Search Results (158)

Background: Signaling pathways like those depending on cAMP/PKA, calcium/calmodulin/CaMK, MEK-1/MAPK or PI3K/Akt have been described to modulate suprachiasmatic nucleus (SCN) neuronal signaling via influencing transcription factors like CREB. Here, we analyzed the effect of cyclic nucleotide phosphodiesterase inhibitors and structurally similar substances commonly used as autophagy modulators on a cell line stably expressing a cyclic nucleotide element-driven luciferase reporter. Methods: We used an SCN cell line stably transfected with a CRE-luciferase reporter (SCNCRE) to evaluate signaling and vitality responses to various isoform-selective PDE inhibitors and autophagy modulators to evaluate the mechanism of action of the latter. Results: In this study the different impacts of common PDE inhibitors and autophagy modulators on CRE-luciferase activity applied alone and in combination with known CRE-luciferase activating agents showed that (1) PDE3, 4 and 5 are present in SCNCRE cells, with (2) PDE3 being the most active and (3) the autophagy inhibitor 3-Methyladenin (3-MA) displaying PDE inhibitor-like behavior. Conclusions: Experiments provide evidence that, in addition to the extracellular signaling pathways components shown before to be involved in CRE-luciferase activity regulation like cAMP analogs, adenylate cyclase activators and beta-adrenoceptor agonists, cyclic nucleotide metabolism as realized by phosphodiesterase activity, or molecule/agents influencing processes like autophagy or inflammation, modulate transcriptional CRE-dependent activity in these cells. Specifically, we provide evidence that the autophagy inhibitor 3-MA, given that PDEs are expressed, may also act as a PDE inhibitor and inducer of CRE-mediated transcriptional activity. Full article

Background: Phosphodiesterase type 5 inhibitors (PDE5i), particularly tadalafil and sildenafil, are the first-line therapies for erectile dysfunction (ED). After the patent expiration of branded tadalafil in 2017, generic formulations became available. Despite equivalent efficacy, skepticism persists regarding the effectiveness and safety of generics. The SHIFT study aimed to evaluate the non-inferiority of a generic tadalafil (Dalerpen) compared with branded and other generic tadalafil in terms of clinical efficacy and patient satisfaction. Methods: A prospective, multicenter study was conducted involving 247 patients treated with tadalafil (either 5 mg or 20 mg) for ED. Patients switched from branded or other generic tadalafil to Dalerpen. Baseline and follow-up assessments included the International Index of Erectile Function—Erectile Function Domain (IIEF-EF) (primary endpoint), Sexual Encounter Profile (SEP-2 and SEP-3), and International Prostatic Symptom Score (IPSS). A one-month follow-up was performed. Results: A total of 247 patients were included in the final analysis. After switching to Dalerpen, significant improvements were observed in both IIEF-EF (18.8 ± 5.6 vs. 16.7 ± 5.4, p < 0.001) and IPSS scores (10.4 ± 6.7 vs. 11.2 ± 6.3, p < 0.001), though the minimal clinically important difference (MCID) was not reached. SEP-3 scores also significantly increased (3 ± 1.2 vs. 2 ± 1.1, p < 0.001). Multivariate analysis identified baseline IIEF, IPSS scores, and post-treatment IPSS as predictors of IIEF-EF improvement (p < 0.001). Switching to Dalerpen was an independent predictor of both IIEF-EF and IPSS improvement. No new adverse events were reported. Conclusions: The SHIFT study demonstrates that Dalerpen is non-inferior to branded tadalafil in terms of clinical efficacy, offering a reliable and cost-effective therapeutic option. Educating patients on bioequivalence and addressing concerns regarding generic drugs are essential to facilitate therapeutic switches. Full article

Phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil, tadalafil, and vardenafil, are primarily prescribed for erectile dysfunction and pulmonary hypertension. Emerging evidence suggests they may also modulate inflammatory pathways and improve vascular function, but their effects on inflammatory biomarkers in humans remain incompletely defined. A systematic review and meta-analysis were conducted to evaluate the impact of PDE5 inhibitors on inflammatory and endothelial markers in adult humans. Randomized controlled trials comparing PDE5 inhibition to placebo were identified through electronic database searches. Outcomes included pro-inflammatory markers (TNF-α, IL-6, IL-8, CRP, VCAM-1, ICAM-1, P-selectin) and anti-inflammatory or signalling markers (IL-10, NO, cGMP), assessed at short-term (≤1 week), intermediate-term (4–6 weeks), or long-term (≥12 weeks) follow-up. Risk of bias was assessed using the Cochrane RoB 2 tool. A total of 20 studies comprising 1549 participants were included. Meta-analyses showed no significant short-term effects of PDE5 inhibition on TNF-α, IL-6, or CRP. Long-term treatment was associated with reduced IL-6 (SMD = −0.64, p = 0.002) and P-selectin (SMD = −0.57, p = 0.02), and increased cGMP (SMD = 0.87, p = 0.0003). Effects on IL-10 and nitric oxide were inconsistent across studies. Most trials had low risk of bias. PDE5 inhibitors may exert anti-inflammatory effects in long-term use by reducing vascular inflammation and enhancing cGMP signalling. These findings support further investigation of PDE5 in chronic inflammatory conditions. Full article

