Nutraceutical COMP-4 confers protection against endothelial dysfunction through the eNOS/iNOS-NO-cGMP pathway.

The nutraceutical COMP-4 -consisting of L-citrulline, ginger extract, and herbal components Paullinia cupana and muira puama-has been shown previously to stimulate the production of nitric oxide (NO) in a variety of tissue types. We hypothesized that COMP-4 may have a protective, stimulatory effect on the vascular endothelial cell. Human umbilical arterial endothelial cells were incubated for 24 hours with or without COMP-4 and, to replicate impairment of endothelial function, co-incubated with or without H2O2.

IFN-γ-mediated control of SARS-CoV-2 infection through nitric oxide.

Introduction: The COVID-19 pandemic has highlighted the need to identify mechanisms of antiviral host defense against SARS-CoV-2. One such mediator is interferon-g (IFN-γ), which, when administered to infected patients, is reported to result in viral clearance and resolution of pulmonary symptoms. IFN-γ treatment of a human lung epithelial cell line triggered an antiviral activity against SARS-CoV-2, yet the mechanism for this antiviral response was not identified.

Activation of the iNOS/NO/cGMP pathway by Revactin® in human corporal smooth muscle cells.

Background: The combination of the nutraceuticals, Paullinia cupana, ginger rhizome, muira puama, and the amino acid L-citrulline (COMP-4) has been shown to stimulate the production of inducible nitric oxide synthase (iNOS), nitric oxide (NO), and cGMP in rat corpora cavernosa smooth muscle cells (CSMC). When administered to middle-aged rats, long-term treatment with COMP-4 resulted in both an increase in the number of CSMC and an improvement in erectile function. We, therefore, aimed to determine whether a commercial formulation of COMP-4, Revactin, could have a similar stimulatory effect on human CSMC.

Exogenous l-ARGININE does not stimulate production OF NO or cGMP within the rat corporal smooth muscle cells in culture.

Background And Aim: Nitric oxide (NO) is the intracellular chemical responsible for initiating a penile erection. Despite conflicting clinical data, it continues to be publicized and promoted that orally administered l-arginine, the putative substrate for NO, enhances the erectile response presumably by stimulating NO production by the corporal tissues resulting in an increase in cGMP production. To shed light on this issue, an in vitro study was conducted to explore the effect of direct exogenous administration of l-arginine as well as its precursor and metabolite, l-citrulline, on the NO-cGMP pathway within the cavernosal smooth muscle (CSM) cell.

Dyslipidemia Is a Major Factor in Stem Cell Damage Induced by Uncontrolled Long-Term Type 2 Diabetes and Obesity in the Rat, as Suggested by the Effects on Stem Cell Culture.

Background: Previous work showed that muscle-derived stem cells (MDSCs) exposed long-term to the milieu of uncontrolled type 2 diabetes (UC-T2D) in male obese Zucker (OZ) rats, were unable to correct the associated erectile dysfunction and the underlying histopathology when implanted into the corpora cavernosa, and were also imprinted with a noxious gene global transcriptional signature (gene-GTS), suggesting that this may interfere with their use as autografts in stem cell therapy.

Aim: To ascertain the respective contributions of dyslipidemia and hyperglycemia to this MDSC damage, clarify its mechanism, and design a bioassay to identify the damaged stem cells.

Methods: Early diabetes MDSCs and late diabetes MDSCs were respectively isolated from nearly normal young OZ rats and moderately hyperglycemic and severely dyslipidemic/obese aged rats with erectile dysfunction.

The two phases of the clinical validation of preclinical translational mechanistic research on PDE5 inhibitors since Viagra's advent. A personal perspective.

The FDA approval of Viagra (sildenafil) for the on demand treatment of erectile dysfunction (ED) through relaxation of the corporal and cavernosal vascular smooth muscle that results in an increase in blood flow to the corporal tissues stemmed from 2 decades of research, mainly at academic centers. This culminated in the finding of the nitric oxide/cGMP pathway as the mediator of penile erection, followed by some years of basic studies and clinical validation at Pfizer. Further on, new translational laboratory and animal research from our group initiated a second phase when we proposed an alternative therapeutic schedule and mechanism of action for PDE5 inhibitors (PDE5i) in both corporal veno-occlusive dysfunction (CVOD) and Peyronie's disease (PD), specifically, continuous long-term administration (CLTA) to achieve sustained levels of cGMP within the penis.

Safety and efficacy of daily Revactin in men with erectile dysfunction: a 3-month pilot study.

