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Search Results: 1 - 10 of 208481 matches for " Dominick L. Auci "
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17 -Ethynyl-androst-5-ene-3 ,7 ,17 -triol (HE3286) Is Neuroprotective and Reduces Motor Impairment and Neuroinflammation in a Murine MPTP Model of Parkinson’s Disease
Ferdinando Nicoletti,Ingrid Philippens,Paolo Fagone,Clarence N. Ahlem,Christopher L. Reading,James M. Frincke,Dominick L. Auci
Parkinson's Disease , 2012, DOI: 10.1155/2012/969418
Abstract: 17α-Ethynyl-androst-5-ene-3β,7β,17β-triol (HE3286) is a synthetic androstenetriol in Phase II clinical development for the treatment of inflammatory diseases. HE3286 was evaluated for blood-brain barrier (BBB) permeability in mice, and efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson’s disease (PD). We found that HE3286 freely penetrated the BBB. HE3286 treatment significantly improved motor function compared to vehicle in the rotarod test (mean 58.2?sec versus 90.9?sec, ), and reduced inflammatory mediator gene expression in the brain (inducible nitric oxide synthase, 20%, ; tumor necrosis factor α, 40%, , and interleukin-1β, 33%, ) measured by reverse-transcriptase polymerase chain reaction. Brain tissue histopathology and immunohistochemistry showed that HE3286 treatment increased the numbers of tyrosine hydroxylase-positive cells by 17% compared to vehicle ( ), and decreased the numbers of damaged neurons by 38% relative to vehicle ( ). L-3,4-dihydroxyphenylalanine (L-DOPA) efficacy was not enhanced by concurrent administration of HE3286. HE3286 administration prior to MPTP did not enhance efficacy. Our data suggest a potential role for HE3286 in PD treatment, and provides incentive for further investigation. 1. Introduction PD is a neurodegenerative disorder characterized by a progressive degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) and decreased levels of dopamine in the putamen of the dorsolateral striatum. The loss of dopamine in the striatum manifests clinically as motor disabilities that include bradykinesia, resting tremor, and muscular rigidity. Diagnosis is based on motor symptoms, which become evident only after the loss of more than 50% of the SNpc DAergic neurons and 60–80% of striatal dopamine [1]. Prolonged treatment of PD with L-DOPA usually results in a dyskinesia that can be more disabling than the disease itself; therefore, there is a great need for alternative therapeutic modalities. The acute MPTP mouse model of nigrostriatal degeneration recapitulates the DAergic neuron loss seen in PD and currently represents the most commonly used toxin-induced mouse model of PD [2]. MPTP’s mechanism of toxicity is complex, and exerted through its toxic metabolite, methyl-4-phenylpyridinium (MPP+) ion, which is taken up selectively by DAergic neurons through the dopamine transporter. Inside the cell, MPP+ is a mitochondrial toxin, which induces neuronal death through several mechanisms that include oxidative stress [3], excitotoxicity [4], and
5-Androstenediol Ameliorates Pleurisy, Septic Shock, and Experimental Autoimmune Encephalomyelitis in Mice
Ferdinando Nicoletti,Dominick L. Auci,Katia Mangano,Jaime Flores-Riveros,Sonia Villegas,James M. Frincke,Christopher L. Reading,Halina Offner
Autoimmune Diseases , 2010, DOI: 10.4061/2010/757432
Abstract: Androstenediol (androst-5-ene-3 ,17 -diol; 5-AED), a natural adrenal steroid, has been shown to suppress experimental autoimmune encephalomyelitis (EAE) in female SJL/J mice. We here report that 5-AED limits inflammation and proinflammatory cytokines including TNF in murine models of carrageenan-induced pleurisy and lippopolysaccaride- (LPS) induced septic shock. 5-AED binds to and transactivates sex steroid receptors with the same general rank order of potency (ERβ > ERα ? AR). 5-AED provides benefit in EAE in a dose-dependent fashion, even when treatment is delayed until onset of disease. The minimally effective dose may be as low as 4?mg/kg in mice. However, benefit was not observed when 5-AED was given in soluble formulation, leading to a short half-life and rapid clearance. These observations suggest that treatment with 5-AED limits the production of pro-inflammatory cytokines in these animal models and, ultimately, when formulated and administered properly, may be beneficial for patients with multiple sclerosis and other Th1-driven autoimmune diseases. 