureterectomy via the transperitoneal approach using the home-made single port. Two patients received LESS bilateral nephroureterectomies and bladder cuffs resection with homemade single ports, which were created by using an Alexis wound retractor as an access platform through a 4 cm incision. Distal ureters were resected through the same incision with Endo-loop. No additional ports were used and both procedures were completed successfully without traditional laparoscopic/open conversion or complication. LESS nephreoureterectomy with bladder cuff excision was performed in 460 and 635 minutes with an estimated blood loss of 50 and 400 mL, respectively. Patients were discharged on postoperative day 3 and 7, respectively. Our report demonstrates that LESS bilateral nephroureterectomy and bladder cuff resection is a safe and feasible procedure for urothelial carcinoma of upper urinary tract in patients at dialysis.

Down-regulation of PKCζ in renal cell carcinoma and its clinicopathological implications.

BACKGROUND: Metastatic renal cell carcinoma (RCC) is highly resistant to systemic chemotherapy. Unfortunately, nearly all patients die of the metastatic and chemoresistant RCC. Recent studies have shown the atypical PKCζ is an important regulator of tumorigenesis. However, the correlation between PKCζ expression and the clinical outcome in RCC patients is unclear. We examined the level of PKCζ expression in human RCC. METHODS: PKCζ mRNA and protein expressions were examined by real-time polymerase chain reaction (PCR) and immunohistochemistry (IHC) respectively in RCC tissues of 144 patients. Cellular cytotoxicity and proliferation were assessed by MTT. RESULTS: PKCζ expression was significantly higher in normal than in cancerous tissues (P<0.0001) by real-time PCR and IHC. Similarly, PKCζ expression was down-regulated in four renal cancer cell lines compared to immortalized benign renal tubular cells. Interestingly, an increase of PKCζ expression was associated with the elevated tumor grade (P=0.04), but no such association was found in TNM stage (P=0.13). Tumors with higher PKCζ expression were associated with tumor size (P=0.048). Expression of higher PKCζ found a poor survival in patients with high tumor grade. Down-regulation of PKCζ showed the significant chemoresistance in RCC cell lines. Inactivation of PKCζ expression enhanced cellular resistance to cisplatin and paclitaxel, and proliferation in HK-2 cells by specific PKCζ siRNA and inhibitor. CONCLUSIONS: PKCζ expression was associated with tumorigenesis and chemoresistance in RCC.

Significant association between serum dihydrotestosterone level and prostate volume among Taiwanese men aged 40-79 years.

INTRODUCTION: We evaluated the association between serum sex hormone levels and prostate volume in Taiwanese men. METHODS: A cross-sectional study was conducted in 505 men (aged 40-79 years, mean age 58 years). Serum total testosterone (TT), free testosterone (FT), dihydrotestosterone (DHT) and estradiol (E2) levels were measured. Total prostate volume (TPV) and transition zone volume (TZV) were measured by transrectal ultrasonography. Body mass index (BMI), DHT/TT and E2/TT were calculated. Correlations were determined using univariate and multivariate regression analyses. RESULTS: Apart from DHT, an age-dependent change of sex hormone levels were observed. On univariate analyses, age, BMI, serum DHT level and DHT/TT ratio, as well as serum E2 level and E2/TT ratio, but not serum TT and FT levels showed a significant association with prostate volume. On multivariate analysis, however, only serum DHT level and DHT/TT ratio remained significant. Logistic regression analysis showed that the odds ratios (95% confidence interval) of the second, third, and fourth quartiles of serum DHT levels for benign prostatic hyperplasia (defined as TPV ≥ 20 ml) risk were 2.06 (1.21-3.51), 2.66(1.56-4.53) and 7.15(4.0-12.6), respectively (p < 0.001). CONCLUSIONS: Higher serum DHT level and DHT/TT ratio were associated with larger prostate volume and higher prevalence of BPH in Taiwanese men.

Testosterone and sex hormone-binding globulin have significant association with metabolic syndrome in Taiwanese men.

