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Search Results: 1 - 10 of 218987 matches for " Christopher L Reading "
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Molecular Targets for 17α-Ethynyl-5-Androstene-3β,7β,17β-Triol, an Anti-Inflammatory Agent Derived from the Human Metabolome
Christopher L. Reading, James M. Frincke, Steven K. White
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032147
Abstract: HE3286, 17α-ethynyl-5-androstene-3β, 7β, 17β-triol, is a novel synthetic compound related to the endogenous sterol 5-androstene-3β, 7β, 17β-triol (β-AET), a metabolite of the abundant adrenal steroid dehydroepiandrosterone (DHEA). HE3286 has shown efficacy in clinical studies in impaired glucose tolerance and type 2 diabetes, and in vivo models of types 1 and 2 diabetes, autoimmunity, and inflammation. Proteomic analysis of solid-phase HE3286-bound bead affinity experiments, using extracts from RAW 264.7 mouse macrophage cells, identified 26 binding partners. Network analysis revealed associations of these HE3286 target proteins with nodes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for type 2 diabetes, insulin, adipokine, and adipocyte signaling. Binding partners included low density lipoprotein receptor-related protein (Lrp1), an endocytic receptor; mitogen activated protein kinases 1 and 3 (Mapk1, Mapk3), protein kinases involved in inflammation signaling pathways; ribosomal protein S6 kinase alpha-3 (Rsp6ka3), an intracellular regulatory protein; sirtuin-2 (Sirt2); and 17β-hydroxysteroid dehydrogenase 1 (Hsd17β4), a sterol metabolizing enzyme.
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
17α-Ethynyl-5α-androstane-3α, 17β-diol Treatment of MNU-Induced Mammary Cancer in Rats
Clarence N. Ahlem,James M. Frincke,Steven K. White,Christopher L. Reading,Richard J. Trauger,Rajkumar Lakshmanaswamy
International Journal of Breast Cancer , 2011, DOI: 10.4061/2011/618757
Abstract: N-methyl-N-nitrosourea (MNU) induces estrogen-dependent mammary tumors in female Lewis rats. We explored the antineoplastic activity of a synthetic androstane derivative, 17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235), as a single agent or in combination with docetaxel compared to tamoxifen, anastrazole, and docetaxel monotherapies against MNU-induced mammary tumors in female Lewis rats. Treatment with HE3235 alone rapidly reduced tumor burden, similar in effect to tamoxifen and anastrozole. The combination of HE3235 with docetaxel was more effective than any single agent, although without apparent toxicity. Only HE3235 or HE3235 plus docetaxel continued to suppress tumor growth after cessation of treatment. HE3235 treatment increased immunohistochemical markers of apoptosis and expression of proapoptotic genes and estrogen receptor beta and decreased expression of antiapoptotic genes, androgen receptor, and estrogen receptor alpha. These data warrant clinical investigation of HE3235 for breast cancer treatment. 1. Introduction Breast cancer is one of the most common cancers among women, and the incidence of breast cancer is increasing worldwide [1]. Approximately 200,000 women are diagnosed with breast cancer annually, with an associated mortality of 40,000 in the United States [2]. Currently, there are few treatments for hormone-dependent breast cancer, with tamoxifen and anastrazole being the most widely used therapies [3]. Although generally well tolerated, these treatments can be associated with significant morbidity [4], and development of resistance is common [5, 6]. The carcinogen N-methyl-N-nitrosourea (MNU) induc-es hormone-dependent mammary tumors in rats. This model has previously been used to develop tamoxifen therapy in women with breast cancer [7], and is considered to be appropriate for studies of novel compounds potentially useful for the treatment of breast cancer. Substantial evidence suggests that this rodent model system mimics human breast cancer: the initiation of cancer occurs primarily at the same site in both humans and rats, the majority of the tumors express estrogen and progesterone receptors, and tumor development is dependent on the reproductive history, diet, and hormonal milieu [8]. Thus the model provides an opportunity to examine cause-and-effect relationships of the in situ environment fully impacted by systemic factors [9]. 17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235) is a synthetic androstane derivative that inhibits 5-androstene-diol [10], testosterone, and estrogen (unpublished) stimulated prostate cancer cell
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
Observations of two melanistic smooth snakes (Coronella austriaca) from Dorset, United Kingdom
Angelo P. Pernetta,Christopher J. Reading
Acta Herpetologica , 2009,
Abstract: We report the capture of two smooth snakes (Coronella austriaca) with melanistic colouration from a site in Dorset. These two individuals constitute the second published report of melanism in smooth snakes from the United Kingdom.
When Information Conveys Meaning
Anthony Reading
Information , 2012, DOI: 10.3390/info3040635
Abstract: While some information is clearly meaningful and some clearly is not, no one has been able to identify exactly what the difference is. The major obstacle has been the way information and meaning are conceptualized: the one in the physical realm of tangible, objective entities and the other in the mental world of intangible, subjective ones. This paper introduces an approach that incorporates both of them within a unified framework by defining them in terms of what they do, rather than what they are. Meaningful information is thus conceptualized here as patterns of matter and energy that have a tangible effect on the entities that detect them, either by changing their function, structure or behavior, while patterns of matter and energy that have no such effects are considered meaningless. The way that meaningful information can act as a causal agent in bio-behavioral systems enables us to move beyond dualistic concepts of ourselves as comprised of a material body that obeys the laws of physics and a non-material essence that is too elusive to study [1].
The dynamics of zero: on digital memories of Mars and the human foetus in the globital memory field
Essachess : Journal for Communication Studies , 2012,
Abstract: The dynamics of digitisation and globalisation are synergetically and dialectically changing the ways in which human beings individually and collectively capture, document, share and preserve memories of the past. This paper develops further the concept of the “globital memory field” with a discursive overview of the development of “digital memory” and the significance of zero in the meaning and practice of digital memory. The paper then explains the key elements of this epistemology, with an emphasis on the significance of zero or nothing in relation to two contrasting examples of the medical imaging of the human f tus to the capturing and sending back to Earth by NASA’s Curiosity robot images from the surface of Mars.
Cambrian Lattices
Nathan Reading
Mathematics , 2004,
Abstract: For an arbitrary finite Coxeter group W we define the family of Cambrian lattices for W as quotients of the weak order on W with respect to certain lattice congruences. We associate to each Cambrian lattice a complete fan, which we conjecture is the normal fan of a polytope combinatorially isomorphic to the generalized associahedron for W. In types A and B we obtain, by means of a fiber-polytope construction, combinatorial realizations of the Cambrian lattices in terms of triangulations and in terms of permutations. Using this combinatorial information, we prove in types A and B that the Cambrian fans are combinatorially isomorphic to the normal fans of the generalized associahedra and that one of the Cambrian fans is linearly isomorphic to Fomin and Zelevinsky's construction of the normal fan as a "cluster fan." Our construction does not require a crystallographic Coxeter group and therefore suggests a definition, at least on the level of cellular spheres, of a generalized associahedron for any finite Coxeter group. The Tamari lattice is one of the Cambrian lattices of type A, and two "Tamari" lattices in type B are identified and characterized in terms of signed pattern avoidance. We also show that open intervals in Cambrian lattices are either contractible or homotopy equivalent to spheres.
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