Background: The European League Against Rheumatism (EULAR), in collaboration with the European Scleroderma Trial and Research group (EUSTAR), published the first set of treatment recommendations for systemic sclerosis (SSc) in 2009, with subsequent updates in 2016 and 2023. Objectives: This study aimed to evaluate how rheumatologists’ clinical approaches to the treatment of SSc evolved following the 2016 update of the clinical management guidelines. Methods: Medication use for SSc was analyzed in a cohort of 378 patients. The patients were stratified based on enrollment before (233 patients) and after (145 patients) the guideline update, and medication usage was compared between the two groups. Results: Although all patients presented with Raynaud’s phenomenon (RP), only 35% received calcium channel blockers. Medications such as iloprost, phosphodiesterase type 5 (PDE-5) inhibitors, fluoxetine, and bosentan, recommended for the treatment of RP and digital ulcers, were not approved for SSc by the Republic Health Insurance Fund. Treatment for pulmonary arterial hypertension (PAH) was administered to only 16 patients (4.2%), including 2 who received bosentan, 10 who received PDE-5 inhibitors, and 4 who were treated with riociguat. The use of PDE-5 inhibitors increased following the 2016 update of the guidelines. Cyclophosphamide was consistently prescribed for interstitial lung disease (ILD), with an increased frequency observed after the guideline update. No significant differences were observed in the use of methotrexate for skin involvement, ACE inhibitors for scleroderma renal crisis, or antibiotics for gastrointestinal symptoms. Proton pump inhibitors (PPIs) were prescribed to 87.3% of patients with gastrointestinal involvement, with an increase in use of both PPIs and prokinetic agents following the guideline update. Conclusions: Rheumatologists’ adherence to the EULAR/EUSTAR guidelines varied considerably, with 25% to 100% of eligible patients receiving the recommended treatments. Concordance improved in the management of PAH, ILD, and gastrointestinal involvement after the 2016 guideline update. Full article

The imbalance of phosphodiesterase 5 (PDE5) enzyme in the male body, or excessive PDE5 enzyme levels, can occur due to factors such as aging, diseases (e.g., cardiovascular disease, diabetes, depressive disorder), and physical behaviors (e.g., alcoholism, smoking, stress). PDE5 is directly associated with erectile dysfunction disease. Currently, many studies aim to find natural PDE5 inhibitors as an alternative to commercial drugs. This study is the first to demonstrate that the ethanolic leaf extract of D. cochinchinensis exhibits potent PDE5-inhibitory activity. The PDE5-inhibitory activity of five plant parts was evaluated: leaf (IC₅₀ = 1.53 ± 0.12 µg/mL), twig (3.37 ± 0.54), fruit (14.92 ± 2.85), heartwood (19.05 ± 5.60), and bark (16.03 ± 2.92). However, there is still uncertainty about which compounds in leaf extract are responsible for the PDE5 inhibition. Therefore, the purpose of this study is to identify the chemical constituents in the leaf of D. cochinchinensis, including determining which of these compounds may act as PDE5 inhibitors. This study was achieved using at-line LC-QTOF-MS². Full article

Sexual dysfunction following abdominal or pelvic surgery is a significant concern that impacts the quality of life (QoL) for both men and women. This paper explores the multifaceted challenges and re-educational strategies associated with post-surgical sexual dysfunction. It highlights the physical and psychological repercussions of surgeries such as hysterectomies, pelvic organ prolapse repairs, radical prostatectomies, and rectal cancer resections. These procedures often lead to complications like dyspareunia, erectile dysfunction, and altered body image, necessitating comprehensive re-educational approaches. The review emphasizes the importance of tailored interventions, including pelvic floor muscle training (PFMT), biofeedback, manual therapy, and advanced techniques like botulinum toxin injections and sacral neuromodulation. For men, strategies such as phosphodiesterase type 5 inhibitors (PDE5i), vacuum erection devices (VEDs), intracavernosal injections, and penile prostheses are explored for their efficacy in restoring erectile function. Psychological support, including cognitive–behavioral therapy and couples counseling, is underscored as essential to addressing emotional and relational aspects of recovery. A multidisciplinary approach involving physiatrists, urologists, gynecologists, physiotherapists, psychologists, and sexual health counselors is advocated for to optimize outcomes. Integrating physical therapy modalities, as well as psychological and relational therapies, into individual rehabilitation projects is crucial for improving sexual function and overall QoL post-surgery. Future research should focus on refining these established strategies and investigating the potential of innovative therapeutic modalities. Full article