1. Introduction Nonglucocorticoid steroids are subjects of intense scientific investigation as perturbations are associated with various diseases including the pathogenesis of autoimmunity [1]. The “gender gap” [2] with respect to incidence and severity of autoimmune disease has been the focus of efforts to uncover new therapies. For example, estrogens [3] and androgens [4, 5] are protective in several autoimmune disease models, including experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Recent work has dissociated the anti-inflammatory effect from the neuroprotective effect of estrogen treatment in EAE and has shown that its neuroprotective effects do not necessarily depend on anti-inflammatory properties [6]. Specifically, an estrogen receptor (ER) agonist reduced central nervous system inflammation, whereas an ER agonist treatment did not, but instead, was neuroprotective. Preliminary clinical results were encouraging. In a pilot trial, oral estriol treatment of relapsing remitting multiple sclerosis patients caused significant decreases in enhancing lesions on brain magnetic resonance imaging [7]. However, sex steroid therapy involves serious risks. For example, estrogen treatment involves increased risk for breast cancer in women [8]. Because such estrogen-related toxicities are mediated almost exclusively through ER , ER ligand treatment has been suggested as a potentially safer neuroprotective strategy in multiple sclerosis and other
5-Androstene-3β,7β,17β-triol (β-AET) Slows Thermal Injury Induced Osteopenia in Mice: Relation to Aging and Osteoporosis
Ajay K. Malik,Sophia Khaldoyanidi,Dominick L. Auci,Scott C. Miller,Clarence N. Ahlem,Christopher L. Reading,Theodore Page,James M. Frincke
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013566
Abstract: 5-androstene-3β,7β,17β-triol (β-AET), an active metabolite of dehydroepiandrosterone (DHEA), reversed glucocorticoid (GC)-induced suppression of IL-6, IL-8 and osteoprotegerin production by human osteoblast-like MG-63 cells and promoted osteoblast differentiation of human mesenchymal stem cells (MSCs). In a murine thermal injury model that includes glucocorticoid-induced osteopenia, β-AET significantly (p<0.05) preserved bone mineral content, restored whole body bone mineral content and endochondral growth, suggesting reversal of GC-mediated decreases in chondrocyte proliferation, maturation and osteogenesis in the growth plate. In men and women, levels of β-AET decline with age, consistent with a role for β-AET relevant to diseases associated with aging. β-AET, related compounds or synthetic derivatives may be part of effective therapeutic strategies to accelerate tissue regeneration and prevent or treat diseases associated with aging such as osteoporosis.
HE3286, an oral synthetic steroid, treats lung inflammation in mice without immune suppression
Douglas Conrad, Angela Wang, Raymond Pieters, Ferdinando Nicoletti, Katia Mangano, Anna M van Heeckeren, Steven K White, James M Frincke, Christopher L Reading, Dwight Stickney, Dominick L Auci
Journal of Inflammation , 2010, DOI: 10.1186/1476-9255-7-52
Abstract: In mice, oral treatment with HE3286 (40 mg/kg) significantly (p < 0.05) decreased neutrophil counts and exudate volumes (~50%) in carrageenan-induced pleurisy, and myeloperoxidase in lipopolysaccharide-induced lung injury. HE3286 (40 mg/kg) was not found to be profoundly immune suppressive in any of the classical animal models of immune function, including those used to evaluate antigen specific immune responses in vivo (ovalbumin immunization). When mice treated for two weeks with HE3286 were challenged with K. pneumoniae, nearly identical survival kinetics were observed in vehicle-treated, HE3286-treated and untreated groups.HE3286 represents a novel, first-in-class anti-inflammatory agent that may translate certain benefits of β-AET observed in rodents into treatments for chronic inflammatory pulmonary disease.Chronic obstructive pulmonary disease (COPD), a term most often used to describe chronic bronchitis and emphysema [1,2] is an inflammatory disease of the lungs marked by a loss of elastic recoil, an increased resistance to airflow and decreased expiratory flow rate leading to dyspnea [3]. Chronic bronchitis, emphysema and cystic fibrosis (CF), all forms of COPD, share many features including a progressive airway remodeling driven by chronic inflammation [4-7]. COPD is a major cause of morbidity and mortality in industrialized countries and novel treatments are urgently needed because many patients respond poorly to conventional therapies [8-10]. Even in responders, narrow therapeutic windows and a myriad of unwanted side effects, including immune suppression are treatment limiting [9-12]. We have suggested that suitable agents may be found within the adrenal metabolome [13].Dehydroepiandrosterone (DHEA) is an abundant adrenal steroid and a precursor in the biosynthesis of androgens, estrogens and other anti-inflammatory immune regulating steroids [14,15]. From studies reporting aberrant metabolism of adrenal steroids in CF patients [16,17] we surmised that
Superluminality and Entanglement in an Electromagnetic Quantum-Relativistic Theory  [PDF]
Massimo Auci
Journal of Modern Physics (JMP) , 2018, DOI: 10.4236/jmp.2018.912139
Abstract: An electromagnetic theory that links quantum and relativistic phenomena in a single context is built. Wave-particle duality is the experimental proof of their common origin. In this context, Quantum Mechanics and Special Relativity are two compatible synergistic theories. The developed theory shows the existence of superluminal effects that suggest an explanation to the entanglement between pairs of particles and photons.
