Pathogenic role of HIF-1α in prostate hyperplasia in the presence of chronic inflammation

Benign prostatic hyperplasia (BPH) commonly occurs in older men with chronic prostatitis. Although BPH is frequently accompanied by inflammation, it is unclear whether inflammation underlies prostate enlargement. Recently, we reported that hypoxia‐inducible factor 1α (HIF-1α), which is known to be induced by proinflammatory cytokines, is involved in testosterone-induced prostate hyperplasia. Therefore, we hypothesized that cytokines secreted from infiltrated macrophages under inflammatory conditions stimulate prostate enlargement by up‐regulating HIF-1α. In the present study, we injected lipopolysaccharide (LPS) into rat prostates to mimic prostatitis and evaluated prostate hyperplasia 14 days later. Epithelial cells of LPS-treated prostates were found to be highly proliferative and HIF-1α levels in prostate tissues to be elevated. When prostate epithelial cells were incubated in conditioned medium from macrophages activated with LPS, they robustly expressed HIF-1α, and under these conditions IL-1β, IL-6, and TNF-α cytokines were found to mediate HIF-1α induction. In addition, HIF-1α was found to enhance the expression of Twist, which initiates epithelial–mesenchymal transition (EMT). Furthermore, profound EMT features were observed in LPS-treated rat prostates, and the natural HIF-1α inhibitors ascorbate and curcumin were found to attenuate EMT and prostate hyperplasia both in vivo and in vitro. Based on these results, we propose that HIF-1α mediates prostate enlargement under inflammatory conditions, and we suggest that HIF-1α be viewed as a promising target for blocking the transition from prostatitis to BPH.     

CYR61, a cellular proliferation marker in dogs with prostatic disease

The life expectancy of dogs is increasing and is associated with a greater frequency of age-related disease, including that of the prostate gland. A marker of cell proliferation, CYR61, may be detected in a number of conditions in humans, including hyperplasia and neoplasia. The objective of the present study was to investigate the degree of CYR61 expression in a number of different prostate diseases in dogs in order to understand the potential of this marker for diagnosis of prostatic disease. Immunohistochemistry with a CYR61 antibody was performed on prostatic tissue from 22 dogs with different diseases. Intense stromal staining was observed in cases of prostatic dysplasia and benign prostate hyperplasia. In contrast, CYR61 staining was very intense in alveolar epithelial cells in cases of epithelial benign prostate hyperplasia and one case of adenocarcinoma. An obvious CYR61 staining pattern was absent in cases of prostatitis. In conclusion, CYR61 may be a useful marker of cell proliferation in a number of prostatic pathologies, although further studies of normal tissue are warranted.     

Inflammatory Responses in a Benign Prostatic Hyperplasia Epithelial Cell Line (BPH-1) Infected with Trichomonas vaginalis

Trichomonas vaginalis causes the most prevalent sexually transmitted infection worldwide. Trichomonads have been detected in prostatic tissues from prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer. Chronic prostatic inflammation is known as a risk factor for prostate enlargement, benign prostatic hyperplasia symptoms, and acute urinary retention. Our aim was to investigate whether T. vaginalis could induce inflammatory responses in cells of a benign prostatic hyperplasia epithelial cell line (BPH-1). When BPH-1 cells were infected with T. vaginalis, the protein and mRNA of inflammatory cytokines, such as CXCL8, CCL2, IL-1β, and IL-6, were increased. The activities of TLR4, ROS, MAPK, JAK2/STAT3, and NF-κB were also increased, whereas inhibitors of ROS, MAPK, PI3K, NF-κB, and anti-TLR4 antibody decreased the production of the 4 cytokines although the extent of inhibition differed. However, a JAK2 inhibitor inhibited only IL-6 production. Culture supernatants of the BPH-1 cells that had been incubated with live T. vaginalis (trichomonad-conditioned medium, TCM) contained the 4 cytokines and induced the migration of human monocytes (THP-1 cells) and mast cells (HMC-1 cells). TCM conditioned by BPH-1 cells pretreated with NF-κB inhibitor showed decreased levels of cytokines and induced less migration. Therefore, it is suggested that these cytokines are involved in migration of inflammatory cells. These results suggest that T. vaginalis infection of BPH patients may cause inflammation, which may induce lower urinary tract symptoms (LUTS).     