OBJECTIVES: To investigate the relationship between sex hormones and metabolic syndrome (MS) in an Asian population. METHODS: A cross-sectional study was conducted in 237 men aged 20-88 years (mean age 52 years). Serum lipids, glucose, insulin, total testosterone (TT), estradiol (E2), sex hormone-binding globulin (SHBG), and dehydroepiandosterone sulfate (DHEA-S) were measured along with body height, weight, waist circumference, and blood pressure. Free testosterone (FT) and bioavailable testosterone (BT) were calculated. Correlations were determined using univariate and multivariate regression analyses. RESULTS: Men with MS had lower levels of TT, BT, FT, SHBG and DHEA-S than men without MS. Multivariate analysis, after adjusting for age and smoking status, indicated that TT (OR: 0.909, 95% CI: 0.836-0.988, p = 0.003) and SHBG (OR: 0.948, 95% CI: 0.913-0.985, p = 0.006) were significantly associated with MS (R(2) = 0.314). TT was associated with waist circumference (p = 0.008) and abnormal triglycerides level (p = 0.006); SHBG was associated with blood pressure (p = 0.003), blood glucose (p = 0.043) and abnormal triglycerides (p = 0.048). A significant trend was observed between decreasing levels of TT, BT, FT, and SHBG and increasing numbers of MS components. CONCLUSION: Results show that serum testosterone and SHBG levels inversely correlate with MS in an Asian population applying the Asian MS definition.

A comparative study of multiport versus laparoendoscopic single-site adrenalectomy for benign adrenal tumors.

BACKGROUND: The safety and feasibility of laparoendoscopic single-site (LESS) adrenalectomy for benign adrenal lesions was proved in early clinical series. However, the advantages of LESS over multiport laparoscopic adrenalectomy still are under investigation. METHODS: Since October 2009, the authors have prospectively performed LESS retroperitoneal adrenalectomy for 21 consecutive patients with benign adrenal tumors (LESS group). Another 28 patients with benign adrenal tumors were prospectively collected between June 2006 and October 2009 and served as a multiport laparoscopic adrenalectomy group. The patients' demographic data, operating time, estimated blood loss, peri- and postoperative complications, and short-term outcome were collected for further analysis. RESULTS: The demographic data were comparable between the two groups in terms of the patient age, gender, body mass index (BMI), laterality, diagnosis, and resected specimen weight. No major complication or mortality occurred in either group. Neither group had any conversions. No differences were observed between the two groups in terms of intraoperative hemodynamic status or peri- or postoperative complications. The LESS patients had quicker resumption of oral intake (0.18 vs 1 day; p < 0.001), a shorter hospital stay (2 vs 4 days; p < 0.001), and a reduced analgesic requirement postoperatively (0 vs 0.84 mg/kg; p = 0.023) than the multiport laparoscopic patients. CONCLUSIONS: The results demonstrate that LESS adrenalectomy is as safe and effective as conventional multiport laparoscopic adrenalectomy for benign adrenal tumors. In addition, LESS adrenalectomy provides short-term convalescence advantages over multiport laparoscopic adrenalectomy.

Advances in understanding of mammalian penile evolution, human penile anatomy and human erection physiology: clinical implications for physicians and surgeons.

Recent studies substantiate a model of the tunica albuginea of the corpora cavernosa as a bi-layered structure with a 360° complete inner circular layer and a 300° incomplete outer longitudinal coat spanning from the bulbospongiosus and ischiocavernosus proximally and extending continuously into the distal ligament within the glans penis. The anatomical location and histology of the distal ligament invites convincing parallels with the quadrupedal os penis and therefore constitutes potential evidence of the evolutionary process. In the corpora cavernosa, a chamber design is responsible for facilitating rigid erections. For investigating its venous factors exclusively, hemodynamic studies have been performed on both fresh and defrosted human male cadavers. In each case, a rigid erection was unequivocally attainable following venous removal. This clearly has significant ramifications in relation to penile venous surgery and its role in treating impotent patients. One deep dorsal vein, 2 cavernosal veins and 2 pairs of para-arterial veins (as opposed to 1 single vein) are situated between Buck's fascia and the tunica albuginea. These newfound insights into penile tunical, venous anatomy and erection physiology were inspired by and, in turn, enhance clinical applications routinely encountered by physicians and surgeons, such as penile morphological reconstruction, penile implantation and penile venous surgery.

Long-term oncologic outcomes of hand-assisted retroperitoneoscopic radical nephrectomy to treat clinically localized renal cell carcinoma.

