University of Tennessee Health Science Center
Memphis, TN, United States

The University of Tennessee Health Science Center in Memphis includes the Colleges of Allied Health science, Dentistry, Graduate Health science, Medicine, Nursing and Pharmacy. Its pediatric residency program is affiliated with Le Bonheur Children's Medical Center and residents in pediatrics, radiology, and other fields spend time working at St. Jude Children's Research Hospital in Memphis. There are also graduate medical education programs in Knoxville, Chattanooga, and Nashville, family medicine centers in Knoxville, Jackson, and Memphis, and public and continuing education programs across the state. The Health Science Center is part of the statewide, multi-campus University of Tennessee system. As of 2010, US News and World Report ranked the College of Pharmacy 16th among American pharmacy schools. Wikipedia.

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Tigyi G.,University of Tennessee Health Science Center
British Journal of Pharmacology | Year: 2010

Lysophosphatidic acid (LPA, 1-radyl-2-hydroxy-sn-glycero-3-phosphate) is the prototype member of a family of lipid mediators and second messengers. LPA and its naturally occurring analogues interact with G protein-coupled receptors on the cell surface and a nuclear hormone receptor within the cell. In addition, there are several enzymes that utilize LPA as a substrate or generate it as a product and are under its regulatory control. LPA is present in biological fluids, and attempts have been made to link changes in its concentration and molecular composition to specific disease conditions. Through their many targets, members of the LPA family regulate cell survival, apoptosis, motility, shape, differentiation, gene transcription, malignant transformation and more. The present review depicts arbitrary aspects of the physiological and pathophysiological actions of LPA and attempts to link them with select targets. Many of us are now convinced that therapies targeting LPA biosynthesis and signalling are feasible for the treatment of devastating human diseases such as cancer, fibrosis and degenerative conditions. However, successful targeting of the pathways associated with this pleiotropic lipid will depend on the future development of as yet undeveloped pharmacons. © 2010 The British Pharmacological Society.

LeDoux M.S.,University of Tennessee Health Science Center
Neurobiology of Disease | Year: 2011

Dystonia is a motor sign characterized by involuntary muscle contractions which produce abnormal postures. Genetic factors contribute significantly to primary dystonia. In comparison, secondary dystonia can be caused by a wide variety of metabolic, structural, infectious, toxic and inflammatory insults to the nervous system. Although classically ascribed to dysfunction of the basal ganglia, studies of diverse animal models have pointed out that dystonia is a network disorder with important contributions from abnormal olivocerebellar signaling. In particular, work with the dystonic (dt) rat has engendered dramatic paradigm shifts in dystonia research. The dt rat manifests generalized dystonia caused by deficiency of the neuronally restricted protein caytaxin. Electrophysiological and biochemical studies have shown that defects at the climbing fiber-Purkinje cell synapse in the dt rat lead to abnormal bursting firing patterns in the cerebellar nuclei, which increases linearly with postnatal age. In a general sense, the dt rat has shown the scientific and clinical communities that dystonia can arise from dysfunctional cerebellar cortex. Furthermore, work with the dt rat has provided evidence that dystonia (1) is a neurodevelopmental network disorder and (2) can be driven by abnormal cerebellar output. In large part, work with other animal models has expanded upon studies in the dt rat and shown that primary dystonia is a multi-nodal network disorder associated with defective sensorimotor integration. In addition, experiments in genetically engineered models have been used to examine the underlying cellular pathologies that drive primary dystonia. This article is part of a Special Issue entitled "Advances in dystonia". © 2010 Elsevier Inc.

McCullers J.A.,University of Tennessee Health Science Center | McCullers J.A.,St Jude Childrens Research Hospital
Nature Reviews Microbiology | Year: 2014

Concern that a highly pathogenic virus might cause the next influenza pandemic has spurred recent research into influenza and its complications. Bacterial superinfection in the lungs of people suffering from influenza is a key element that promotes severe disease and mortality. This co-pathogenesis is characterized by complex interactions between co-infecting pathogens and the host, leading to the disruption of physical barriers, dysregulation of immune responses and delays in a return to homeostasis. The net effect of this cascade can be the outgrowth of the pathogens, immune-mediated pathology and increased morbidity. In this Review, advances in our understanding of the underlying mechanisms are discussed, and the key questions that will drive the field forwards are articulated. © 2014 Macmillan Publishers Limited. All rights reserved.