Canine prostatic disease: a review of anatomy, pathology, diagnosis, and treatment

Disease conditions affecting the canine prostate gland are encountered frequently in small animal practice. The most common conditions affecting the canine prostate include benign prostatic hyperplasia, prostatitis, prostatic cysts, and prostatic neoplasia. Clinical signs associated with each of these conditions often overlap; therefore, it is important to reach a definitive diagnosis prior to initiating treatment. This paper reviews the diseases associated with the prostate gland of the dog, their diagnosis, as well as current treatment options for management of these conditions. Emphasis is placed on proper diagnostic sampling of the prostate gland, its fluid, and interpretation of findings, as well as emerging medical options for treatment of canine prostatic disease.     

Alpha-blockers for the treatment of prostatitis-like syndromes

Prostatitis is a common medical diagnosis. The etiology of this symptomatic syndrome can be an acute or chronic bacterial infection, a noninfectious initiator (the most common cause), or iatrogenic heat or radiation; the syndrome may coexist with benign prostatic hyperplasia. Alpha-blockers have a role in the treatment of the prostatitis syndromes. In Category I, acute bacterial prostatitis, alpha-blockers have been shown to possibly ameliorate obstructive and irritative voiding symptoms. In Category II, chronic bacterial prostatitis, alpha-blockers seem to reduce the risk of clinical and bacteriological recurrence. In Category III, chronic pelvic pain syndrome, alpha-blockers improve symptoms and quality of life. Alpha-blockers also seem to ameliorate the symptoms and reduce the risk of acute urinary retention in patients who suffer from either heat- or radiation-induced prostatic inflammation. Alpha-blockers improve lower urinary tract symptoms, including pain, in patients who are diagnosed with both prostatitis and benign prostatic hyperplasia. Evidence has proven there is definitely a role for alpha-blockers in the management of the prostatitis syndromes.     

The role of estrogens and estrogen receptors in normal prostate growth and disease

Estrogens have significant direct and indirect effects on prostate gland development and homeostasis and have been long suspected in playing a role in the etiology of prostatic diseases. Direct effects are mediated through prostatic estrogen receptors alpha (ERalpha) and beta (ERbeta) with expression levels changing over time and with disease progression. The present review examines the evidence for a role of estrogens and specific estrogen receptors in prostate growth, differentiation and disease states including prostatitis, benign prostatic hyperplasia (BPH) and cancer and discusses potential therapeutic strategies for growth regulation via these pathways.     

Benign prostatic hyperplasia-associated prostate-specific antigen (BPSA) shows unique immunoreactivity with anti-PSA monoclonal antibodies.

We previously identified a modified molecular form of prostate-specific antigen that is significantly elevated in the nodular transition zone tissue of prostates with benign prostatic hyperplasia. This prostate-specific antigen form, designated BPSA, is inactive and contains clipped polypeptide bonds at amino-acid residues Lys145-146 and Lys182-183. BPSA is not elevated in prostate cancer tissues and may therefore be a prostate-specific antigen marker to better discriminate benign prostatic hyperplasia from early prostate cancer. In this work we characterize the immunoreactivity of BPSA in competition assays with prostate-specific antigen using anti-prostate-specific antigen mAb recognizing six different epitopes on the prostate-specific antigen molecule. One mAb showed > 50% loss of immunoreactivtiy with BPSA compared with prostate-specific antigen, while the binding of two mAbs was largely unaffected and three mAbs had intermediate reactivity. BPSA purified from prostate tissue and seminal plasma, as well as BPSA generated in vitro by mild trypsin-treatment were found to have a similar pattern of reactivity to the six mAbs. However, other forms of inactive seminal plasma prostate-specific antigen, either intact or clipped at Lys145 only, had immunoreactivity similar to total prostate-specific antigen. These results demonstrate that BPSA has unique immunological properties from other forms of prostate-specific antigen, which should allow the development of BPSA-specific mAbs for the study of benign prostatic hyperplasia. Measurement of BPSA levels in the serum may help discriminate benign prostatic hyperplasia from early prostate cancer.     

