Mingchao Li

S-allyl cysteine restores erectile function through inhibition of reactive oxygen species generation in diabetic rats

Excessive production of reactive oxygen species (ROS) by an overactive nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system in penile tissue is an important mechanism of erectile dysfunction (ED). S‐allyl cysteine (SAC), a bioactive component derived from garlic, was recently reported to exert versatile antioxidant properties. We hypothesized that SAC would be able to resolve diabetes‐related ED by reducing ROS generation, and designed this study to investigate this possibility as well as to determine the related underlying mechanisms. A streptozotocin‐induced diabetes rat model was established and used for comparative analysis of 4‐week treatment regimens with insulin or SAC. The ratio of maximal intracavernous pressure (ICP) to mean arterial blood pressure (MAP) was measured to determine erectile function. Differential levels of ROS, NADPH oxidase subunits, nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signalling pathway, and apoptosis were evaluated in cavernous tissues. Max ICP/MAP was found to be markedly decreased in untreated diabetic rats; SAC, but not insulin, treatment restored the ratio to baseline (in non‐diabetic untreated controls). The corpus cavernosum of untreated diabetic rats showed increased p47phox and p67phox expression, ROS production and penile apoptotic index, and decreased phospho‐endothelial nitric oxide synthase (phospho‐eNOS, Ser1177) expression, cGMP concentration, B‐cell lymphoma 2 (Bcl‐2)/Bcl‐2‐associated X protein (Bax) ratio and smooth muscle cell number. SAC treatment normalized all the diabetes‐induced effects, whereas insulin treatment partially normalized the alterations, but produced no effects on P47phox expression, penile ROS level, apoptotic index, Bcl‐2/Bax ratio and smooth muscle cell number. Collectively, these data indicate that SAC treatment can restore erectile function in diabetic rats by preventing ROS formation through modulation of NADPH oxidase subunit expression. Furthermore, the poor efficacy of conventional insulin treatment for diabetic ED may be associated with an elevated level of ROS in penile tissue.

Apocynin Improves Erectile Function in Diabetic Rats through Regulation of NADPH Oxidase Expression

INTRODUCTION Diabetes is a risk factor for erectile dysfunction (ED). The proposed mechanisms responsible for diabetic ED are associated with an increase in reactive oxygen species (ROS) production, overactivity of RhoA/ROCK signaling pathway and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, as seen in experimental models of diabetic rats. AIM The aim of this study was to investigate whether NADPH oxidase inhibitor apocynin can ameliorate Streptozotocin (STZ)-induced diabetes-related ED by reducing the ROS production and inhibiting the activity of RhoA/ROCK signaling pathway. METHODS The diabetic rats were treated with and without the NADPH oxidase inhibitor apocynin. MAIN OUTCOME MEASURES Erectile responses were evaluated by determining mean arterial blood pressure (MAP) and intracavernosal pressure (ICP) with electrical stimulation of the cavernous nerve. Levels of mRNA expression were measured by real-time polymerase chain reaction (RT-PCR). Levels of protein expression were examined by Western Blot. ROS production was measured by dihydroethidium (DHE) staining and thiobarbituric acid reactive substances assay. RESULTS The ratio of Maximum ICP-to-MAP (MaxICP/MAP) was significantly decreased in diabetic ED rats, compared to that of age-matched control rats (P < 0.05). Apocynin improved erectile function of diabetic rats (P < 0.05). Expression levels of RhoA (cytosol), nNOS and eNOS were reduced, compared to those of control rats (P < 0.05). Apocynin significantly elevated their expression levels in diabetic rats (P < 0.05). Expression levels of ROCK1, RhoA (membrane fraction), p-MYPT1 and NADPH oxidase subunits p47(phox) and p67(phox) were increased in diabetic rats when compared to those of control rats (P < 0.05), and it was observed that apocynin significantly reduced their expression levels in diabetic rats (P < 0.05). ROS production was increased in diabetic rats when compared to that of control rats (P < 0.05), the effect of apocynin was a reduction in the ROS production in diabetic rats (P < 0.05). CONCLUSION NADPH oxidase inhibitor apocynin can ameliorate diabetes-related ED by reducing the ROS production and inhibiting the activity of RhoA/ROCK signaling pathway.