Background: The earliest sign of an ongoing change in a man's erectile function (EF) is the increase in his refractory period. This is due to the onset of an aging related apoptosis of the corporal smooth muscle cells (CSMC) as a result of oxidative stress (ROS) within the CSMC itself. In response, the CSMC begin to upregulate the inducible nitric oxide synthase (iNOS) enzyme presumably to achieve high levels of nitric oxide (NO) used to combat ROS.

Effect of ginger, Paullinia cupana, muira puama and l- citrulline, singly or in combination, on modulation of the inducible nitric oxide- NO-cGMP pathway in rat penile smooth muscle cells.

Introduction: COMP-4 is a natural compound-based dietary supplement consisting of the combination of ginger, Paullinia cupana, muira puama and l-citrulline, which when given long-term has been shown in the aged rat to a) upregulate iNOS in the penile smooth muscle cells (SMC), b) reverse the corporal SMC apoptosis and fibrosis associated with corporal veno-occlusive dysfunction (CVOD), and c) improve resulting erectile function. To elucidate the mechanism of how COMP-4 and its individual components modulate the iNOS-cGMP pathway, an in vitro study was conducted using a rat corporal primary SMC culture to determine its effect on NOS, soluble guanylate cyclase (sGC), cGMP and the phosphodiesterase 5 enzyme (PDE5).

Materials And Methods: Primary SMC cultures using the explant technique were initiated by cutting small pieces of corporal tissue from 8 week old Sprague-Dawley rats.

Cardiovascular Health, Erectile Dysfunction, and Testosterone Replacement: Controversies and Correlations.

Erectile dysfunction and cardiovascular disease share a similar underlying pathophysiology, and low serum testosterone, known as hypogonadism, is a significant player in both conditions. Hypogonadism is a known risk factor for cardiovascular events and worsened mortality, thus influencing physicians to recommend testosterone replacement in hypogonadal men. However, at least 4 recent reports suggest that testosterone replacement may worsen cardiovascular risk, heightening hesitancy in the medical community to treat patients with hypogonadism with testosterone.

Myostatin, a profibrotic factor and the main inhibitor of striated muscle mass, is present in the penile and vascular smooth muscle.

Myostatin is present in striated myofibers but, except for myometrial cells, has not been reported within smooth muscle cells (SMC). We investigated in the rat whether myostatin is present in SMC within the penis and the vascular wall and, if so, whether it is transcriptionally expressed and associated with the loss of corporal SMC occurring in certain forms of erectile dysfunction (ED). Myostatin protein was detected by immunohistochemistry/fluorescence and western blots in the perineal striated muscles, and also in the SMC of the penile corpora, arteries and veins, and aorta.

Aging related erectile dysfunction-potential mechanism to halt or delay its onset.

Erectile dysfunction (ED) will visit every man at some time in his life. The age at when that knock on the door is heard is totally dependent on one's genetics as well as other extrinsic factors. Unlike guests who come for a visit and then leave, once ED shows up it tends to hang around forever.

The Role of Estrogen Modulators in Male Hypogonadism and Infertility.

Estradiol, normally considered a female hormone, appears to play a significant role in men in a variety of physiologic functions, such as bone metabolism, cardiovascular health, and testicular function. As such, estradiol has been targeted by male reproductive and sexual medicine specialists to help treat conditions such as infertility and hypogonadism. The compounds that modulate estradiol levels in these clinical conditions are referred to as selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs).

Implanted Muscle-Derived Stem Cells Ameliorate Erectile Dysfunction in a Rat Model of Type 2 Diabetes, but Their Repair Capacity Is Impaired by Their Prior Exposure to the Diabetic Milieu.

Introduction: Muscle-derived stem cells (MDSCs) and other SCs implanted into the penile corpora cavernosa ameliorate erectile dysfunction in type 1 diabetic rat models by replenishing lost corporal smooth muscle cells (SMCs) and decreasing fibrosis. However, there are no conclusive data from models of type 2 diabetes (T2D) and obesity.

Aim: To determine whether MDSCs from obese Zucker (OZ) rats with T2D at an early stage of diabetes (early diabetic SCs isolated and cultured in low-glucose medium [ED-SCs]) counteract corporal veno-occlusive dysfunction and corporal SMC loss or lipo-fibrosis when implanted in OZ rats at a late stage of diabetes and whether MDSCs from these OZ rats with late diabetes (late diabetic SCs isolated and cultured in high-glucose medium [LD-SC]) differ from ED-SCs in gene transcriptional phenotype and repair capacity.

Erectile Dysfunction and Essential Hypertension: The Same Aging-related Disorder?

An erection is a mechanical event dependent primarily on corporeal vascular dynamics wherein arterial inflow and storage of blood within the corpora is greater than the egress of blood from the corpora. The most common cause of erectile dysfunction (ED) is the inability of the corporal tissue to store the blood within the corporal sinusoids once inflow into the corpora begins. This failure to store is primarily due to a corporal smooth muscle dysfunction and, in most men, is most likely an aging-related occurrence.

