Explore the vast range of titles available.

PurposePhosphodiesterase type-5 inhibitor administration in diabetic men with erectile dysfunction (ED) is associated with reduced waist circumference. We evaluated potential effects of daily tadalafil administration on body composition and investigated its possible mechanism(s) of action in C2C12 skeletal muscle cells in vitro.MethodsForty-three men on stable caloric intake (mean age 48.5 ± 7; BMI 25.5 ± 0.9 kg/m2) complaining mild ED and/or low urinary tract symptoms (LUTS) were randomly assigned to receive tadalafil (TAD) 5 mg/daily (once-a-day=OAD-TAD; n = 23) or 20 mg on-demand (on-demand=OD-TAD; n = 20) for 2 months. Primary outcomes were variations of body composition measured by Dual-energy X-ray absorptiometry; secondary outcomes were ED/LUTS questionnaire scores along with hormone (testosterone, estradiol, insulin) and endothelial function (Endopat2000) variations.ResultsOAD-TAD increased abdominal lean mass (p < 0.01) that returned to baseline after 2 months withdrawal. LUTS scores improved (p<0.01) in OD-TAD while ED scores improved (p < 0.01) in both groups. We found significant improvements in endothelial function (p < 0.05) that directly correlated with serum insulin (p < 0.01; r = 0.3641) and inversely correlated with estradiol levels (p < 0.01; r = 0.3655) even when corrected for potential confounders. Exposure of C2C12 cells upon increasing tadalafil concentrations (10−7 to 10−6 M) increased total androgen receptor mRNA and protein expression as well as myogenin protein expression after 24 and 72 h (2.8 ± 0.4-fold and 1.4 ± 0.02-fold vs. control, respectively, p < 0.05).ConclusionsDaily tadalafil improved lean mass content in non-obese men probably via enhanced insulin secretion, estradiol reduction, and improvement of endothelial function in vivo. The in vitro increased myogenin and androgen receptor protein expression in skeletal muscle cells suggests a translational action of phosphodiesterase type-5 on this receptor.

Purpose Several severe drug interactions have been reported when sildenafil, a potent drug for the treatment of erectile dysfunction, is co-administered with drugs or herbal remedies that inhibit cytochrome P450 (CYP) 3A4. This study evaluates the effects of two citrus fruit juices, lemon and Seville orange, on the pharmacokinetics of sildenafil in male healthy subjects following a single oral dose. Methods We conducted an open-label, three-way crossover study in nine healthy male volunteers. Participants received a single oral dose of sildenafil (50 mg) after pretreatment with 250 mL of either water (control), undiluted lemon juice, or Seville orange juice for 3 consecutive days. All subjects were monitored for adverse effects during the study period. Plasma samples were collected for 12 h after dosing and analyzed for sildenafil concentration. Results Compared with pretreatment with water, Seville orange juice significantly increased the area under the plasma concentration-time curve from time zero to infinity and the peak plasma concentration of sildenafil by 44 % (90 % confidence interval [CI] 30–60) and 18 % (90 % CI 108–129), respectively, without affecting the time to reach peak plasma concentration. Additionally, Seville orange juice significantly reduced the apparent oral clearance of sildenafil by 30 % (90 % CI 63–75) without affecting its elimination half-life. In contrast, lemon juice did not cause any significant alterations in the pharmacokinetics of sildenafil. There was no significant treatment-related adverse effects reported during the study. Conclusions Although it is considered as a moderate CYP3A4 inhibitor, Seville orange only caused a mild increase in exposure to sildenafil after a single oral dose, without manifestation of any adverse effects. The enhanced bioavailability of sildenafil by Seville orange may be attributed to inhibition of its intestinal first-pass effect (CYP3A4 and or p-glycoprotein). Lemon juice, in contrast, had no effects on the pharmacokinetics of sildenafil.

