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We evaluated the effect of a chronic treatment with Tadalafil on progenitor cells (PCs) number and endothelial function in patients with erectile dysfunction (ED) with or without cardiovascular risk factors. Twenty-six subjects with ED and 23 aged matched controls were studied. All subjects underwent blood tests, International Index of Erectile Function (IIEF-5), Nocturnal Penile Tumescence Rigidity Monitoring test (NPTRM), brachial artery flow-mediated dilation (FMD) and PCs count. International index of erectile function, FMD and PC count were re-evaluated in all subjects at the end of Tadalafil and placebo treatment. With respect to controls patients had lower basal FMD ( P <0.05) and basal PCs ( P <0.05). Treatment with Tadalafil determined a significant increase in PCs ( P <0.001) and FMD ( P <0.001) with respect to basal level. Positive correlation was found between basal FMD and PCs ( P <0.05) and between basal FMD and PCs increase after Tadalafil treatment ( P <0.05). Tadalafil promotes a mobilization of PCs and improves endothelial function in ED patients.

The exchange of solutes between the blood and the nerve tissue is mediated by specific and high selective barriers in order to ensure the integrity of the different compartments of the nervous system. At peripheral level, this function is maintained by the Blood Nerve Barrier (BNB) that, in the presence, of specific stressor stimuli can be damaged causing the onset of neurodegenerative processes. An essential component of BNB is represented by the endothelial cells surrounding the sub-structures of peripheral nerves and increasing evidence suggests that endothelial dysfunction can be considered a leading cause of the nerve degeneration. The purpose of this review is to highlight the main mechanisms involved in the impairment of endothelial cells in specific diseases associated with peripheral nerve damage, such as diabetic neuropathy, erectile dysfunction and inflammation of the sciatic nerve.

Erectile dysfunction (ED) in diabetes often resists phosphodiesterase type 5 inhibitors due to neuropathy and vasculopathy, both worsened by neuroinflammation. This study evaluated light-emitting diode (LED) therapy’s effects on diabetes-induced neurovascular damage using a diabetic mouse model. Diabetes was induced in C57BL/6 mice with streptozotocin, followed by treatment with RED (660 nm) and near-infrared (NIR; 830 nm) LED light, separately and combined, for ten days over two weeks. Functional and molecular analyses assessed neurovascular regeneration. LED therapy significantly improved intra-cavernous pressure (ICP), with combined RED and NIR wavelengths restoring ICP to 90% of normal levels, indicating enhanced nerve and vascular function. Histological analyses showed increased endothelial cell density, angiogenesis, pericyte recruitment, and neural regeneration. Molecular findings revealed upregulation of neurotrophic factors (NGF, NT-3, BDNF), angiogenic markers (VEGF, eNOS), and phosphorylated PI3K, alongside reduced apoptosis and increased cell proliferation. These results demonstrate that LED therapy mitigates diabetes-induced neuropathy and vasculopathy by enhancing neurovascular repair and modulating neuroinflammatory pathways. The study highlights the potential of combined RED and NIR LED therapy as a non-invasive treatment for diabetic ED and related neurovascular complications, offering a promising approach to improving patient outcomes.

