Probucol improves erectile function by regulating endoplasmic reticulum stress in rats with streptozotocin-induced diabetes.

This study was to explore the effect and mechanism of Probucol on STZ-induced erectile dysfunction in diabetic rats. Thirty SD male rats aged 12 weeks were given intraperitoneal injection of STZ after fasting for 12 hr. Diabetic rats were haphazardly partitioned under two assemblies and administered 0 or 500 mg/kg probucol by oral gavage to 12 weeks. Control group was intraperitoneally injected with physiological saline, and saline was administered by oral gavage daily. Intracorporeal pressure was used to evaluate erectile function. Levels of proteins were detected using immunohistochemistry and Western blotting. α-SMA and vWF were detected using immunofluorescence staining. After treatment, erectile function in probucol group was significantly improved. Endoplasmic reticulum stress-related proteins were expressed higher in DM group than in sham group, while expression of these proteins decreased significantly in probucol group. However, α-SMA and vWF were expressed at lower levels in DM group than in sham group, and probucol treatment reversed this phenomenon. Finally, Bax and Caspase3 were expressed at higher levels and Bcl-2 was expressed at lower levels in DM group, while the opposite result was obtained in probucol group. In conclusions, probucol improves erectile function by reducing endothelial dysfunction and inhibiting PERK/ATF4/CHOP pathway in STZ-induced diabetic rats.

miR-200a-3p-enriched MSC-derived extracellular vesicles reverse erectile function in diabetic rats by targeting Keap1.

BACKGROUND: The administration of mesenchymal stem cells (MSCs) through intracavernous injection is a potential therapeutic approach for managing diabetes mellitus-induced erectile dysfunction (DMED). However, pulmonary embolism and tumorigenicity are fatal adverse events that limit the clinical application of MSCs. In this study, we examined the therapeutic efficacy and potential mechanism of MSC-derived extracellular vesicles (MSC-EVs). METHODS: In this study, forty 8-week-old male SpragueDawley (SD) rats were utilised. In the control group, ten rats were administered an intraperitoneal injection of PBS. STZ (60 mg/kg) was intraperitoneally injected into the remaining rats to establish a diabetes mellitus (DM) model. Afterwards, the diabetic rats were divided into three groups at random: the DM group (intracavernosal injection of PBS), the EVs group (intracavernosal injection of MSC-EVs), and the EVs-200a group (intracavernosal injection of miR-200a-3p-enriched extracellular vesicles). Erectile function was determined by measuring intracavernous pressure in real time and utilising electrical stimulation of the cavernous nerves. The smooth muscle content was evaluated through the investigation of penile tissue using immunofluorescence staining, Masson's trichrome staining, and western blotting after euthanasia. Superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) levels in the corpus cavernosum were measured via ELISA. In vitro, hydrogen peroxide (H2O2) was used to induce oxidative stress. The viability of corpus cavernosum smooth muscle cells (ccSMCs) incubated with or without H2O2 was measured using a CCK8 assay. Flow cytometry was used to assess the levels of reactive oxygen species (ROS) and apoptosis in ccSMCs. Furthermore, a dual-luciferase reporter assay was performed to validate the relationship between miR-200a-3p and Keap1. RESULTS: Reversal of erectile function was observed in the EVs groups, especially in the EVs-200a group. DM increased the MDA level and decreased the SOD and GSH levels. In the DM group, the expression of alpha-smooth muscle actin (α-SMA) and smooth muscle 22 alpha (SM22α) was decreased, and the expression of osteopontin (OPN) was increased. Western blotting revealed decreased Nrf2, HO-1, and Bcl2 expression and increased Keap1, Bax and cleaved caspase3 expression in the cavernous tissue. miR-200a-3p-enriched extracellular vesicles (EVs-200a) reversed these changes and inhibited the loss of smooth muscle content and cavernous fibrosis. In vitro, H2O2 induced high ROS levels in ccSMCs and increased apoptosis, and these effects reversed by EVs-200a. H2O2 reduced Nrf2, HO-1, and Bcl2 expression and increased Keap1, Bax and cleaved caspase-3 expression, and these effects were reversed by MSC-EVs, especially EVs-200a. The of dual-luciferase reporter assay results indicated that miR-200a-3p directly targeted Keap1 in a negative manner. CONCLUSION: MSC-EVs, especially EVs-200a, alleviated erectile dysfunction in diabetic rats through the regulation of phenotypic switching, apoptosis and fibrosis. Mechanistically, miR-200a-3p targeted the Keap1/Nrf2 pathway to attenuate oxidative stress in diabetic rats.

Effects of endoplasmic reticulum stress on erectile function in rats with cavernous nerve injury.