Review of Azithromycin Ophthalmic 1% Solution (AzaSite ) for the Treatment of Ocular Infections
Dominick L. Opitz and Jennifer S. Harthan
Ophthalmology and Eye Diseases , 2012, DOI: 10.4137/OED.S7791
Abstract: AzaSite (azithromomycin 1.0%) ophthalmic solution was approved in 2007 by the US Food and Drug Administration (FDA) as the first commercially available formulation of ophthalmic azithromycin for the treatment of bacterial conjunctivitis. AzaSite utilizes a vehicle delivery system called DuraSite , which stabilizes and sustains the release of azithromycin to the ocular surface, leading to a longer drug residence time, less frequent dosing, and an increase in patient compliance. AzaSite is a broad spectrum antibiotic, effective against Gram-positive, Gram-negative, and atypical bacteria. AzaSite has been studied for the treatment of ocular conditions beyond its clinical indication. A number of clinical studies have evaluated its efficacy and safety in the management of ocular conditions such as bacterial conjunctivitis and blepharitis on both the pediatric and adult populations. This article aims to evaluate the peer-reviewed published literature on the use of azithromycin 1.0% ophthalmic for current and possible future ophthalmic uses.
Review of Azithromycin Ophthalmic 1% Solution (AzaSite ) for the Treatment of Ocular Infections
Dominick L. Opitz,Jennifer S. Harthan
Ophthalmology and Eye Diseases , 2012,
Abstract:
Self-gravitational red shift effect and micro-black holes production in dipolar electromagnetic sources
Massimo Auci
Physics , 2009,
Abstract: Using Bridge Theory to describe the electromagnetic interactions occurring between high energy pairs of particles, we predict an anomalous self-gravitational red-shift in the frequency of the EM source produced during the interaction. The extreme consequence is the introduction of an upper limit in the electromagnetic spectrum. Hypothesizing a scattering energy greater than 5.55 10^22 Mev,the source collapses under his events horizon, becoming a neutral spin less micro-black hole: perfect candidates to contribute to the dark matter of the Universe.
On the Compatibility Between Quantum and Relativistic Effects in an Electromagnetic Bridge Theory
Massimo Auci
Physics , 2010,
Abstract: The Dipolar Electromagnetic Source (DEMS) model, based on the Poynting Vector Conjecture, conduces in Bridge Theory to a derivation of the Lorentz transformation connecting pairs of events. The results prove a full compatibility between quantum and relativistic effects.
Bridge Theory: Oltre la Frontiera Quantistica
Massimo Auci
Physics , 2009,
Abstract: Bridge Theory was born in 1979 from a simple idea. An observer of a dipolar source cannot measure instantaneously all the energy and momentum effectively produced along the own line of view because the source has not a spherical symmetry. This physical circumstance has as consequence that the energy and momentum localised inside the source zone is equivalent to one of a photon. The new approach to quantisation appears to be a bridge between quantum mechanics and electromagnetic theory with many intriguing future develops.
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