Circadian rhythm disruption (CRD) is highly prevalent in modern society and contributes to numerous disorders, including erectile dysfunction (ED). Melatonin (MT) possesses well-established functions in regulating circadian rhythm and demonstrating antioxidant ability; however, whether MT could preserve CRD-induced ED and the underlying mechanism has never been reported. A rat model with CRD-induced ED was designed by changing light-dark cycle (2h:2h alteration) and then intraperitoneally administering MT with low (5 mg/kg/day) and high (10 mg/kg/day) dosages. A total of 4 weeks later, rats' erectile function was measured and penile corpus cavernosum was subsequently harvested for analysis. In addition, bioinformatics analysis was performed to filter the possible molecular target, while lipopolysaccharide (LPS)-treated human umbilical vein endothelial cells (HUVECs) were selected to imitate CRD stimulation in vivo to further verify the underlying molecular mechanism. CRD significantly reduced rats' maximal intracavernous pressure (mICP) and mICP/mean arterial pressure (MAP) ratio, it also inhibited endothelial nitric oxide synthase/nitric oxide/cyclic guanosine monophosphate concentrations and injured normal penile corpus cavernosum structure, suggesting rats' normal erectile function was impaired; however, this CRD-induced ED was preserved by MT. The in vivo and in vitro experiments respectively proved that CRD increased oxidative stress of penile corpus cavernosum and HUVECs by reducing nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) production, while MT increased Nrf2/HO-1 to inhibit the oxidative stress. Meanwhile, CRD promoted pyroptosis in penile corpus cavernosum and HUVECs by increasing NLR family pyrin domain containing 3 (NLRP3) activation, which was relieved by MT through the attenuation of oxidative stress. Moreover, the reactive oxygen species inhibitor (NAC) inhibited CRD-induced pyroptosis of HUVECs to preserve normal function, which confirmed that MT alleviated NLRP3-mediated pyroptosis to preserved CRD-induced ED by reducing oxidative stress. In conclusion, it was demonstrated that CRD-induced ED by triggering an oxidative stress-pyroptosis cascade. Conversely, MT treatment effectively counteracts this pathology by activating the Nrf2/HO-1 pathway to suppress oxidative stress, thereby attenuating NLRP3-mediated pyroptosis and ultimately restoring erectile function. These results provide the first systematic evidence for the central role of the oxidative stress-pyroptosis axis in CRD-induced ED, establishing a solid theoretical foundation for MT as a promising therapeutic strategy for CRD-related ED.

Diabetes mellitus (DM) is a chronic metabolic disease that often leads to vascular endothelial injury and peripheral neuropathy. Erectile dysfunction (ED), a common condition in andrology, is frequently associated with DM. The incidence of diabetes mellitus-induced ED (DMED) is second only to the cardiovascular complications of diabetes. Compared to other types of ED, DMED presents with more severe symptoms, rapid progression, and notable resistance to phosphodiesterase type 5 inhibitors (PDE5is). Various forms of programmed cell death (PCD)—including apoptosis, autophagy, pyroptosis, and ferroptosis—play pivotal roles in the pathogenesis of DMED. An exacerbation of DMED is linked to critical irritants like advanced glycation end-products (AGEs) and reactive oxygen species (ROS) in the corpus cavernosum tissue. These irritants can spark anomalous activations of diverse PCDs, which damage primary corpus cavernosum cells like cavernous nerve cells, endothelial cells, and myocytes, leading to ED. Hence, we reviewed current knowledge on the mechanisms and therapeutic potential of targeting PCDs in DMED, aiming to advance strategies for enhancing erectile function.

The aim of this study was to determine the possibility of improving erectile dysfunction using cell therapy with either human urine-derived stem cells (USCs) or USCs genetically-modified with FGF2 in a type 2 diabetic rat model. Human USCs were collected from 3 healthy donors. USCs were transfected with FGF2 (USCs-FGF2). Sixty-five SD male rats were divided into five groups (G). A control group of normal rats (G1, n = 10), and four other test groups of type 2 diabetic erectile dysfunction rats: PBS as a negative control (G2, n = 10), USCs (G3, n = 15), lentivirus-FGF2 (G4, n = 15), and USCs-FGF2 (G5, n = 15). Diabetes was induced in the rats via a high fat diet for 28 days and a subsequent intraperitoneal injection of streptozotocin (35 mg/kg). Erectile dysfunction was screened with apomorphine (100 μg/kg). Cell injections in the test groups (G2-G5) occurred directly into the corpora cavernosa. The implanted cells were tracked at 7 days (n = 5 animals/G) and 28 days (n = 10 animals/G) post injection. Mean arterial pressure (MAP), intracavernosal pressure (ICP), expression of endothelial markers (CD31, VEGF and eNOS), smooth muscle markers (desmin and smoothelin), histological changes and erectile function were assessed for each group. USCs expressed mesenchymal stem cell markers, and secreted a number of proangiogenic growth factors. USCs expressed endothelial cell markers (CD31 and vWF) after transfection with FGF2. Implanted USCs or USCs-FGF2 displayed a significantly raised ICP and ICP/MAP ratio (p<0.01) 28 days after intracavernous injection. Although few cell were detected within the implanted sites, histological and western blot analysis demonstrated an increased expression of endothelial and smooth muscle markers within the cavernous tissue following USC or USC-FGF2 injection. The paracrine effect of USCs or USCs-FGF2 induced improvement of erectile function in type 2 diabetic rats by recruiting resident cells and increasing the endothelial expression and contents of smooth muscle.