BACKGROUND/PURPOSE: To evaluate the long-term oncological outcomes of hand-assisted retroperitoneoscopic radical nephrectomy (HARRN) for treating clinically localized renal cell carcinoma. METHODS: We retrospectively collected and analyzed the data and clinical outcomes of 46 patients who underwent HARRN and 50 patients who underwent conventional open radical nephrectomy (ORN) at our institution for clinical localized renal cell carcinoma (RCC). RESULTS: The median follow-up period of the HARRN group was 56.5 months (range: 14.6-78.7 months); for the ORN group, the median follow-up period was 110.8 months (range: 15.5-123 months). Patient age, sex, body mass index, pathologic parameters, and classification based on the guidelines of the American Society of Anesthesiologists were not significantly different between the two groups. The HARRN group had a significantly longer operative time (218 minutes vs. 178 minutes, p = 0.003) and less blood loss (203 mL vs. 670 mL, p < 0.001). The complication rates of the ORN and HARRN groups were similar (8% and 4.3%, respectively, p = 0.46). No conversions to an open procedure or intraoperative mortality occurred in the HARRN group. The disease-free and disease-specific survival rates were comparable between the two groups. CONCLUSION: The results of our study indicate that HARRN is a feasible, minimally invasive treatment for managing clinically organ-confined RCC with a good long-term oncological outcome.

Finasteride upregulates expression of androgen receptor in hyperplastic prostate and LNCaP cells: implications for chemoprevention of prostate cancer.

BACKGROUND: Although finasteride is recognized for its role as a chemopreventive agent for prostate cancer, higher grades of malignancy have been reported. It is questioned whether blocking of testosterone conversion to dihydrotestosterone (DHT) by finasteride in prostate tissue will change expression of androgen receptor (AR). Therefore, this study evaluated the effects of finasteride on AR expression in prostate tissue and in the LNCaP cell line. METHODS: Between January and December 2006, we retrospectively selected and evaluated 47 cases of benign prostatic hyperplasia treated with variable duration of finasteride (5 mg QD) before transurethral resection of the prostate. AR expression in prostate tissue was semiquantified by immunostaining and compared with duration of finasteride treatment. An androgen-dependent prostate cancer cell line (LNCaP) was cultured in charcoal/dextran-treated FBS with DHT or testosterone, and treated with finasteride for 1-3 weeks. Samples of total RNA were collected to analyze expression of AR by real-time quantitative reverse transcription polymerase chain reaction. RESULTS: Immunohistochemical study revealed significant upregulation of ARs by finasteride treatment for 30-180 days. In cell line study, quantitative real-time reverse transcription polymerase chain reaction revealed significant upregulation of ARs treated by finasteride. CONCLUSIONS: In our study, finasteride influenced AR expression in benign prostate tissue and prostate cancer cell. Before we can use finasteride in chemoprevention with confidence, we still need to clarify the influence of finasteride in ARs and its regulation pathway.

Anti-angiogenic effects and mechanism of prazosin.

BACKGROUND: Alpha1-adrenoceptors antagonists (doxazosin, terazosin, prazosin) are commonly prescribed for benign prostate hyperplasia and hypertension. Doxazosin and terazosin exhibit anti-angiogenic effects and apoptotic activities against multiple cell types and are potential preventive agents for prostate cancer. Prazosin induces apoptosis in three prostate cancer cell lines. We hypothesized that prazosin, a more potent alpha1-adrenoceptor antagonist with a distinct mechanism, exhibits anti-angiogenic activity. METHODS: We examined the effect of prazosin on growth and tube formation of human umbilical vascular endothelial cells (HUVECs). We used flow cytometry to assess the effect of prazosin on cell cycle progression and Western blotting to assess its effect on the expression of various apoptotic proteins. RESULTS: Prazosin inhibited the growth of HUVEC with an IC(50) of 6.53 µM and suppressed tube formation in a dose-dependent manner. Unlike prostate cancer cells, prazosin did not arrest cell cycle progression at the G2/M checkpoint. We used rhodamine 123 staining to show that prazosin (20 µM) treatment induced a loss of mitochondrial membrane potential by 12 hr. Prazosin treatment of HUVECs resulted in reduced MCL-1 expression, increased Bad, and Bcl-xL expression, cytochrome c release, and induction of apoptosis via the intrinsic apoptosis pathway. Prazosin induced apoptosis in prostate cancer cells and normal HUVEC cells via different mechanisms. CONCLUSIONS: These data suggest that prazosin exhibits anti-angiogenic activity and differentially modulates apoptotic pathways depending on the cell type.