Kita T.,University of Tennessee Health Science Center | Kita H.,University of Tennessee Health Science Center
Journal of Neuroscience | Year: 2012

The frontal cortex provides strong excitatory inputs to the subthalamic nucleus (STN), and these cortico-STN inputs play critical roles in the control of basal ganglia activity. It has been assumed from anatomical and physiological studies that STN is innervated mainly by collaterals of thick and fast conducting pyramidal tract axons originating from the frontal cortex deep layerVneurons, implying that STN directly receives efferent copies of motor commands. To more closely examine this assumption, we performed biotinylated dextran amine anterograde tracing studies in rats to examine the cortical layer of origin, the sizes of parent axons, and whether or not the cortical axons emit any other collaterals to brain areas other than STN. This study revealed that the cortico-STN projection is formed mostly by collaterals of a small fraction of small-to-medium-sized long-range corticofugal axons, which also emit collaterals that innervate multiple other brain sites including the striatum, associative thalamic nuclei, superior colliculus, zona incerta, pontine nucleus, multiple other brainstem areas, and the spinal cord. The results imply that some layer V neurons are involved in associative control of movement through multiple brain innervation sites and that the cortico-STN projection is one part of this multiple corticofugal system. © 2012 the authors.

Yue J.,University of Tennessee Health Science Center
Advanced Drug Delivery Reviews | Year: 2011

miRNAs are a new class of endogenous small RNAs that negatively regulate gene expression at the posttranscriptional level. Accumulating experimental evidence shows that miRNAs regulate cellular apoptosis, proliferation, differentiation, and migration. Dysregulation of miRNA expression leads to various human diseases including cancer and cardiovascular disease. miRNA maturation is regulated at multiple steps by different mechanisms, including miRNA editing, hairpin loop binding, self-regulation, and cross-talk with other signaling pathways. Vascular cell movement plays a pivotal role in the development of various cancers and cardiovascular diseases. miRNAs have been found to regulate vascular cell movement. Presently the chemically synthesized antagomir and miRNA mimics have been widely used in investigating the biological functions of miRNA genes. The viral vectors, including adenoviral, lentiviral, and adeno-associated viral vectors, have been used to efficiently overexpress or knockdown miRNAs in vitro and in vivo. Therefore, targeting vascular cell movement using miRNA-based drug or gene therapy would provide a novel therapeutic approach in the treatment of cancers and vascular diseases. © 2011 Elsevier B.V.

Luce E.A.,University of Tennessee Health Science Center
Plastic and Reconstructive Surgery | Year: 2015

Summary: Relationships between physicians and industry, whether it be pharmaceutical companies, medical device manufacturers, or purveyors of medical technology, contain both an element of potential for good and a potential for harm. Certainly, the potential for good is realized when the collaboration results in improved plastic surgery patient care due to product and technology development. If the collaboration contains a financial component, the potential for harm exists in the form of a financial conflict of interest on the part of the physician. Recently, considerable discussion has been directed toward the pervasiveness of financial conflict of interest in all three arenas of the profession of medicine: education, research, and clinical practice, although an overlap exists among all three with respect to the issue of conflict of interest. This article will focus on conflict of interest in plastic surgery education, both continuing medical education for practitioners and graduate medical education for plastic surgery residents, as well as conflict of interest in research, such as conflicts related to publications in our literature. © 2015 by the American Society of Plastic Surgeons.

Quarles L.D.,University of Tennessee Health Science Center
Experimental Cell Research | Year: 2012

FGF23 is a bone-derived hormone that regulates systemic phosphate homeostasis, vitamin D metabolism and α-Klotho expression through a novel bone-kidney axis. FGF23 inhibits renal tubular reabsorption of phosphate through mechanisms independent of PTH as well as reduces circulating 1, 25(OH) 2D through its dual effects to suppress Cyp27b1 production and to stimulate Cyp24 catabolism of 1,25(OH) 2D. 1,25(OH) 2D and other factors regulating bone remodeling/mineralization are the major physiological regulators of FGF23 expression. FGF23 also suppresses the gene transcription of α-klotho by the kidney, which exists as a membrane and soluble protein. Membrane Klotho acts as a coreceptor for and dictates organ specificity of FGF23, whereas soluble Klotho act as an endocrine factor that regulates activity of cell surface glycoproteins and receptors in multiple tissues. Elevated FGF23 levels are responsible for several hereditary and acquired hypophosphatemic rickets disorders. FGF23 and Klotho deficiency have similar phenotypes characterized by hyperphosphatemia, elevated 1,25(OH) 2D and tumoral calcinosis. FGF23 levels progressively increase during chronic kidney disease (CKD). FGF23 has been proposed to be the initial adaptive response leading to reductions in 1,25(OH) 2D and secondary hyperparathyroidism (HPT) in CKD. The overall biological effect of this initial step may be to orchestrate a coordinated adaptation to protect the organism from the adverse effects of excess phosphate retention. The second step involves the effects of PTH on bone remodeling that further stimulates FGF23 production through both direct and indirect mechanisms related to alterations in extracellular matrix factors. PTH further amplifies FGF23 expression in later stages of CKD to compensate for the increased phosphate efflux from bone caused by excessive bone turnover. While many aspects of the regulation and functions of FGF23 remain to be established, the idea that FGF23 hormone is the initial adaptive hormonal response in CKD that suppresses 1,25(OH) 2D, reduces gastrointestinal calcium and phosphate absorption and leads to a secondary HPT represents a paradigm shift in the conceptualization of the pathogenesis of secondary hyperparathyroidism. In addition, the prevalent thought that CKD is a functional "vitamin D deficient state" requiring therapy with 1,25(OH) 2D analogs is challenged by effects of FGF23 to potentially lower both 25(OH)D and 1,25(OH)D by induction of Cyp24-mediated degradation. Finally, increments in FGF23 are associated with increased cardiovascular mortality in CKD. Whether these effects represent direct effects of FGF23 or represent a marker of other abnormalities in CKD remains to be determined. © 2012 Elsevier Inc.