Background/Objectives: Phosphodiesterase 5 (PDE5) inhibitors, sildenafil, vardenafil, and tadalafil, activate the cyclic guanosine monophosphate pathway resulting in vascular smooth muscle relaxation. They have been tested for a broad variety of conditions from cancer to Alzheimer’s disease with a positive impact. The known mechanism of action of these drugs could not explain such a plethora of effects. We studied the influence of PDE5 inhibitors on lipid bilayers as a possible application point of their action. Methods: To monitor the membrane changes induced by PDE5 inhibitors, the differential scanning microcalorimetry and the molecular dynamics simulation were used. Results: We found that sildenafil, vardenafil, and tadalafil change elastic properties of model membranes: PDE5 inhibitors disorder thin membranes and order thick membranes. Moreover, PDE inhibitors were able to induce lipid interdigitation. To address the biological aspect of the findings, we performed molecular dynamics on smooth muscle cell’s lipid raft treated with PDE5 inhibitors and revealed the increased density of the lipids. Furthermore, we showed that the lipid condensation in the PDE inhibitors presence increases nitric oxide permeability. Conclusions: The obtained results may be of biological relevance as lipid raft thickening might have an impact on membrane protein function. Moreover, improved nitric oxide flow through membrane may partially explain therapeutic action of these drugs. The presented results are useful for finding novel implications for PDE inhibitors. Full article

The prevalence of erectile dysfunction (ED) among the male population worldwide has significant ramifications for their quality of life and psychological well-being. This narrative review explores both conventional treatments, such as pharmacotherapy and surgery, and emerging approaches, including regenerative therapies, dietary interventions, physiotherapy, and vacuum erection devices (VEDs). Unlike prior reviews, this study emphasises unconventional therapies and their role in comprehensive ED management. A systematic literature review was conducted using PubMed, Embase, and Medline, including studies published up to 2024. Keywords such as “ED”, “pharmacotherapy”, “shock wave therapy”, “regenerative medicine”, and “dietary interventions” were used to identify relevant studies. Eligible studies examined treatment efficacy, mechanisms, and patient outcomes. Phosphodiesterase type 5 (PDE5i) inhibitors remain the primary treatment, demonstrating effectiveness across diverse populations. Regenerative therapies, including stem cells and platelet-rich plasma (PRP), show promise, but require further validation. Surgical interventions, particularly penile prostheses, provide high patient and partner satisfaction. Non-invasive methods, including physiotherapy and dietary changes like adoption of the Mediterranean diet, improve vascular health and erectile function. The efficacy of VEDs as standalone or adjunct treatments has been demonstrated, enhancing outcomes in prosthetic surgery. A multimodal, personalised approach is essential for optimising ED treatment. Despite promising advancements, gaps remain in terms of long-term data, standardised protocols, and partner-centred outcomes. Future research should focus on large-scale, multi-centre trials and synergistic treatment approaches to improve therapeutic outcomes and patient satisfaction. Full article

Background: Acid sphingomyelinase deficiency (ASMD), most commonly known as Niemann–Pick disease (NPD), is a rare progressive genetic disorder regarding lipid storage. Subtypes A and B are inherited in an autosomal recessive fashion and consist of a genetic defect which affects the sphingomyelin phosphodiesterase 1 gene, leading to residual or lack of enzymatic activity of acid sphingomyelinase (ASM). Materials and Methods: This paper provides a brief history and overview to date of the disease and a comprehensive review of the current literature on ASMD in children, conducted on published papers from the past 10 years. Results: We identified 19 original publications (16 individual case reports and three series of cases—30 patients). The male/female ratio was 1.4. The youngest patient at disease onset was a female newborn with NPD-A. The youngest patient was diagnosed at 4 months. The longest timeframe between onset symptoms and diagnostic moment was 5 years 3 months. A total of nine patients exhibited red cherry macular spots. A total of 13 children exhibited associated lung disease, and four NPD-A patients with pulmonary disease died due to respiratory complications. A total of 11 children exhibited associated growth impairment. Genetic assays were performed in 25 cases (15 homozygous; 9 heterozygous). A total of four children (13.3%) received enzyme replacement therapy (ERT). Therapy outcomes included decreased liver and spleen volumes, improved platelet and leukocytes counts, and body mass index and stature improvement. Conclusions: Sometimes, a small child with a big belly hides a huge dilemma; inherited metabolic disorders are here to challenge clinicians and set the record straight, and genetics is the way of the future in terms of diagnosis and novel treatments. NPD must be considered children with persistent and progressive hepatosplenomegaly and growth failure. Diagnosis requires good clinical skills and access to genetic assays. Since 2022, the FDA has given a green light to a revolutionary enzymatic replacement therapy with human recombinant ASM called Olipudase-alfa. Clinical trial outcomes support its reliability and efficacy in the pediatric population. Full article

