Leilei Zhu

Superparamagnetic iron oxide nanoparticle targeting of adipose tissue-derived stem cells in diabetes-associated erectile dysfunction.

Erectile dysfunction (ED) is a major complication of diabetes, and many diabetic men with ED are refractory to common ED therapies. Adipose tissue-derived stem cells (ADSCs) have been shown to improve erectile function in diabetic animal models. However, inadequate cell homing to damaged sites has limited their efficacy. Therefore, we explored the effect of ADSCs labeled with superparamagnetic iron oxide nanoparticles (SPIONs) on improving the erectile function of streptozotocin-induced diabetic rats with an external magnetic field. We found that SPIONs effectively incorporated into ADSCs and did not exert any negative effects on stem cell properties. Magnetic targeting of ADSCs contributed to long-term cell retention in the corpus cavernosum and improved the erectile function of diabetic rats compared with ADSC injection alone. In addition, the paracrine effect of ADSCs appeared to play the major role in functional and structural recovery. Accordingly, magnetic field-guided ADSC therapy is an effective approach for diabetes-associated ED therapy.

Predictors of pregnancy outcome for infertile couples attending IVF and ICSI programmes.

The purpose of this study was to evaluate the predictors of pregnancy outcome for infertile couples attending in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) programmes. Infertile couples attending IVF or ICSI procedures were included in this study. Related data including semen parameters and male and female age and body mass index were collected and analysed. The main outcome was clinical pregnancy, defined as an ultrasound detection of foetal heartbeat 6 weeks after embryo transfer. A total of 1316 couples who underwent IVF and 266 who underwent ICSI were recruited for this study. A multivariate logistic regression with likelihood ratio test revealed the following predictors of pregnancy outcome: female age and sperm DNA fragmentation index (DFI) and acrosomal activity in IVF procedures (chi‐square of likelihood ratio = 26.42, d.f. = 3, P < 0.005) and female age and DFI in ICSI procedures (chi‐square of likelihood ratio = 18.88, d.f. = 2, P < 0.005). In conclusion, our study indicated that sperm DFI, female age and acrosomal levels have a significant effect on ART pregnancy outcome.

Somatosensory evoked potentials assess the efficacy of circumcision for premature ejaculation.

To assess the efficacy and mechanism of circumcision in the treatment of premature ejaculation (PE) with redundant prepuce, we enrolled a total of 81 PE patients who received circumcision. The patients’ ejaculatory ability and sexual performances were evaluated before and after circumcision by using questionnaires (Intravaginal ejaculation latency time (IELT), Chinese Index of PE with 5 questions (CIPE-5) and International Index of Erectile function- 5 (IIEF-5)). Furthermore, somatosensory evoked potentials (SEPs) including dorsal nerve (DNSEP) and glans penis (GPSEP) of the patients were also measured. The mean IELTs of preoperation and post operation were 1.10±0.55 and 2.48±2.03 min, respectively (P<0.001). In addition, the geometric mean IELT after operation was 2.16 min, compared with the baseline 1.07 min before the operation, the fold increase of the IELT was 2.02. Compared with the uncircumcised status, scores of CIPE-5 showed a significant increase after circumcision (P<0.001). The mean latencies (and amplitudes) of GPSEP and DNSEP were 38.1±4.0 ms (3.0±1.9 uV) and 40.5±3.4 ms (2.8±1.6 uV) before circumcision, respectively; and 42.8±3.3 ms (2.8±1.6 uV) and 40.5±4.1 ms (2.4±1.2 uV) in the follow-up end point after circumcision. Only the latencies of GPSEP showed significant prolongation before and after circumcision (P<0.001). The ejaculation time improvement after circumcision is so small, and equal to placebo response, therefore it could not be interpreted as a therapeutic method in men with PE.

Demethylation treatment restores erectile function in a rat model of hyperhomocysteinemia.

