Xianzhen Jiang

Increased adenosine contributes to penile fibrosis, a dangerous feature of priapism, via A2B adenosine receptor signaling

Priapism is a condition of persistent penile erection in the absence of sexual excitation. Of men with sickle cell disease (SCD), 40% display priapism. The disorder is a dangerous and urgent condition, given its association with penile fibrosis and eventual erectile dysfunction. Current strategies to prevent its progression are poor because of a lack of fundamental understanding of the molecular mechanisms for penile fibrosis in priapism. Here we demonstrate that increased adenosine is a novel causative factor contributing to penile fibrosis in two independent animal models of priapism, adenosine deaminase (ADA)‐deficient mice and SCD transgenic mice. An important finding is that chronic reduction of adenosine by ADA enzyme therapy successfully attenuated penile fibrosis in both mouse models, indicating an essential role of increased adenosine in penile fibrosis and a novel therapeutic possibility for this serious complication. Subsequently, we identified that both mice models share a similar fibrotic gene expression profile in penile tissue (including procollagen I, TGF‐ß1, and plasminogen activator inhibitor‐1 mRNA), suggesting that they share similar signaling pathways for progression to penile fibrosis. Thus, in an effort to decipher specific cell types and underlying mechanism responsible for adenosine‐mediated penile fibrosis, we purified corpus cavernosal fibroblast cells (CCFCs), the major cell type involved in this process, from wild‐type mice. Quantitative RT‐PCR showed that the major receptor expressed in these cells is the adenosine receptor A2BR Based on this fact, we further purified CCFCs from A2BR‐deficient mice and demonstrated that A2BR is essential for excess adenosine‐mediated penile fibrosis. Finally, we revealed that TGF‐ß functions downstream of the A2BR to increase CCFC collagen secretion and proliferation. Overall, our studies identify an essential role of increased adenosine in the pathogenesis of penile fibrosis via A2BR signaling and offer a potential target for prevention and treatment of penile fibrosis, a dangerous complication seen in priapism.—Wen, J., Jiang, X., Dai, Y., Zhang, Y., Tang, Y., Sun, H., Mi, T., Phatarpekar, P. V., Kellems, R E., Blackburn, M. R, Xia, Y. Increased adenosine contributes to penile fibrosis, a dangerous feature of priapism, via A2B adenosine receptor signaling. FASEB J. 24, 740–749 (2010). www.fasebj.org

Adenosine deaminase enzyme therapy prevents and reverses the heightened cavernosal relaxation in priapism.

INTRODUCTION Priapism featured with painful prolonged penile erection is dangerous and commonly seen in sickle cell disease (SCD). The preventive approaches or effective treatment options for the disorder are limited because of poor understanding of its pathogenesis. Recent studies have revealed a novel role of excess adenosine in priapism caused by heightened cavernosal relaxation, and therefore present an intriguing mechanism-based therapeutic possibility. AIM The aim of this study was to determine the therapeutic effects of adenosine deaminase (ADA) enzyme therapy to lower adenosine in priapism. METHODS Both ADA-deficient mice and SCD transgenic (Tg) mice display priapism caused by excessive adenosine. Thus, we used these two distinct lines of mouse models of priapism as our investigative tools. Specifically, we treated both of these mice with different dosages of polyethylene glycol-modified ADA (PEG-ADA) to reduce adenosine levels in vivo. At the end points of the experiments, we evaluated the therapeutic effects of PEG-ADA treatment by measuring adenosine levels and monitoring the cavernosal relaxation. MAIN OUTCOME MEASURES Adenosine levels in penile tissues were measured by high-performance liquid chromatography, and cavernosal relaxation was quantified by electrical field stimulation (EFS)-induced corporal cavernosal strip (CCS) assays. RESULTS We found that lowering adenosine levels in penile tissues by PEG-ADA treatment from birth in ADA-deficient mice prevented the increased EFS-induced CCS relaxation associated with priapism. Intriguingly, in both ADA-deficient mice and SCD Tg mice with established priapism, we found that normalization of adenosine levels in penile tissues by PEG-ADA treatment relieved the heightened EFS-induced cavernosal relaxation in priapism. CONCLUSIONS Our studies have identified that PEG-ADA is a novel, safe, and mechanism-based drug to prevent and correct excess adenosine-mediated increased cavernosal relaxation seen in two independent priapic animal models, and suggested its therapeutic possibility in men suffering from priapism.