86例超声引导下经会阴前列腺穿刺体会

目的分析86例经直肠超声(TRUS)引导下经会阴前列腺穿刺病理,提高前列腺癌活检阳性率。方法86例(年龄71-89岁,PSA.>10 ng/ml,PSAD>0.3),直肠超声(TRUS)引导下经会阴前列腺穿刺,6+X法。结果前列腺癌39例,前列腺增生46例,前列腺炎1例。前列腺癌阳性中:有可疑病灶32例,无可疑病灶7例,前列腺癌敏感性82%(32/39),其中第二次穿刺病例8例,阳性4例,第三次穿刺2例,阳性2例。结论对70岁以上高老人的前列腺穿刺活检病人,因个性化对待,重点对可疑病灶点和外周带的穿刺。     

Cancer de la prostate : les marqueurs biologiques

Normal prostate cells and prostate cancer cells produce prostate-specific antigen (PSA): thus, it is frequently increased in non-malignant conditions such as prostatitis and benign prostatic hyperplasia. Indeed, PSA is an excellent biomarker to monitor disease progression. The low diagnostic specificity of PSA leads to many false-positive and a large number of biopsies. These well-recognized limitations of PSA suggest that new prostate cancer biomarkers could play a useful role in reducing the number of unnecessary biopsies.     

Effect of castration monotherapy on the levels of adrenal androgens in cancerous prostatic tissues

The mechanism accounting for the development of castration-resistant prostate cancer (CRPC) remains unclear. Studies in CRPC tissues suggest that, after androgen deprivation therapy (ADT), the adrenal androgens may be an important source of testosterone (T) and 5-alpha dihydrotestosterone (DHT) in CRPC tissues. To clarify the role of adrenal androgens in the prostatic tissues (prostatic tissue adrenal androgens) during ADT, we developed a high sensitive and specific quantification method for the levels of androgens in prostatic tissue using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Human prostatic tissues were purified using mixed-mode reversed-phase, strong anion exchange Oasis cartridges (Oasis MAX). Analysis of steroids was performed using LC-MS/MS after picolinic acid derivatization. The validation tests showed that our method of quantitative analysis was precise and sensitive enough for the quantification of dehydroepiandrosterone (DHEA), androstenedione, androstenediol, T, and DHT in the prostatic tissue. The levels of adrenal androgens in prostate cancer tissues after ADT were similar to those in untreated PCa. Especially, DHEA was the most existing androgen precursor in PCa tissues after ADT. The levels of DHEA were high in PCa tissues, irrespective of ADT. We assumed that DHEA played a significant role in the synthesis of T and DHT in PCa tissues after ADT.     