Psychogenic erectile dysfunction (pED) is a prevalent male sexual dysfunction lacking organic etiology. Endeavors have been made in previous studies to disclose the brain pathological mechanisms of pED. However, the cortical morphological characteristics in pED patients remained largely unknown. This study enrolled 50 pED patients and 50 healthy controls (HC). The surface-based morphometry (SBM) analysis was conducted, and the between-group comparisons of the four cortical morphological parameters, including the cortical thickness, sulcus depth, gyrification index, and fractal dimension, were performed to investigate the cortical morphological alterations in pED patients, followed by correlation analysis between clinical data and SBM metrics. Furthermore, a classifier was developed based on a support vector classification algorithm and cortical morphological features to explore the feasibility of discriminating between pED patients and HC at an individual level. The results demonstrated that pED patients manifested consistent alteration in cortical morphology cross metrics in the orbitofrontal cortex, anterior and middle cingulate cortex, dorsolateral prefrontal cortex, and precentral gyrus, which were significantly correlated with the clinical symptoms in pED patients. Additionally, the classifier built based on 11 cortical morphological features achieved an accuracy of 82% in discriminating pED patients from HC. The current study provided new evidence of cortical morphological aberrations in pED patients, which deepened our understanding of the central pathology pattern of pED and was expected to facilitate the objective diagnosis of pED and the development of neuromodulation techniques targeting the alterations above.

Background Cavernous nerve injury-induced erectile dysfunction (CNI-ED) is a common complication after radical prostatectomy. Conventional treatment approaches have had little success in treating the severe cavernous fibrosis which is a consequence of CNI-ED. Methods Pre-treatment of adipose-derived stem cells with melatonin allows for the extraction of active exosomes (MT-hASC-EVs) from the conditioned medium. The therapeutic effects of MT-hASC-EVs were assessed in a rat model of CNI-ED, and the anti-fibrotic properties were evaluated. MicroRNA sequencing was used to identify specific microRNAs highly expressed in MT-hASC-EVs, and differential microRNAs were screened for regulatory pathways through target gene enrichment analysis. Finally, the conclusions from bioinformatics analysis were validated through in vitro experiments. Results Intracavernous injection of MT-hASC-EVs significantly restored erectile function and reduced the extent of corpus cavernosum fibrosis in the CNI-ED rat model. MT-hASC-EVs promoted the proliferation and anti-apoptotic effects of corpus cavernosum smooth muscle cells (CCSMCs) in vitro. Mechanistically, MT-hASC-EVs inhibit fibrosis by delivering miR-145-5p, which targets TGF-β2/Smad3 axis. Conclusions MT-hASCs-EVs can inhibit cavernous fibrosis and improve erectile function in a rat model of CNI-ED by targeting the miR-145-5p/TGF-β/Smad axis.