Pathophysiological studies of overactive bladder and bladder motor dysfunction in a rat model of metabolic syndrome.

PURPOSE: We studied bladder motor dysfunction and searched for markers of neurogenic and myogenic alterations among fructose fed rats with or without abnormal voiding behavior. MATERIALS AND METHODS: Female Wistar rats were fed with a fructose rich diet (60%) or a normal diet for 6 months. Based on cystometry and voiding behavior the fructose fed rats were divided into 3 groups, including a group with normal detrusor function with normal micturition frequency, a group with detrusor overactivity with increased micturition frequency and a group with acontractile detrusor with increased micturition frequency. Denuded bladder tissues were obtained to assess in vitro detrusor contractility, postsynaptic receptors, smoothelin, nitrosative products and the intrinsic pathway of apoptosis. RESULTS: Fructose fed rats with abnormal voiding behavior had obvious neurogenic and myogenic alterations, including increased expression of postsynaptic receptors, dysregulation of smoothelin and decreased expression of Bcl-2 with a subsequent increase in apoptotic cells in the bladder stroma, causing decreased carbachol induced contractility. Rats with detrusor overactivity were also insulted by nitrosative stress associated with nitrotyrosine up-regulation in the bladder tissue. Up-regulation of M(2) and M(3)-muscarinic receptors, and P2X(1) receptors appeared to be generalized alterations of fructose fed rats and not exclusive to those with detrusor overactivity. CONCLUSIONS: Up-regulation of postsynaptic receptors and dysregulation of smoothelin contribute to overactive bladder symptoms in rats with metabolic syndrome. Nitrosative stress and decreased Bcl-2 expression lead to bladder muscle cell loss via the intrinsic pathway of apoptosis, which may further deteriorate bladder function.

Non-inferiority of silodosin to tamsulosin in treating patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH).

UNLABELLED: What's known on the subject? and What does the study add? Silodosin administered by 4 mg twice daily is as effective as tamsulosin 0.2 mg daily in treating patients with LUTS associated with BPH. Relative to tamsulosin, silodosin has less cardiovascular side effects as judged by the minimal changes of blood pressure and pulse rats after treatment. OBJECTIVE: • To test the hypothesis that the efficacy of silodosin would not be inferior to tamsulosin in treating patients with lower urinary tract symptoms associated with benign prostate hyperplasia (BPH). PATIENTS AND METHODS: • At nine medical centres, 209 patients with an International Prostate Symptom Score (IPSS) of ≥13 were randomized to silodosin (4 mg twice daily) or tamsulosin (0.2 mg once daily) for 12 weeks. • The primary efficacy measure was the mean change from baseline to endpoint in IPSS. • The non-inferiority margin of the IPSS change was set at 1.0. • Secondary efficacy measures included change in maximal urinary flow rate (Q(max)) and health-related quality of life (HRQL) score. RESULTS: • Of the 170 (81.3%) patients who completed the study, 86.2% in the silodosin group vs 81.9% in the tamsulosin group achieved a ≥25% decrease in IPSS (P= 0.53). • The mean difference (silodosin minus tamsulosin) in IPSS change from baseline was -0.60 (95% confidence interval -2.15, 0.95), inferring the non-inferiority of silodosin to tamsulosin. • The mean changes in the Q(max) and HRQL score from baseline were comparable between the groups (both, P > 0.05). Although patients receiving silodosin had a significantly higher incidence of abnormal ejaculation (9.7% vs tamsulosin 1.0%, P= 0.009), only 1.9% discontinued treatment. • Tamsulosin treatment resulted in a significant reduction in mean systolic blood pressure (-4.2 mmHg, within-group P= 0.004) relative to the negligible change of silodosin (-0.1 mmHg, within-group P= 0.96) CONCLUSION: • The trial shows the non-inferiority of silodosin 4 mg twice daily to tamsulosin 0.2 mg once daily in patients with symptoms of BPH.