遂宁地区良性前列腺增生术后LUTS相关危险因素分析

目的:调查与分析遂宁地区良性前列腺增生术后下尿路症状(Lower Urinary Tract Symptoms,LUTS)发生的相关危险因素。方法:2014年9月到2019年10月选择在遂宁市中心医院诊治的遂宁地区良性前列腺增生症患者172例,所有患者都给予手术治疗,记录术后LUTS发生情况,调查患者的临床资料并进行影响因素分析。结果:在172例患者中,术后平均国际前列腺症状评分量表(International prostate symptom scores,IPSS)评分为5.67±0.13分,其中储尿期症状评分3.01±0.11分,排尿期症状评分为1.76±0.22分,排尿后症状评分0.89±0.14分,发生LUTS 18例(LUTS组),发生率为10.5%。LUTS组的生活质量评分高于非LUTS组(P<0.05);LUTS组的年龄、体重指数、低密度脂蛋白、总胆固醇、前列腺体积与非LUTS组对比差异有统计学意义(P<0.05);Pearson分析显示年龄、体重指数、低密度脂蛋白、总胆固醇、前列腺体积都与LUTS存在相关性(P<0.05);二元Logistic回归分析显示年龄、体重指数、低密度脂蛋白、总胆固醇、前列腺体积都为导致LUTS发生的主要因素(P<0.05)。结论:遂宁地区良性前列腺增生术后LUTS的发生比较常见,可严重影响患者的生活质量,年龄、体重指数、低密度脂蛋白、总胆固醇、前列腺体积都为导致LUTS发生的主要因素。     

Susceptibility Weighted Imaging: A New Tool in the Diagnosis of Prostate Cancer and Detection of Prostatic Calcification

Background

Susceptibility weighted imaging (SWI) is a new MRI technique which has been proved very useful in the diagnosis of brain diseases, but few study was performed on its value in prostatic diseases. The aim of the present study was to investigate the value of SWI in distinguishing prostate cancer from benign prostatic hyperplasia and detecting prostatic calcification.

Methodology/Principal Findings

23 patients with prostate cancer and 53 patients with benign prostatic hyperplasia proved by prostate biopsy were scanned on a 3.0T MR and a 16-row CT scanner. High-resolution SWI, conventional MRI and CT were performed on all patients. The MRI and CT findings, especially SWI, were analyzed and compared. The analyses revealed that 19 out of 23 patients with prostate cancer presented hemorrhage within tumor area on SWI. However, in 53 patients with benign prostatic hyperplasia, hemorrhage was detected only in 1 patient in prostate by SWI. When comparing SWI, conventional MRI and CT in detecting prostate cancer hemorrhage, out of the 19 patients with prostate cancer who had prostatic hemorrhage detected by SWI, the prostatic hemorrhage was detected in only 7 patients by using conventional MRI, and none was detected by CT. In addition, CT demonstrated calcifications in 22 patients which were all detected by SWI whereas only 3 were detected by conventional MRI. Compared to CT, SWI showed 100% in the diagnostic sensitivity, specificity, accuracy, positive predictive value(PPV) and negative predictive value(NPV) in detecting calcifications in prostate but conventional MRI demonstrated 13.6% in sensitivity, 100% in specificity, 75% in accuracy, 100% in PPV and 74% in NPV.

Conclusions

More apparent prostate hemorrhages were detected on SWI than on conventional MRI or CT. SWI may provide valuable information for the differential diagnosis between prostate cancer and prostatic hyperplasia. Filtered phase images can identify prostatic calcifications as well as CT.     

原发性高血压对良性前列腺增生病程发展的影响研究

目的：探讨原发性高血压与良性前列腺增生（BPH）发生与-临床进展的相关性。方法：将确诊为良性前列腺增生的78例BPH患者分为单纯性BPH组和BPH合并有高血压组两组,其中BPH组33例,BPH合并有高血压组45例。对两组患者的尿流率、残尿量、血清前列腺特异性抗原（PSA）、血尿发生率、前列腺体积、国际前列腺症状（tPSS）评分、尿潴留次数及不稳定膀胱发生率指标进行对比分析。结果：两组患者间在年龄、尿流率、残尿量、PSA、最大膀胱容量及最大逼尿肌压力指标差异无统计学意义（P〉0．05）。而BPH合并高血压患者在血尿发生率、前列腺体积、IPSS评分、尿潴留次数及不稳定膀胱发生率指标上明显大于单纯良性前列腺增生组,差异有统计学意义（P〈0．05）。结论：原发性高血压患者发生前列腺增生的病例报道越来越多,高血压状态能够促进BPH的发生以及临床进展。     

