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.

Effects of sildenafil and/or muscle derived stem cells on myocardial infarction.

Background: Previous studies have shown that long-term oral daily PDE 5 inhibitors (PDE5i) counteract fibrosis, cell loss, and the resulting dysfunction in tissues of various rat organs and that implantation of skeletal muscle-derived stem cells (MDSC) exerts some of these effects. PDE5i and stem cells in combination were found to be more effective in non-MI cardiac repair than each treatment separately. We have now investigated whether sildenafil at lower doses and MDSC, alone or in combination are effective to attenuate LV remodeling after MI in rats.

Glycosaminoglycan storage in neuroanatomical regions of mucopolysaccharidosis I dogs following intrathecal recombinant human iduronidase.

Intrathecal (IT) recombinant human α-l-iduronidase (rhIDU) has been shown to reduce mean brain glycosaminoglycans (GAGs) to normal levels in mucopolysaccharidosis I (MPS I) dogs. In this study, we examined storage in neuroanatomical regions of the MPS I dog brain, including frontal lobe, cerebellum, basal ganglia, thalamus, hippocampal formation, and brainstem, to determine the response of these functional regions to treatment with IT rhIDU. GAG storage in untreated MPS I dogs was significantly different from normal dogs in all examined sections.

Proteasome inhibitor up regulates liver antioxidative enzymes in rat model of alcoholic liver disease.

Oxidative stress occurs in the liver of rats fed with alcohol chronically due to ethanol metabolism by CYP2E1, causing liver injury. The proteasome is considered as an antioxidant defense in the cell because of its activity in removing damaged and oxidized proteins, but a growing body of evidence shows that proteasome inhibitor treatment, at a non toxic low dose, provides protection against oxidative stress. In the present study, rats were fed with ethanol for 4 weeks and were treated with the proteasome inhibitor PS-341 (Bortezomib, Velcade®).

Effects of ethanol on the proteasome interacting proteins.

Proteasome dysfunction has been repeatedly reported in alcoholic liver disease. Ethanol metabolism end-products affect the structure of the proteasome, and, therefore, change the proteasome interaction with its regulatory complexes 19S and PA28, as well as its interacting proteins. Chronic ethanol feeding alters the ubiquitin-proteasome activity by altering the interaction between the 19S and the 20S proteasome interaction.

SAMe prevents the induction of the immunoproteasome and preserves the 26S proteasome in the DDC-induced MDB mouse model.

Mallory-Denk bodies (MDBs) form in the liver of alcoholic patients. This occurs because of the accumulation and aggregation of ubiquitinated cytokeratins, which hypothetically is due to the ubiquitin-proteasome pathway's (UPP) failure to degrade the cytokeratins. The experimental model of MDB formation was used in which MDBs were induced by refeeding DDC to drug-primed mice.

Treatment of Peyronie's disease with PDE5 inhibitors: an antifibrotic strategy.

Peyronie's disease (PD) is a localized fibrotic condition of the tunica albuginea that is associated with risk factors for corpora cavernosa fibrosis (such as advanced age and diabetes) and Dupuytren contracture, another localized fibrotic process. Most of the current pharmacological treatments for PD are not based on antifibrotic approaches that have shown promising results in animal models and clinical efficacy in other fibrotic conditions, which may explain why they are generally unsuccessful. Evidence gathered in human specimens and animal models of PD have elucidated aspects of its etiology and histopathology, showing that overexpression of transforming growth factor beta1, plasminogen activator inhibitor 1, reactive oxygen species and other profibrotic factors, which are, in most cases, assumed to be induced by trauma to the tunica albuginea, leads to myofibroblast accumulation and excessive deposition of collagen.

SAMe prevents the up regulation of toll-like receptor signaling in Mallory-Denk body forming hepatocytes.

Mallory-Denk body (MDB) formation is a component of alcoholic and non alcoholic hepatitis. In the present study, the role of the toll-like receptor (TLR) signaling pathway was investigated in the mechanism of MDB formation in the DDC-fed mouse model. Microarray analysis data mining, performed on the livers of drug-primed mice refed DDC, showed that TLR2/4 gene expression was significantly up regulated by DDC refeeding.