saRNA Guided iNOS Up-Regulation Improves Erectile Function of Diabetic Rats

PURPOSE Promoter targeted saRNAs mediate sequence specific up-regulation of gene expression. We explored the therapeutic effect of RNA activation mediated iNOS gene activation on improving erectile function in a rat model of diabetes mellitus. MATERIALS AND METHODS An optimal saRNA sequence specific for iNOS promoter was cloned into an adenoviral vector, resulting in AdU6/shiNOS and AdU6/shControl. The corresponding viruses were used to transduce cultured rat cavernous smooth muscle cells. Streptozotocin induced diabetes models were established in rats and used to test the effects of intracavernous delivery of iNOS saRNA viruses on erectile function. iNOS expression in the cavernous smooth muscle cells or penile tissue of treated rats was assessed by reverse transcriptase-polymerase chain reaction and Western blot. Cyclic guanosine monophosphate was analyzed by enzyme-linked immunosorbent assay. Intracavernous pressure in response to cavernous nerve stimulation was measured using a data acquisition system on post-injection days 1, 3, 5, 7, 10 and 14. RESULTS Adenovirus mediated expression of iNOS saRNA caused sustained up-regulation of iNOS in cavernous smooth muscle cells. Intracavernous injection of AdU6/shiNOS activated iNOS expression in vivo and significantly increased peak intracavernous pressure in streptozotocin induced diabetic rats via nitric oxide/intracellular cyclic guanosine monophosphate activation. CONCLUSIONS Results show that saRNA mediated iNOS over expression in the penis can restore erectile function in streptozocin diabetic rats via the nitric oxide-cyclic guanosine monophosphate pathway.

Taurine Supplementation Improves Erectile Function in Rats with Streptozotocin-induced Type 1 Diabetes via Amelioration of Penile Fibrosis and Endothelial Dysfunction

INTRODUCTION For patients with diabetes, erectile dysfunction (ED) is common and greatly affects quality of life. However, these patients often exhibit a poor response to first-line oral phosphodiesterase type 5 inhibitors. AIM To investigate whether taurine, a sulfur-containing amino acid, affects diabetic ED (DED). METHODS Type 1 diabetes mellitus was induced in male rats by using streptozotocin. After 12 weeks, an apomorphine test was conducted to confirm DED. Only rats with DED were administered taurine or vehicle for 4 weeks. Age-matched nondiabetic rats were administered saline intraperitoneally for 4 weeks. MAIN OUTCOME MEASURES Erectile function was evaluated by electrical stimulation of the cavernous nerve. Histologic and molecular alterations of the corpus cavernosum also were analyzed. RESULTS Erectile function was significantly reduced in the diabetic rats compared with in the nondiabetic rats, and was improved in the diabetic rats treated with taurine. The corpus cavernosum of the rats with DED exhibited severe fibrosis and decreased smooth muscle content. Deposition of extracellular matrix proteins was increased in the diabetic rats, while expression of endothelial nitric oxide synthase/cyclic guanosine monophosphate/nitric oxide pathway-related proteins was reduced. Taurine supplementation ameliorated erectile response as well as histologic and molecular alterations. CONCLUSION Taurine supplementation improves erectile function in rats with DED probably by potential antifibrotic activity. This finding provides evidence for a potential new therapy for DED.

Effects of apocynin on oxidative stress and expression of apoptosis-related genes in testes of diabetic rats

Reactive oxygen species (ROS) are important in the development of diabetic testicular dysfunction. Overproduction of ROS promotes the process of apoptosis, which shows that there is a crosstalk between oxidative stress and apoptosis. Recent research has suggested that NADPH oxidase is the main source of ROS. In this study, we investigated whether the NADPH oxidase inhibitor, apocynin, can improve diabetes‑induced testicular dysfunction by suppressing oxidative stress. The streptozocin (STZ)-induced diabetic rats were administered apocynin, and the mRNA and protein expression of Bax, Bcl-2, p47phox and p67phox was examined by real-time PCR (RT-PCR) and western blot analysis. Production of ROS was measured by thiobarbituric acid reactive substances (TBARS) assay. Terminal-deoxynucleoitidyl transferase mediated nick end-labeling (TUNEL) assay was used to detect apoptosis and ELISA was used to detect total testosterone levels. The mRNA and protein expression of Bcl-2 was significantly reduced, and that of Bax, p47phox and p67phox was significantly increased in the diabetic rats compared to the control group. Apocynin significantly increased the expression of Bcl-2 and decreased the expression of Bax, p47phox and p67phox at both the mRNA and protein levels. The production of ROS and apoptotic cells significantly increased in the diabetic group compared to the control group. Apocynin significantly reduced the production of ROS and apoptotic cells and increased the total testosterone level. In conclusion, apocynin is capable of ameliorating testicular dysfunction.