Testosterone replacement therapy in men with prostate cancer: a time-varying analysis.

Introduction: The use of testosterone replacement therapy (TRT) in men with prostate cancer is controversial given concerns of androgen-related cancer progression. Although emerging evidence suggests that TRT may be safe in this setting, no study has investigated dose-related effects.

Aim: We used time-varying analysis to determine whether increasing TRT exposure is associated with worse outcomes.

The transcriptional signatures of cells from the human Peyronie's disease plaque and the ability of these cells to generate a plaque in a rat model suggest potential therapeutic targets.

Introduction: The success of medical therapies for Peyronie's disease (PD) has not been optimal, possibly because many of them went directly to clinical application without sufficient preclinical scientific research. Previous studies revealed cellular and molecular pathways involved in the formation of the PD plaque and in particular the role of the myofibroblast.

Aims: The current work aimed to determine under normal and fibrotic conditions what differentiates PD cells from tunica albuginea (TA) and corpora cavernosa (CC) cells by defining their global transcriptional signatures and testing in vivo whether PD cells can generate a PD-like plaque.

Fournier's gangrene: a model for early prediction.

Early diagnosis remains the cornerstone of management of Fournier's gangrene. As a result of variable progression of disease, identifying early predictors of necrosis becomes a diagnostic challenge. We present a scoring system based on objective admission criteria, which can help distinguish Fournier's gangrene from nonnecrotizing scrotal infections.

Oral Bisphenol A (BPA) given to rats at moderate doses is associated with erectile dysfunction, cavernosal lipofibrosis and alterations of global gene transcription.

Bisphenol A (BPA), a suspected reproductive biohazard and endocrine disruptor, released from plastics is associated with ED in occupationally exposed workers. However, in rats, despite the induction of hypogonadism, apoptosis of the penile corporal smooth muscle (SM), fat infiltration into the cavernosal tissue and changes in global gene expression with the intraperitoneal administration of high dose BPA, ED was not observed. We investigated whether BPA administered orally rather than intraperitoneally to rats for longer periods and lower doses will lead to ED.

Chronic high dose intraperitoneal bisphenol A (BPA) induces substantial histological and gene expression alterations in rat penile tissue without impairing erectile function.

Introduction: Bisphenol A (BPA), released from plastics and dental sealants, is a suspected endocrine disruptor and reproductive toxicant. In occupationally exposed workers, BPA has been associated with erectile dysfunction (ED).

Aims: To determine whether long-term exposure to high doses of BPA in the rat affects serum levels of testosterone (T) and estradiol (E2), and induces corporal histopathology and resultant ED.

Early onset erectile dysfunction is usually not associated with abnormal cavernosal arterial Inflow.

Endothelial dysfunction, a marker for atherosclerosis and hence arterial disease, has recently been proffered as the main offender within the vascular system to predict not only the future onset of erectile dysfunction (ED) but also as the main cause of the ED. To glean more insight into whether arterial disease is indeed operative during the early onset of ED, we reviewed the duplex ultrasound scans of 23 men with ED who were younger than 50 years of age. Depending on the criteria used for abnormal arterial responses, it was determined in this cohort of young men that there was only a 4-13% incidence of abnormal arterial responses.

Separate or combined treatments with daily sildenafil, molsidomine, or muscle-derived stem cells prevent erectile dysfunction in a rat model of cavernosal nerve damage.

Introduction: Long-term daily administration of phosphodiesterase type 5 (PDE5) inhibitors in the rat prevents or reverses corporal veno-occlusive dysfunction (CVOD) and smooth muscle cell (CSMC) loss and fibrosis, in both aging and bilateral cavernosal nerve resection (BCNR) models for erectile dysfunction. In the aging rat model, corporal implantation of skeletal muscle-derived stem cells (MDSC) reverses CVOD. Nitric oxide (NO) and cyclic guanosine monophosphate can modulate stem cell lineage.

Pre-embolization evaluation of high-flow priapism: magnetic resonance angiography of the penis.

Purpose: High-flow priapism is often a sequela of perineal trauma resulting in an arteriocavernosal fistula (ACF) between a cavernosal artery and lacunar spaces of the penis. We report our experience utilizing magnetic resonance angiography (MRA) in addition to color Doppler Sonography (CDS) in the workup and treatment planning of 4 patients with high-flow priapism.

Methods: All patients had suspected high-flow priapism diagnosed by clinical exam and CDS and underwent MRA of the penis prior to sub-selective arterial embolization (SSAE) of the feeding vessel(s).