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths globally. Current treatment options including chemotherapy and targeted therapies face challenges such as resistance and toxicity. Cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase 5 (PDE5) has emerged as a promising target for CRC therapy due to its role in regulating cellular processes like proliferation and apoptosis. This study focuses on the in silico design of a novel PDE5 inhibitor MS01 derived from the lead compound exisulind which has shown apoptotic effects but failed due to hepatotoxicity. Using Schrödinger’s Induced Fit Docking (IFD) and molecular dynamic simulations, MS01 was designed to enhance binding affinity and reduce toxicity. The docking studies showed that MS01 exhibits stronger interactions with key PDE5 residues, particularly Gln817 and Phe820. ADMET predictions indicate favorable pharmacokinetic profiles, with reduced risk of drug–drug interactions and improved bioavailability. Toxicity assessments revealed that MS01 and its analogs have moderate toxicity, with MS20 and MS21 demonstrating lower hepatotoxicity compared to exisulind. These findings suggest that MS01 has the potential to be a more effective and safer PDE5 inhibitor for CRC treatment pending further experimental validation. Full article

Phosphodiesterases, particularly the type 5 isoform (PDE5), have gained recognition as pivotal regulators of male reproductive physiology, exerting significant influence on testicular function, sperm maturation, and overall fertility potential. Over the past several decades, investigations have expanded beyond the original therapeutic intent of PDE5 inhibitors for erectile dysfunction, exploring their broader reproductive implications. This narrative review integrates current evidence from in vitro studies, animal models, and clinical research to clarify the roles of PDEs in effecting the male reproductive tract, with an emphasis on the mechanistic pathways underlying cyclic nucleotide signaling, the cellular specificity of PDE isoform expression, and the effects of PDE5 inhibitors on Leydig and Sertoli cell functions. Although certain findings suggest potential improvements in sperm motility, semen parameters, and a more favorable biochemical milieu for spermatogenesis, inconsistencies in study design, limited sample sizes, and inadequate long-term data temper definitive conclusions. Addressing these gaps through standardized protocols, larger and more diverse patient cohorts, and explorations of mechanistic biomarkers could pave the way for incorporating PDE5 inhibitors into evidence-based fertility treatment strategies. In the future, such targeted approaches may inform individualized regimens, optimize male reproductive outcomes, and refine the clinical application of PDE5 inhibitors as part of comprehensive male fertility management. Full article

Phosphodiesterase (PDE) enzymes regulate intracellular signaling pathways crucial for brain development and the pathophysiology of neurological disorders. Among the 11 PDE subtypes, PDE4 and PDE5 are particularly significant due to their regulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling, respectively, which are vital for learning, memory, and neuroprotection. This review synthesizes current evidence on the roles of PDE4 and PDE5 in neurological health and disease, focusing on their regulation of second messenger pathways and their implications for brain function. Elevated PDE4 activity impairs synaptic plasticity by reducing cAMP levels and protein kinase A (PKA) activity, contributing to cognitive decline, acute brain injuries, and neuropsychiatric conditions such as bipolar disorder and schizophrenia. Similarly, PDE5 dysregulation disrupts nitric oxide (NO) signaling and protein kinase G (PKG) pathways, which are involved in cerebrovascular homeostasis, recovery after ischemic events, and neurodegenerative processes in Alzheimer’s, Parkinson’s, and Huntington’s diseases. PDE4 and PDE5 are promising therapeutic targets for neurological disorders. Pharmacological modulation of these enzymes offers potential to enhance cognitive function and mitigate pathological mechanisms underlying brain injuries, neurodegenerative diseases, and psychiatric disorders. Further research into the regulation of PDE4 and PDE5 will advance therapeutic strategies for these conditions. Full article