Background: Erectile dysfunction (ED) occurs in an increasing number of patients after radical prostatectomy and cystectomy, and the phenotypic modulation of corpus cavernosum smooth muscle cells is closely related to ED. Aim: To determine whether endoplasmic reticulum stress (ERS) is implicated in the phenotypic modulation of ED induced by bilateral cavernous nerve injury (BCNI). Methods: In total, 36 Sprague-Dawley rats were randomly divided into 3 groups: sham, in which rats received sham surgery with bilateral cavernous nerve exposure plus phosphate-buffered saline; control, in which rats received BCNI plus phosphate-buffered saline; and experimental, in which rats received BCNI plus 4-phenylbutyric acid. Analysis of variance and a Bonferroni multiple-comparison test were utilized to evaluate differences among groups. Outcomes: Erectile function, smooth muscle/collagen ratios, and the expression levels of phenotypic modulation and ERS were measured. Results: Two ratios-maximum intracavernosal pressure/mean arterial pressure and smooth muscle/collagen-were decreased in the control group as compared with the sham group. In penile tissue, there was increased expression of GRP78 (78-kDa glucose-regulated protein), p-PERK/PERK (phosphorylated protein kinase R-like endoplasmic reticulum kinase/protein kinase R-like endoplasmic reticulum kinase), caspase 3, CHOP (C/EBP homologous protein), and OPN (osteopontin) but decreased expression of nNOS (neuronal nitric oxide synthase) and α-SMA (α-smooth muscle actin). As compared with the control group, erectile function was improved and pathologic changes were partially recovered in the experimental group. Clinical Translation: The present study demonstrated that ERS is involved in ED caused by cavernous nerve injury, thereby providing a new target and theoretical basis for clinical treatment. Strengths and Limitations: The present study demonstrated for the first time that ERS is related to ED caused by cavernous nerve injury. Inhibition of ERS reverses phenotypic modulation and improves erectile function in rats with BCNI. Additional in vitro studies should be performed to verify these conclusions and explore the specific mechanism of phenotypic modulation. Conclusion: The present study demonstrated that inhibiting ERS reverses phenotypic modulation and enhances erectile function in rats with BCNI.

Efficacy and Safety of 1470 nm Diode Laser Enucleation of the Prostate in Elderly Benign Prostatic Hyperplasia Patients.

Objective: The aim of this study was to evaluate efficacy and safety of 1470 nm diode laser enucleation of the prostate (DiLEP) and plasmakinetic resection of the prostate (PKRP) in elderly benign prostatic hyperplasia (BPH) patients with lower urinary tract symptoms. Methods: A total of 123 elderly patients with BPH were randomized to undergo either 1470 nm DiLEP or PKRP by means of a random number table from September 2020 to April 2022. The perioperative and postoperative data were studied during a 3- and 6-month follow-up. Results: The patients treated with 1470 nm DiLEP had significantly decreased operation time (74.6 ± 17.0 vs 98.8 ± 18.9 minutes, p < 0.001), hemoglobin loss (1.06 ± 0.49 vs 1.59 ± 0.60 g/dL, p < 0.001), bladder irrigation time (22.1 ± 8.1 vs 33.9 ± 10.0 hours, p < 0.001), catheter duration (3.2 ± 1.3 vs 5.8 ± 1.0 days, p < 0.001), and hospital stay (7.6 ± 1.4 vs 9.6 ± 1.3 days, p < 0.001) compared with the PKRP group. Besides, International Index of Erectile Function-5 score of 1470 nm DiLEP group at postoperative 3- and 6-month follow-up was significantly higher than PKRP group. No differences achieving statistical significance were identified in total prostate-specific antigen, maximum urinary flow rate, International Prostate Symptom Score, quality-of-life score, and the postvoid residual urine volume, transient incontinence, urethral stricture, bladder neck contracture, and retrograde ejaculation at 3- and 6-month follow-up. Conclusions: 1470 nm DiLEP is safer than PKRP, with a smaller effect on sexual function, and it is comparable with the efficacy of PKRP, thus making it more suitable for elderly BPH patients. Clinical Trial Registration number: S2021-463-01.

Extraperitoneal Laparoscopic Modified Y-V Plasty for the Treatment of Refractory Bladder Neck Contracture.

Bladder neck contracture (BNC) is a rare, late complication of transurethral resection of the prostate (TURP). Although the endoscopic procedure is the primary treatment for BNC, the recurrence rate remains high. Y-V plasty offers excellent surgical results for those individuals with refractory and recurrent BNC. Traditional open operations usually fail to provide satisfactory exposure to the operating field and lead to greater invasiveness. Interrupted sutures lead to prolonged operative time and increased anastomotic leakage. Laparoscopic modified Y-V plasty is performed through extraperitoneal access to the pelvis, which provides adequate exposure to the surgical view and avoids intra-abdominal injury. After incising the anterior bladder wall neck in a Y-shaped fashion, anastomosis is performed using two absorbable barbed sutures. The mucosa and submucosa layer of the bladder is closed to both sides with consecutive sutures in a V-shape before suturing serosa, and tunica muscularis are sutured to reinforce. The aforementioned procedures reduce leakage from the anastomosis and decrease operative time and patient trauma. Extraperitoneal laparoscopic modified Y-V plasty offers significant advantages over the open approach in terms of post-surgical recovery and invasiveness, making it a feasible and safe surgical option for patients with refractory BNC.