地奥司明对前列腺增生伴前列腺炎患者HSP, CRP及PSA的影响

目的:探讨地奥斯明对前列腺增生伴前列腺炎患者血清热休克蛋白(HSP)、C反应蛋白(CRP)及血清PSA水平的影响。方法:选取已确诊为前列腺增生伴前列腺炎的患者39例,随机分为实验组及对照组。对照组19例,予普适泰片治疗;实验组20例,予地奥司明治疗。28天为一个治疗疗程。比较两组患者治疗前后热休克蛋白、C反应蛋白及血清PSA水平的变化。结果:实验组总有效率(95.0%)高于对照组(78.9%),差异具有统计学意义(P0.05);与对照组比较,实验组热休克蛋白、C反应蛋白及血清PSA水平较低(P0.05),慢性前列腺炎评分(NIH-CPSI)评分较低(P0.05),不良反应发生率(10.0%)低于对照组(31.6%),差异存在统计学意义(P0.05)。结论:地奥司明片可以明显改善男性前列腺增生伴前列腺炎患者的排尿困难及尿频尿急等症状,有效降低患者热休克蛋白、C反应蛋白及血清PSA水平。     

Adiponectin as a potential marker of prostate cancer progression: studies in organ-confined and locally advanced prostate cancer

Serum levels of adiponectin were measured in patients with benign prostatic hyperplasia and prostate cancer of pT2 and pT3 stage. Adiponectin ELISA assay, immunohistochemistry, and selected metabolic and biochemical parameters measurement was performed in 25 patients with benign prostatic hyperplasia and 43 with prostate cancer (17 patients with organ-confined and 26 patients with locally advanced disease). Serum adiponectin levels did not differ between prostate benign hyperplasia and cancer clinical stage T2, but was significantly higher in pT3 relative to pT2 group (14.51+/-4.92 vs. 21.41+/-8.12, P = 0.003). Tissue immunohistochemistry showed enhanced staining in neoplastic prostate glands and intraepithelial neoplasia relative to benign prostatic hyperplasia without distinction between disease grade and stage. Serum adiponectin levels are higher in locally advanced relative to organ-confined prostate cancer and may thus serve as an auxiliary marker providing further improvement for discrimination between pT2 and pT3 stages.     

The contribution of prostatic acid phosphatase and prostatic specific antigen in the diagnosis of prostatic cancer

Prostatic acid phosphatase (PAP) and prostatic specific antigen (PSA) were measured by immunochemical methods using test preparations from two different companies. In 66 patients with benign hyperplasia of the prostate a good correlation was found only between PSA levels (orthogonal regression analysis: y = 1.77 x -0.68; r = 0.995). Discrimination analysis between benign hyperplasia and new prostatic cancer (28 patients), using ROC curves, revealed a sensitivity for prostatic cancer of about 30 percent using both PAP methods and of about 58 percent using both PSA methods at the 95-percentile of benign hyperplasia. The PSA methods were both more sensitive in detecting prostatic cancer than the PAP methods.     

The androgen receptor CAG repeat length polymorphism associates with prostate volume in Finnish men with benign prostatic hyperplasia

The development of benign prostatic hyperplasia requires the presence of testicular androgens during prostate development, puberty, and ageing. We thus examined the association of three polymorphisms, namely, CYP3A5 6986A>G, CYP19A1 1531C>T, and androgen receptor (AR) gene CAG repeat length, which have previously been linked to the androgen pathway and with clinical characteristics of benign prostatic hyperplasia. Tissue samples from 262 consecutive prostate operations were used for genotyping. Prostate volumes and prostate-specific antigen values were collected from patient records. Linear regression analysis was performed to study the polymorphisms in an age-adjusted model. We did not find any association between the CYP3A5 6986A>G polymorphism and clinical characteristics of benign prostatic hyperplasia. Further, the previously published CYP19A1 1531C>T polymorphism association with an enlarged prostate could not be confirmed with this material. However, we detected an association between short AR gene CAG repeat length and a small prostate volume, which confirms a previous finding in the Finnish population. The data presented suggest a negligible role for the CYP3A5 6986A>G polymorphism in benign prostate enlargement in the Finnish population. However, the results presented do provide further evidence for potentially different genetic mechanisms behind benign prostatic hyperplasia in Finnish and other Caucasian populations. This is based on the conflicting results for AR gene CAG repeat length associations with benign prostatic hyperplasia found in published works.     