Peripheral Blood Mitochondrial DNA Copy Number Is Associated with Prostate Cancer Risk and Tumor Burden

Alterations of mitochondrial DNA (mtDNA) have been associated with the risk of a number of human cancers; however, the relationship between mtDNA copy number in peripheral blood leukocytes (PBLs) and the risk of prostate cancer (PCa) has not been investigated. In a case-control study of 196 PCa patients and 196 age-paired healthy controls in a Chinese Han population, the association between mtDNA copy number in PBLs and PCa risk was evaluated. The relative mtDNA copy number was measured using quantitative real-time PCR; samples from three cases and two controls could not be assayed, leaving 193 cases and 194 controls for analysis. PCa patients had significantly higher mtDNA copy numbers than controls (medians 0.91 and 0.82, respectively; P<0.001). Dichotomized at the median value of mtDNA copy number in the controls, high mtDNA copy number was significantly associated with an increased risk of PCa (adjusted odds ratio  = 1.85, 95% confidence interval: 1.21–2.83). A significant dose-response relationship was observed between mtDNA copy number and risk of PCa in quartile analysis (P trend = 0.011). Clinicopathological analysis showed that high mtDNA copy numbers in PCa patients were significantly associated with high Gleason score and advanced tumor stage, but not serum prostate-specific antigen level (P = 0.002, 0.012 and 0.544, respectively). These findings of the present study indicate that increased mtDNA copy number in PBLs is significantly associated with an increased risk of PCa and may be a reflection of tumor burden.

Multicenter pathophysiologic investigation of erectile dysfunction in clinic outpatients in China.

OBJECTIVE To assess the pathophysiologic composition and age structure of erectile dysfunction (ED) in men visiting outpatient clinics in China. METHODS We studied 3327 consecutive ED outpatients (median age 39 years) from 2006 to 2010 in the 5 training hospitals in China. Every patient was independently evaluated by an experienced urologist/andrologist using comprehensive diagnostic procedures. The simplified International Index of Erectile Function was used to assess the severity of ED. RESULTS Most patients (95.0%) were <60 years old, and none were >70 years old. The psychogenic patients were younger and had greater percentage than any other patients. Vasculogenic factors were a major etiology of organic ED. A significant difference was found in the age distribution between the patients with psychogenic ED and those with organic ED (P = .000). Diabetes, hypertension, coronary artery disease, and hyperlipidemia played significant roles in affecting the severity of ED in a statistical model, including age. The International Index of Erectile Function scores decreased with age (rs = -0.199, P = .000). Moreover, the percentage of severe and moderate cases increased with age (P = .003 and P = .002, respectively). However, the constituent ratio of patients sharply declined from 30.3% to 4.5% with age. CONCLUSION The number of men visiting outpatient clinics with psychological ED is greater than the number with organic causes in China. The age of the Chinese patients with ED who seek medical help is young and this is mainly because of inadequate sex education to young men and because most older patients are reluctant to visit the hospital just for the loss of erectile function.

Bias in Evaluating Erectile Function in Lifelong Premature Ejaculation Patients with the International Index of Erectile Function—5

INTRODUCTION Lifelong premature ejaculation (LPE) is the most important ejaculating dysfunction. Relatively little is known about erectile function in this population. AIMS We attempted to evaluate the erectile function of patients with LPE using the International Index of Erectile Function-5 (IIEF-5) to determine if it is sufficiently reliable and accurate to make such an assessment. METHODS A total of 406 patients with LPE were enrolled in our study. The participants voluntarily answered the Premature Ejaculation Diagnostic Tool (PEDT) and IIEF-5 questionnaires and underwent a full history evaluation and clinical examination by doctors. Their answers were converted into data analyzed by a statistic software. MAIN OUTCOME MEASURES The patients were diagnosed with LPE based on the diagnostic criteria and PEDT scores. The intravaginal ejaculation latency time was recorded according to patient self-reports. The IIEF-5 was used to evaluate their erectile function. Thorough history and clinical examination helped doctors make more correct diagnoses of erectile dysfunction (ED). RESULTS Of the 406 patients, 70 (17.24%) patients had ED, as confirmed by doctors. IIEF-5 was accurate for the assessment of the erectile function of LPE patients when the cutoff was decreased to 15.5. Question 5 (1.34 ± 0.53) was the main reason for the drop in the total IIEF-5 score. Questions 1 and 5 shared low consistency with the other three IIEF-5 items, thus they lowered the reliability of the IIEF-5 scores. These questions created a confounding bias that decreased the diagnostic threshold of IIEF-5. However, they could not be removed from the IIEF-5 because they did not reduce its diagnostic accuracy in patients with LPE. CONCLUSIONS Bias from questions 1 and 5 lowered the reliability of the IIEF-5 scores; however, it did not reduce the diagnostic accuracy of the IIEF-5. The recommendation is to edit questions 1 and 5 when they are applied to populations with LPE.