Flightless I Homolog Represses Prostate Cancer Progression through Targeting Androgen Receptor Signaling

Purpose: Flightless I (FLII), member of the gelsolin superfamily of actin-remodeling proteins, functions as a transcriptional coregulator. We aim to evaluate a tumor-suppressive function of FLII in regulating androgen receptor (AR) in prostate cancer progression. Experimental Design: We examined FLII protein and mRNA expression in clinical prostate cancer specimens by immunohistochemistry. Kaplan–Meier analysis was conducted to evaluate the difference in disease-overall survival associated with the expression levels of FLII and AR. Prostate cancer cells stably expressing FLII or shRNA knockdown were used for functional analyses. Immunoprecipitation, Luciferase reporter, and immunofluorescence staining assays were performed to examine the functional interaction between FLII and AR. Results: Our analysis of the expression levels of FLII in a clinical gene expression array dataset showed that the expression of FLII was positively correlated with the overall survival of prostate cancer patients exhibiting high levels of AR expression. Examination of protein and mRNA levels of FLII showed a significant decrease of FLII expression in human prostate cancers. AR and FLII formed a complex in a ligand-dependent manner through the ligand-binding domain (LBD) of AR. Subsequently, we observed a competitive binding to AR between FLII and the ligand. FLII inhibited AR transactivation and decreased AR nuclear localization. Furthermore, FLII contributed to castration-sensitive and castration-resistant prostate cancer cell growth through AR-dependent signaling, and reintroduction of FLII in prostate cancer cells sensitized the cells to bicalutamide and enzalutamide treatment. Conclusions: FLII plays a tumor-suppressive role and serves as a crucial determinant of resistance of prostate cancer to endocrine therapies. Clin Cancer Res; 22(6); 1531–44. ©2015 AACR.

Efficacy and safety of solifenacin plus tamsulosin oral controlled absorption system in men with lower urinary tract symptoms: a meta-analysis.

We performed a meta-analysis to compare treatment with a combination of solifenacin plus tamsulosin oral controlled absorption system (TOCAS) with placebo or TOCAS monotherapy. The aim of the meta-analysis was to clarify the efficacy and safety of the combination treatments method for lower urinary tract symptoms (LUTS). We searched for trials of men with LUTS that were randomized to combination treatment compared with TOCAS monotherapy or placebo. We pooled data from three placebo-controlled trials meeting inclusion criteria. Primary outcomes of interest included changes in International Prostate Symptom Score (IPSS) and urinary frequency. We also assessed postvoid residual, maximum urinary flow rate, incidence of urinary retention (UR), adverse events. Data were pooled using random or fixed effect models for continuous outcomes and the Mantel-Haenszel method to generate risk ratio. Reductions in IPSS storage subscore and total urgency and frequency score (TUFS) were observed with solifenacin 6 mg plus TOCAS compared with placebo (P< 0.0001 and P< 0.0001, respectively). Reductions in IPSS storage subscore and TUFS were observed with solifenacin 9 mg plus TOCAS compared with placebo (P = 0.003 and P= 0.0006, respectively). Reductions in TUFS was observed with solifenacin 6 mg plus TOCAS compared with TOCAS (P = 0.01). Both combination treatments were well tolerated, with low incidence of UR. Solifenacin 6 mg plus TOCAS significantly improved total IPSS, storage and voiding symptoms compared with placebo. Solifenacin 6 mg plus TOCAS also improved storage symptoms compared with TOCAS alone. There was no additional benefit of solifenacin 9 mg compared with 6 mg when used in combination with TOCAS.