The effect of propranolol on gene expression during the blood alcohol cycle of rats fed ethanol intragastrically.

Propranolol, a beta adrenergic blocker prevents the blood alcohol (BAL) cycle in rats fed ethanol intragastrically at a constant rate by preventing the cyclic changes in the metabolic rate caused by fluctuating levels of norepinephrine released into the blood. The change in the rate of metabolism changes the rate of alcohol elimination in the blood which causes the BAL to cycle. Microarray analysis of the livers from the rats fed ethanol and propranolol showed similar changes in clusters of functionally related gene expressions.

Diabetes-relevant regulation of cultured blood outgrowth endothelial cells.

Many cell and tissue abnormalities in diabetes mellitus are mediated by auto- and paracrine TGFbeta which is induced by high ambient glucose and glycated proteins. In most cell types TGFbeta reduces cell proliferation and enhances apoptosis which are mediated through the TGFbeta type I receptor, Alk5. In contrast, early diabetic microangiopathy is characterized by endothelial cell proliferation.

Mechanisms of penile fibrosis.

Introduction: Penile fibrosis has been conceptually identified with the plaque that develops in the tunica albuginea in Peyronie's disease (PD), or with localized processes induced in the corpora cavernosa by ischemic or traumatic events. Recently, it has been proposed that a diffuse, progressive, and milder intracorporal fibrosis, which affects also the media of the penile arteries, is responsible for vasculogenic erectile dysfunction (ED) associated with aging, smoking, diabetes, hypertension, and post-radical prostatectomy. These processes differ in etiology, time course, target cells, and treatment, but have many features in common.

Localization and gestation-dependent pattern of corticotrophin-releasing factor receptor subtypes in ovine fetal distal colon.

Meconium passage is frequently observed in association with feto-maternal stress factors such as hypoxia and infection, but the triggering mechanism is unknown. We hypothesize that differential regulation of corticotrophin-releasing factor (CRF) receptors during gestation play an important role in determining the susceptibilities of the fetus to stress-induced in utero meconium passage at term. We examined the innervation patterns of CRF-receptor type 1 (CRF-R1), a stimulator of gastrointestinal motility and CRF-receptor type II (CRF-R2), an inhibitor of gastrointestinal motility in ovine fetal distal colonic segments from very preterm to term gestation.

CYP2E1 induced by ethanol causes oxidative stress, proteasome inhibition and cytokeratin aggresome (Mallory body-like) formation.

The role of oxidative stress in alcoholic liver disease and cytokeratin aggresome formation is the focus of this in vitro study. HepG2 cells transduced to over express CYP2E1 (E47) and control HepG2 cells (C34) were first treated with arachidonic acid, then Fe-NAT, and finally with ethanol. In the E47 ethanol-treated cells, CYP2E1 was induced and a higher level of reactive oxygen species and carbonyl proteins were generated.

The pleiotropic effects of inducible nitric oxide synthase (iNOS) on the physiology and pathology of penile erection.

The contribution of the neuronal and endothelial isoforms of nitric oxide synthase (nNOS and eNOS, respectively) in the synthesis of nitric oxide as a mediator of penile erection, at the levels of both the penile corpora cavernosa and the hypothalamic regions that control the erectile response, are well established. More recently, the role of the third NOS isoform, the inducible NOS (iNOS), has also started to be elucidated. iNOS does not appear to intervene directly in physiological penile erection or in its central control, but its transcriptional induction is postulated to be a key factor in two opposite related pathological processes, namely neurotoxicity in critical related regions of the hypothalamus during senescence, and as a defense mechanism against the aging or injury-associated fibrosis in the penile corpora cavernosa, the media of the penile arteries, and the tunica albuginea.

Protective effect of prenatal water restriction on offspring cardiovascular homeostasis in response to hemorrhage.

We determined the cardiovascular and AVP responses of prenatally dehydrated (PreDehy) neonates to intravascular hemorrhage. Ewes with singleton fetuses were subjected to water restriction from 110 days of gestation to full term to achieve hypernatremia of 8-10 meq/l. Water and food were provided ad libitum to control ewes.