Bilateral cavernous nerve injury-related erectile dysfunction (BCNI-ED) shows a limited response to type 5 phosphodiesterase inhibitors. Furthermore, lacosamide (LCM) can alleviate peripheral neuropathy. To explore whether LCM can improve the erectile response after BCNI, we randomly divided 30 young Sprague-Dawley rats into three groups ( n  = 10 per group), namely, the sham operation, 0.9% normal saline-treated (BCNI + 0.9% NS), and LCM-treated BCNI (BCNI + LCM) groups. LCM was injected intraperitoneally at a dose of 90 mg/kg/day for 7 consecutive days. Erectile function was assessed by measuring the ratio of peak intracavernous pressure (ICP) to mean arterial pressure (MAP), and tissues were harvested for transmission electron microscopy, immunofluorescence, Masson’s trichrome staining, TUNEL staining, and Western blot analysis. The BCNI + 0.9% NS group showed reduced ICP/MAP ratio (0.93 ± 0.04 vs. 0.44 ± 0.05, P  < 0.0001). An increased proportion of TUNEL-positive cells (0.04 ± 0.01 vs 0.87 ± 0.03, P  < 0.0001) and a decreased smooth muscle/collagen ratio (0.44 ± 0.01 vs. 0.33 ± 0.01, P  < 0.001) were observed in the BCNI + 0.9% NS compared with the sham group. Administration of LCM significantly restored the ICP/MAP ratio (0.44 ± 0.05 vs. 0.74 ± 0.05, P  < 0.001) and decreased the proportion of TUNEL positive cells (0.87 ± 0.03 vs. 0.60 ± 0.04, P  < 0.0001) in the corpus cavernosum following BCNI. The ratio of smooth muscle to collagen (0.43 ± 0.01vs. 0.33 ± 0.01, P  < 0.01) and expression of α-SMA ( P  < 0.0001) in the BCNI + LCM group significantly increased compared with BCNI + 0.9% NS group, indicating alleviation of fibrosis. Apoptotic markers, including Bax/Bcl-2 ( P  < 0.01) and Caspase-3 ( P  < 0.0001) in the BCNI + LCM group was significantly lower than that in the BCNI + 0.9% NS group. LCM treatment partially upregulated the expression of vWF and eNOS in cavernous tissue in rats subjected to BCNI ( P  < 0.05). Increases in S100-β and nNOS expression in the major pelvic ganglion (MPG) were observed after LCM administration. In summary, LCM can recover erectile function in BCNI-ED rat model by suppressing corporal apoptosis and fibrosis, and protecting the cavernous nerve.

Patients with Benign prostatic hyperplasia, low urinary tract symptoms, and erectile dysfunction (BPH/LUTS-ED) present chronic inflammation. We studied in patients with BPH/LUTS-ED the effect of tadalafil treatment (5 mg/day) on changes in peripheral inflammation, cognitive function, and the auditory evoked potential, “mismatch negativity” (MMN). Nine patients with BPH/LUTS-ED and 12 controls performed psychometric tests, MMN. IL-6, IL-17, IL-18, cGMP and CD4 + CD28 − autoreactive T-cells were measured in blood. Patients with BPH/LUTS-ED performed psychometric tests, MMN, and blood extraction at baseline and after tadalafil treatment. Patients with BPH/LUTS-ED showed increased CD4 + CD28 − autoreactive T-cells (p < 0.05), and higher levels of pro-inflammatory interleukins IL-6 (p < 0.001), IL-17 and IL-18 (p < 0.05), compared to controls. Patients got lower scores than controls in psychometric tests assessing mental processing speed and attention (p < 0.05), and showed lower amplitude (p < 0.01) and area (p < 0.05) of MMN wave than controls. Inflammatory, psychometric and electrophysiological parameters were normalized after tadalafil treatment. In conclusion, there is a pro-inflammatory environment in blood in patients with BPH/LUTS-ED which would induce cognitive impairment and alter MMN. Phosphodiesterase-5 inhibition with tadalafil exerts anti-inflammatory effects and ameliorates cognitive function and MMN parameters. Tadalafil could be a promising candidate for chronic treatment in other inflammatory pathologies associated with mild cognitive impairment.