Methylation modification is an important cellular mechanism of gene expression regulation. Dimethylarginine dimethylaminohydrolase-2 (DDAH-2) protein is a pivotal molecular for endothelium function. To explore the effects of 5-aza-deoxycytidine (5-aza), a demethylation agent, in hyperhomocysteinemia (hhcy)-related erectile dysfunction (ED) rats, 5-aza (1 mg kg−1 ) was administrated to Sprague-Dawley hhcy-rats induced by supplemented methionine chow diet. Erectile function, nitric oxide-cyclic guanosine monophosphate (NO-cGMP) levels, expression of DDAH-2 protein and promoter methylation status of DDAH-2 were studied in the corpora cavernosa. We found that supplemented methionine diet induced a high homocysteine level after 6 weeks of treatment. DDAH-2 protein was down-regulated in the corpora cavernosa while the administration of 5-aza up-regulated DDAH-2 expression and restored erectile function. The methionine-fed rats showed high methylation levels of DDAH-2 promoter region while the group treated with 5-aza demonstrated lower-methylation levels when compared to the methionine-fed group. Besides, the administration of 5-aza improved NO and cGMP levels in methionine-fed rats. Therefore, the methylation mechanism involves in ED pathogenesis, and demethylation offers a potential new strategy for ED treatment.

Inhibition of penile tunica albuginea myofibroblasts activity by adipose‑derived stem cells

The activation of tunica albuginea myofibroblasts (MFs) serves an essential role in Peyronies disease (PD). Increasing evidence has reported that adipose tissue-derived stem cells (ADSCs) have been demonstrated to attenuate the symptoms of PD in animal models. However, the mechanisms of the antifibrotic effects of ADSCs in PD remain to be fully elucidated. In the present study, the inhibitory effects and possible mechanism of ADSCs on the activation of MFs derived from rat penile tunica albuginea were investigated. ADSCs were obtained from the paratesticular fat of Sprague Dawley rats. MFs were transformed from rat penile tunica albuginea fibroblasts through stimulation with 5 ng/ml tumor growth factor-β1. Transwell cell cultures were adopted for co-culture of ADSCs and MFs. Western blot analysis was used to assess changes in the expression levels of α smooth muscle actin (αSMA), collagen I, phosphorylated (p)-SMAD family member 2 (Smad2), Smad2, ras homolog family member A (RhoA), Rho associated coiled-coil containing protein kinase (ROCK)1 and ROCK2, caspase3, caspase9, and matrix metalloproteinases (MMPs). Collagen gel assays were used to assess cell contractility. Additionally, the concentration of hydroxyproline in the culture medium was detected using commercially available kits. It was demonstrated that ADSCs reduced the expression of αSMA and collagen I of MFs. Furthermore, p-Smad2, RhoA, ROCK1 and ROCK2 expression was significantly reduced in the MFs+ADSCs group compared with that in the MFs-only culture, while the expression of MMPs (MMP2, MMP3, MMP9 and MMP13) and caspases (caspase3 and caspase9) was upregulated. In addition, ADSCs were able to downregulate the concentration of hydroxyproline in the culture medium of MFs and reverse the contraction of MFs. Collectively, these results suggested that ADSCs inhibited the activation of MFs, decreased collagen production, and suppressed the contraction of myofibroblasts, via Smad and RhoA/ROCK signaling pathways. Furthermore, ADSCs reduced the deposition of collagen and promoted the apoptosis of MFs via MMPs, and caspases. Accordingly, the application of ADSCs may provide a novel therapeutic strategy for PD.

Epalrestat, an Aldose Reductase Inhibitor, Restores Erectile Function in Streptozocin-induced Diabetic Rats

Epalrestat, an aldose reductase inhibitor (ARI), was adopted to improve the function of peripheral nerves in diabetic patients. The aim of this study was to investigate whether epalrestat could restore the erectile function of diabetic erectile dysfunction using a rat model. From June 2016, 24 rats were given streptozocin (STZ) to induce the diabetic rat model, and epalrestat was administered to ten diabetic erectile dysfunction (DED) rats. Intracavernous pressure (ICP) and mean systemic arterial pressure (MAP), levels of aldose reductase (AR), nerve growth factor (NGF), neuronal nitric oxide synthase (nNOS), α-smooth muscle antigen (α-SMA), and von Willebrand factor (vWF) in the corpus cavernosum were analyzed. We discovered that epalrestat acted on cavernous tissue and partly restored erectile function. NGF and nNOS levels in the corpora were increased after treatment with epalrestat. We also found that the content of α-SMA-positive smooth muscle cells and vWF-positive endothelial cells in the corpora cavernosum were declined. Accordingly, epalrestat might improve erectile function by increasing the upregulation of NGF and nNOS to restore the function of the dorsal nerve of the penis.