Local anesthesia for transrectal ultrasound-guided biopsy of the prostate: A meta-analysis

A meta-analysis was performed to evaluate the efficacy of local anesthesia in alleviating pain during prostate biopsy. We searched relevant articles in PubMed and Embase. The included studies should be randomized controlled trials (RCT) using local anesthesia to alleviate pain during biopsy, which was recorded by a pain scale. Analgesic efficacy of different local anesthesia techniques were analyzed, including intrarectal local anesthesia (IRLA), periprostatic nerve block (PNB), pelvic plexus block (PPB) and intraprostatic local anesthesia (IPLA). We included 46 RCTs. PNB significantly reduced pain score compared with placebo (−1.27 [95% confidence interval [95% CI] −1.72, −0.82]) or no injection (−1.01 [95% CI −1.2, −0.82]). IRLA with prilocaine-lidocaine cream could also reduced pain (−0.45 [95% CI −0.76, −0.15]), while the IRLA with lidocaine gel was not effective (−0.1 [95% CI −0.24, 0.04]). PNB lateral to the neurovascular bundle had better analgesic effect than at prostate apex (P = 0.02). Combination use of PPB and IRLA considerably alleviated pain of patients compared with the combination of PNB and IRLA (−1.32 [95% CI −1.59, −1.06]). In conclusion, local anesthesia could alleviate patients’ pain during the prostate biopsy. PNB was not so effective as PPB.

Stem Cell Therapy for Diabetic Erectile Dysfunction in Rats: A Meta-Analysis

Introduction Stem cell therapy is a novel method for the treatment of diabetic erectile dysfunction (ED). Many relative animal studies have been done to evaluate the efficacy of this therapy in rats. Aims This meta-analysis was performed to compare the efficacy of different stem cell therapies, to evaluate the influential factors and to determine the optimal stem cell therapeutic strategy for diabetic ED. Methods We searched the studies analyzing the efficacy of stem cell therapy for diabetic ED in rats published before September 30, 2015 in PubMed, Web of Science and EBSCO. A random effects meta-analysis was conducted to assess the outcomes of stem cell therapy. Subgroup analysis was also performed by separating these studies based on their different characteristics. Changes in the ratio of intracavernous pressure (ICP) to mean arterial pressure (MAP) and in the structure of the cavernous body were compared. Results 10 studies with 302 rats were enrolled in this meta-analysis. Pooled analysis of these studies showed a beneficial effect of stem cell therapy in improving erectile function of diabetic rats (SMD 4.03, 95% CI = 3.22 to 4.84, P< 0.001). In the stem cell therapy group, both the smooth muscle and endothelium content were much more than those in control group. There was also significant increase in the expression of endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS), the ratio of smooth muscle to collagen, as well as the secretion of vascular endothelial growth factor (VEGF). Besides, apoptotic cells were reduced by stem cell treatment. The subgroup analysis indicated that modified stem cells were more effective than those without modification. Conclusions Our results confirmed that stem cell therapy could apparently improve the erectile function of diabetic rats. Some specific modification, especially the gene modification with growth factors, could improve the efficacy of stem cell therapy. Stem cell therapy has potential to be an effective therapeutic strategy for diabetic ED.

Predictive value of FSH, testicular volume, and histopathological findings for the sperm retrieval rate of microdissection TESE in nonobstructive azoospermia: a meta-analysis

We performed this meta-analysis to evaluate the predictive value of different parameters in the sperm retrieval rate (SRR) of microdissection testicular sperm extraction (TESE) in patients with nonobstructive azoospermia (NOA). All relevant studies were searched in PubMed, Web of Science, EMBASE, Cochrane Library, and EBSCO. We chose three parameters to perform the meta-analysis: follicle-stimulating hormone (FSH), testicular volume, and testicular histopathological findings which included three patterns: hypospermatogenesis (HS), maturation arrest (MA), and Sertoli-cell-only syndrome (SCOS). If there was a threshold effect, only the area under the summary receiver operating characteristic curve (AUSROC) was calculated. Otherwise, the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and the diagnostic odds ratio (DOR) were also calculated. Twenty-one articles were included in our study finally. There was a threshold effect among studies investigating FSH and SCOS. The AUSROCs of FSH, testicular volume, HS, MA, and SCOS were 0.6119, 0.6389, 0.6758, 0.5535, and 0.2763, respectively. The DORs of testicular volume, HS, and MA were 1.98, 16.49, and 1.26, respectively. The sensitivities of them were 0.80, 0.30, and 0.27, while the specificities of them were 0.35, 0.98, and 0.76, respectively. The PLRs of them were 1.49, 10.63, and 1.15, respectively. And NLRs were 0.73, 0.72, and 0.95, respectively. All the investigated factors in our study had limited predictive value. However, the histopathological findings were helpful to some extent. Most patients with HS could get sperm by microdissection TESE.