This study aimed at comparing the effects of atorvastatin and vitamin E on erectile dysfunction in patients initially irresponsive to sildenafil, with investigation into the underlying possible mechanisms. Sixty patients were randomly divided into three groups: the atorvastatin group received 80 mg daily, the vitamin E group received 400 IU daily and the control group received placebo capsules. Patients were examined both before and after 6 weeks of treatment for biochemical tests; Superoxide dismutase (SOD), glutathione peroxidase (GPO), C-reactive protein (CRP), interleukin-6 (IL-6), nitric oxide (NO) and endothelial nitric oxide synthase (eNOS) and for erectile function tests; International index of erectile function (IIEF-5) scores and Rigiscan. Both atorvastatin and vitamin E showed a statistically significant GPO increase ( P <0.05) and a statistically significant IL-6 decrease ( P <0.05). Only atorvastatin showed a statistically significant increase in NO (15.19%, P <0.05), eNOS (20.58%, P <0.01), IIEF-5 score (53.1%, P <0.001) and Rigiscan rigidity parameters ( P <0.01), in addition to a statistically significant decrease in CRP (57.9%, P <0.01). However, SOD showed a statistically significant increase only after vitamin E intake (23.1%, P <0.05). Both atorvatstain and vitamin E had antioxidant and anti-inflammatory activities. Although activating eNOS by atorvastatin was the real difference, and expected to be the main mechanism for NO increase and for improving erectile dysfunction. Atorvastatin, but not vitamin E, is a promising drug for sildenafil nonresponders.

Erectile dysfunction (ED) is a multifactorial disease associated with vascular dysfunction, low nitric oxide (NO) bioavailability, and oxidative stress. However, it is not known whether low NO bioavailability and oxidative stress affect the responsiveness of ED patients to sildenafil. We tested this hypothesis by studying 28 healthy subjects (control group), 26 patients with ED without comorbidities (ED group), and 18 patients with ED and diabetes mellitus (ED/DM group). The International Index for Erectile Function (IIEF) questionnaire was used to assess the erectile function of all participants, and their responsiveness to sildenafil was assessed as the percentage of change in the five-item version of IIEF score before and after sildenafil treatment. Levels of whole blood nitrite, antioxidants markers (ferric reducing ability of plasma (FRAP) and reduced glutathione), and oxidative stress markers (thiobarbituric acid reactive substance and protein carbonyl) were determined. We found a negative correlation between whole blood nitrite levels and the responses to sildenafil in both ED groups ( P  < 0.05). FRAP correlated negatively with the responses to sildenafil in the ED/DM group ( P  < 0.05). No other significant associations were found. Our findings show evidence that low NO bioavailability is associated with better responses to sildenafil in patients with ED (with or without DM).

Erectile dysfunction (ED) is a prevalent condition affecting male sexual health, characterized by the inability to achieve or maintain satisfactory erections. ED has a multifactorial pathogenesis in which psychological, hormonal, neurologic, cardiovascular, and lifestyle factors all contribute to a progressive decline of erectile function. A critical underlying mechanism involves oxidative stress (OS), an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, which disrupts endothelial function, reduces nitric oxide (NO) bioavailability, and contributes to vascular dysfunction. This narrative review explores the interplay between OS and ED, focusing on the roles of ROS sources such as NADPH oxidase, xanthine oxidase, uncoupled nitric oxide synthase, and mitochondrial dysfunction. It examines the impact of OS on chronic conditions like hypertension, diabetes mellitus, hyperlipidemia, hypogonadism, and lifestyle factors like smoking and obesity, which exacerbate ED through endothelial and systemic effects. Emerging research underscores the potential of antioxidant therapies and lifestyle interventions to restore redox balance, improve endothelial function, and mitigate ED’s progression. This review also highlights gaps in understanding the molecular pathways linking ROS to ED, emphasizing the need for further research to develop targeted therapeutic strategies.

The high prevalence of diabetes mellitus-induced erectile dysfunction (DMED) in males and the limited efficacy of existing therapies necessitate deeper mechanistic insights. We identify pathological lactate accumulation in the corpus cavernosum as a major driver of DMED in male mice, promoting structural degeneration and smooth muscle cell loss. Mechanistically, transcriptional repression and functional impairment of fructose-1,6-bisphosphatase 1 ( Fbp1 ), a rate-limiting gluconeogenic enzyme, underlie this lactate accumulation. Epigenetic profiling revealed suppression of Fbp1 transcription associated with histone H3 lysine 9 trimethylation and histone H3 lysine 27 trimethylation. Palmitoylation at the FBP1 Cys282 residue, catalyzed by zinc finger DHHC-type containing 13, further disrupted its gluconeogenic function, exacerbating lactate accumulation. To rescue these defects, we engineered lipid nanoparticles loaded with the Fbp1 -C282S mutant mRNA, restoring FBP1 expression, blocking pathological palmitoylation, and ultimately improving erectile function in diabetic male mice. Here, our study in male mice identifies cavernosal lactate accumulation as a central pathological factor, elucidates its molecular regulation, and provide a targeted therapeutic strategy for DMED. The study identifies cavernosal lactate as a driver of diabetes-induced erectile dysfunction through FBP1 dysfunction, histone methylation and palmitoylation.

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.

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.

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.