Effect of Silodosin,an Alpha1A-Adrenoceptor Antagonist,on Ventral Prostatic Hyperplasia in the Spontaneously Hypertensive Rat

Background

A decreased prostatic blood flow could be one of the risk factors for benign prostatic hyperplasia/benign prostatic enlargement. The spontaneously hypertensive rat (SHR) shows a chronic prostatic ischemia and hyperplastic morphological abnormalities in the ventral prostate. The effect of silodosin, a selective alpha_1A-adrenoceptor antagonist, was investigated in the SHR prostate as a prostatic hyperplasia model focusing on prostatic blood flow.

Methods

Twelve-week-old male SHRs were administered perorally with silodosin (100 μg/kg/day) or vehicle once daily for 6 weeks. Wistar Kyoto (WKY) rats were used as normotensive controls and were treated with the vehicle. The effect of silodosin on blood pressure and prostatic blood flow were estimated and then the prostates were removed and weighed. The tissue levels of malondialdehyde (MDA), interleukin-6 (IL-6), chemokine (C-X-C motif) ligand 1/cytokine-induced neutrophil chemoattractant 1 (CXCL1/CINC1), tumor necrosis factor-alpha (TNF-α), transforming growth factor beta 1 (TGF-β1), basic fibroblast growth factor (bFGF) and alpha-smooth muscle actin (α-SMA) were measured. The histological evaluation was also performed by hematoxylin and eosin staining.

Results

There was a significant increase in blood pressure, prostate weight, prostate body weight ratio (PBR), tissue levels of MDA, IL-6, CXCL1/CINC1, TNF-α, TGF-β1, bFGF and α-SMA in the SHR compared to the WKY rat. The ventral prostate in the SHR showed the morphological abnormalities compared to the WKY rat. Prostatic blood flow was decreased in the SHR. However, treatment with silodosin significantly restored the decreased prostatic blood flow in the SHR. Moreover, silodosin normalized tissue levels of MDA, IL-6, CXCL1/CINC1, TNF-α, TGF-β1, bFGF and α-SMA, and it ameliorated ventral prostatic hyperplasia in the SHR excluding blood pressure. Silodosin decreased PBR but not prostate weight in the SHR.

Conclusions

Silodosin can inhibit the progression of prostatic hyperplasia through a recovery of prostatic blood flow.     

Cholesterol and benign prostate disease

The origins of benign prostatic diseases, such as benign prostatic hyperplasia (BPH) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), are poorly understood. Patients suffering from benign prostatic symptoms report a substantially reduced quality of life, and the relationship between benign prostate conditions and prostate cancer is uncertain. Epidemiologic data for BPH and CP/CPPS are limited, however an apparent association between BPH symptoms and cardiovascular disease (CVD) has been consistently reported. The prostate synthesizes and stores large amounts of cholesterol and prostate tissues may be particularly sensitive to perturbations in cholesterol metabolism. Hypercholesterolemia, a major risk factor for CVD, is also a risk factor for BPH. Animal model and clinical trial findings suggest that agents that inhibit cholesterol absorption from the intestine, such as the class of compounds known as polyene macrolides, can reduce prostate gland size and improve lower urinary tract symptoms (LUTS). Observational studies indicate that cholesterol-lowering drugs reduce the risk of aggressive prostate cancer, while prostate cancer cell growth and survival pathways depend in part on cholesterol-sensitive biochemical mechanisms. Here we review the evidence that cholesterol metabolism plays a role in the incidence of benign prostate disease and we highlight possible therapeutic approaches based on this concept.