Objective: Peripheral artery disease (PAD) is a prevalent vascular condition characterized by arterial narrowing, which impairs blood flow and manifests as intermittent claudication, a pain or cramping sensation induced by physical activity or ambulation. Walking distance is a crucial clinical indicator of peripheral artery disease, and it correlates with the disease severity and risk of mortality. It reflects the severity of the disease, with reduced mobility indicating an increased risk of morbidity. It can also inform on the efficacy of the treatment. Cilostazol, a phosphodiesterase III inhibitor, has been demonstrated to enhance walking distance in patients with peripheral artery disease through the dilation of blood vessels and the inhibition of platelet aggregation. With this preliminary study, we aimed to elucidate other possible effects of cilostazol, specifically its influence on the structural properties of red blood cells. Methods: 10 patients (5 men, 5 women) with PAD were treated with cilostazol over a three-month period. Its biochemical effects on RBCs were determined using differential scanning calorimetry (DSC). Patient’s blood samples were collected at the start of treatment, then after two weeks, one month, two months, and three months of therapy. Results: The DSC analysis revealed shifts in thermal properties, including change in peak (melting or denaturation) temperature (T_p) and calorimetric enthalpy (ΔH_cal), which indicate significant structural changes in red blood cells. These thermal property changes correlated with clinical improvements in walking distance reported by patients. Conclusions: Our findings suggest that cilostazol induces substantial biochemical modifications in red blood cells, enhancing their functional properties and contributing to improved clinical outcomes. This study highlights the potential of differential scanning calorimetry as an adjunctive method for assessing the effectiveness of treatments for peripheral artery disease at the cellular level. However, further investigation with larger patient cohorts is required to confirm these initial results. Full article

Pharmacological treatment of diabetes mellitus-induced erectile dysfunction (DMED) has become increasingly challenging due to the limited efficacy of phosphodiesterase type 5 inhibitors (PDE5i). As the global prevalence of DM continues, there is a critical need for novel therapeutic strategies to address DMED. In our previous studies, we found that Glutathione peroxidase 4 (GPX4), a ferroptosis inhibitor, can ameliorate DMED in diabetic rats. However, the specific role of GPX4 in corpus cavernosum smooth muscle cells (CCSMCs) and its regulatory mechanisms remain unclear. In this study, we established primary cultures of CCSMCs and systematically analyzed the role of GPX4 under high-glucose conditions. To further elucidate the upstream regulatory pathways of GPX4, we employed immunoprecipitation coupled with mass spectrometry (IP-MS) to identify potential interacting proteins. Additionally, co-immunoprecipitation (Co-IP) and cycloheximide (CHX) chase assays were conducted to explore the regulatory dynamics and post-translational stability of GPX4. Under high-glucose conditions, the expression of GPX4 in CCSMCs is significantly downregulated, leading to an increase in intracellular oxidative stress and heightened levels of ferroptosis, accompanied by dysfunction in smooth muscle cell relaxation. Furthermore, the CHX chase assay revealed that high glucose accelerates GPX4 protein degradation via the ubiquitin–proteasome pathway. Subsequent IP-MS identified NEDD4, an E3 ubiquitin ligase, as a potential interacting partner of GPX4. Further validation demonstrated that NEDD4 modulates the ubiquitination process of GPX4, thereby influencing its stability and expression. In conclusion, we identified NEDD4 as a key regulator of GPX4 stability through ubiquitin-mediated proteasomal degradation. These findings suggest potential therapeutic strategies targeting the NEDD4-GPX4 axis to alleviate DMED pathology. Full article

Erectile dysfunction (ED) is a multifactorial social problem affecting men worldwide. While phosphodiesterase type 5 inhibitors (PDE5) like sildenafil are commonly used, they often present side effects, underscoring the need for alternative therapies. Therefore, this study investigated the potential of phytochemicals from Detarium senegalense in the management of ED. A library of phytochemicals from Detarium senegalense was generated, prepared, and interacted with six key enzymes implicated in ED, including PDE5, using the Schrödinger Maestro suite. The results identified catechin, epicatechin, and gallic acid as the leading compounds with significant binding affinities for the targeted enzymes. Catechin and epicatechin (−9.877 and −11.408 kcal/mol, respectively) exhibited comparable binding affinities to sildenafil (−11.926 kcal/mol) on PDE5. The MD simulation results also revealed superior stability and ability to maintain interaction with key amino acids at the active site of PDE5 over the entire simulation period for these compounds. These compounds also demonstrated favorable ADMET profiles over sildenafil, including high gastrointestinal absorption and no violation of Lipinski’s rule, indicating good bioavailability and drug likeness. These findings suggest that flavonoids from Detarium senegalense, especially catechin and epicatechin, have potential in the management of ED by interacting with multiple targets involved in its pathogenesis. Full article