Lack of association between aryl hydrocarbon receptor gene Arg554Lys polymorphism and male infertility risk: A systematic review and meta-analysis

OBJECTIVES The association between aryl hydrocarbon receptor gene (AhR) polymorphism and male infertility risk remains conflicting. We conducted a meta-analysis to examine the AhR Arg554Lys polymorphism in relation to the susceptibility to male infertility. STUDY DESIGN Studies concerning the association between AHR polymorphism and male infertility were searched and related information were extracted from the included studies. The STATA 12.0 software was used to perform a meta-analysis. Pooled odd ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to estimate the association. RESULTS Six case-control studies with 1234 cases and 1755 controls were included after literature research and data collection. Overall, the results indicated there was no association between the AhR Arg554Lys polymorphism and male infertility risk (G versus A, OR (95%CI) = 0.958 (0.710-1.291); GG vs AA, OR (95%CI) = 0.874 (0.702-1.088); GA versus AA, OR (95%CI) = 0.911(0.477-1.740); GG + GA vs AA, OR (95%CI) = 0.891 (0.468-1.696); GG versus GA + AA, OR (95%CI) = 1.049(0.896-1.229)). Subgroup analysis by study population revealed there was no association between AhR Arg554Lys polymorphism and susceptibility to male infertility in Asian population (G versus A, OR (95%CI) = 1.099 (0.940-1.286); GG vs AA, OR (95%CI) = 0.982 (0.781-1.235); GA versus AA, OR (95%CI) = 1.220 (0.726-2.052); GG + GA vs AA, OR (95%CI) = 1.221 (0.740-1.982); GG versus GA + AA, OR (95%CI) = 1.087 (0.919-1.286)). CONCLUSIONS The association between AHR Arg55Lys polymorphism and male infertility risk was not confirmed in our meta-analysis. However, the results should be interpreted with caution and further studies are required.

Impact of varicocelectomy on the proteome profile of testicular tissues of rats with varicocele

Varicocele (VC) is a common cause of male infertility, but the molecular mechanisms involved in its pathogenesis are unknown. We investigated the impact of varicocelectomy (VCT) on proteome profiles in testicular tissues of rats with VC, and analysed associated target genes and signalling pathways. Sixty male rats with VC were divided into two groups: control (n = 30), and VCT (n = 30). Tissues were collected 4 weeks after sham or VCT surgery. Matrix‐assisted laser desorption/ionisation time‐of‐flight/time‐of‐flight mass spectrometry (MALDI‐TOF/TOF MS) was used to analyse the comparative proteome profiles. Kyoto Encyclopaedia of Genes and Genomes (KEGG) Orthology‐Based Annotation System was used for bioinformatic analysis. Fifteen proteins were differentially expressed between control and VCT groups. These differentially expressed proteins are associated with several specific cellular processes associated with the pathogenesis of testicular growth arrest associated with VC. Furthermore, the evaluation by transmission electron micrograph showed that VCT could decrease apoptosis of spermatogenic cells in rats. Understanding such molecular pathways might provide physicians with a better insight into VC and with potential targets for treatment.

Repeated Micro-Trauma of the Penile Tunica Albuginea: A New Animal Model of Peyronie's Disease

Objectives: To compare effects of repairing injured tunica albuginea (PTA) of rat penis by single or repeated local injections of chlorhexidine ethanol (ChE) into the PTA and to establish a new animal model of Peyronies disease (PD). Materials and Methods: Forty-two rats were divided into 7 groups. Rats either served as the normal control group with 1-5 injections of 0.9% saline or they received a single injection, 2, 3, 4, or 5 injections of ChE (0.1% chlorhexidine gluconate plus 15% ethanol dissolved in saline); rats in the positive control group were injected with TGF-β1. At 60 days after the last injection, the intracavernous pressure, degree of penile curvature, and histology were evaluated. Results: Compared with the single injection of the ChE group, we found the following in the repeat ChE injections groups: an increase in the degree of penile curvature, fibrous plaques in the PTA and/or corpus cavernosum, broken elastic fibers, slightly decreased erectile function, and an increased expression of TGF-β1 and αSMA. Conclusions: Repeated ChE injuries of PTA may lead to fibrosis. This represents an excellent model of PD that involves repeated injections of ChE into the local PTA as well as reveals the pathophysiologic mechanism of PD.