Nelson D.R.,University of Tennessee Health Science Center
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

The neighbourhoods of cytochrome P450 (CYP) genes in deuterostome genomes, as well as those of the cnidarians Nematostella vectensis and Acropora digitifera and the placozoan Trichoplax adhaerens were examined to find clues concerning the evolution of CYP genes in animals. CYP genes created by the 2R whole genome duplications in chordates have been identified. Both microsynteny and macrosynteny were used to identify genes that coexisted near CYP genes in the animal ancestor. We show that all 11 CYP clans began in a common gene environment. The evidence implies the existence of a single locus, which we term the 'cytochrome P450 genesis locus', where one progenitor CYP gene duplicated to create a tandem set of genes that were precursors of the 11 animal CYP clans: CYP Clans 2, 3, 4, 7, 19, 20, 26, 46, 51, 74 and mitochondrial. These early CYP genes existed side by side before the origin of cnidarians, possibly with a few additional genes interspersed. The Hox gene cluster, WNT genes, an NK gene cluster and at least one ARF gene were close neighbours to this original CYP locus. According to this evolutionary scenario, the CYP74 clan originated from animals and not from land plants nor from a common ancestor of plants and animals. The CYP7 and CYP19 families that are chordate-specific belong to CYP clans that seem to have originated in the CYP genesis locus as well, even though this requires many gene losses to explain their current distribution. The approach to uncovering the CYP genesis locus overcomes confounding effects because of gene conversion, sequence divergence, gene birth and death, and opens the way to understanding the biodiversity of CYP genes, families and subfamilies, which in animals has been obscured by more than 600 Myr of evolution.

Dwivedi N.,University of Tennessee Health Science Center
Arthritis and rheumatism | Year: 2012

To test the hypothesis that autoantigen modifications by peptidylarginine deiminase type 4 (PAD-4) increase immunoreactivity. We assembled sera from patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Felty's syndrome (FS), and antineutrophil cytoplasmic antibody-associated vasculitides (AAVs), as well as sera from control subjects without autoimmune diseases. The sera were tested for binding to activated neutrophils, deiminated histones, and neutrophil extracellular chromatin traps (NETs). IgG binding to lipopolysaccharide-activated neutrophils was assessed with confocal microscopy, and binding to in vitro-deiminated histones was measured using enzyme-linked immunosorbent assay (ELISA) and Western blotting. In addition, we quantitated histone deimination in freshly isolated neutrophils from the blood of patients and control subjects. Increased IgG reactivity with activated neutrophils, particularly binding to NETs, was paralleled by preferential binding to deiminated histones over nondeiminated histones by ELISA in a majority of sera from FS patients but only in a minority of sera from SLE and RA patients. Immunoblotting revealed autoantibody preference for deiminated histones H3, H4, and H2A in most FS patients and in a subset of SLE and RA patients. In patients with AAVs, serum IgG preferentially bound nondeiminated histones over deiminated histones. Increased levels of deiminated histones were detected in neutrophils from RA patients. Circulating autoantibodies in FS are preferentially directed against PAD-4-deiminated histones and bind to activated neutrophils and NETs. Thus, increased reactivity with modified autoantigens in FS implies a direct contribution of neutrophil activation and the production of NET-associated nuclear autoantigens in the initiation or progression of FS. Copyright © 2012 by the American College of Rheumatology.

Nelson D.R.,University of Tennessee Health Science Center
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2013

The world we live in is a biosphere influenced by all organisms who inhabit it. It is also an ecology of genes, with some having rather startling effects. The premise put forth in this issue is cytochrome P450 is a significant player in the world around us. Life and the Earth itself would be visibly different and diminished without cytochrome P450s. The contributions to this issue range from evolution on the billion year scale to the colour of roses, from Darwin to Rachel Carson; all as seen through the lens of cytochrome P450. © 2013 The Author(s) Published by the Royal Society. All rights reserved.

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