Medical Pharmacology Commons^™

Elevating Endogenous Cannabinoids Reduces Opioid Withdrawal In Mice, Divya Ramesh

Theses and Dissertations

Delta9-tetrahydrocannbinol (THC), the primary active constituent of Cannabis sativa, has long been known to reduce opioid withdrawal symptoms. Although THC produces most of its pharmacological actions through the activation of CB1 and CB2 cannabinoid receptors, the role these receptors play in reducing opioid withdrawal symptoms remains unknown. The endogenous cannabinoids, N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonylglycerol (2-AG), activate both cannabinoid receptors, but are rapidly metabolized by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The objective of this dissertation was to test whether increasing AEA or 2-AG, via inhibition of their respective hydrolytic enzymes, reduces morphine withdrawal symptoms in …

Gucy2c Opposes Systemic Genotoxic Tumorigenesis By Regulating Akt-Dependent Intestinal Barrier Integrity, Jieru Egeria Lin, Adam Eugene Snook, Peng Li, Brian Arthur Stoecker, Gilbert Won Kim, Michael Sullivan Magee, Alex Vladimir Mejia Garcia, Michael Anthony Valentino, Terry Hyslop, Stephanie Schulz, Scott Arthur Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The barrier separating mucosal and systemic compartments comprises epithelial cells, annealed by tight junctions, limiting permeability. GUCY2C recently emerged as an intestinal tumor suppressor coordinating AKT1-dependent crypt-villus homeostasis. Here, the contribution of GUCY2C to barrier integrity opposing colitis and systemic tumorigenesis is defined. Mice deficient in GUCY2C (Gucy2c^−/−) exhibited barrier hyperpermeability associated with reduced junctional proteins. Conversely, activation of GUCY2C in mice reduced barrier permeability associated with increased junctional proteins. Further, silencing GUCY2C exacerbated, while activation reduced, chemical barrier disruption and colitis. Moreover, eliminating GUCY2C amplified, while activation reduced, systemic oxidative DNA damage. This genotoxicity was associated …

Method For Treating Hair Growth Disorders, Such As Female Pattern Alopecia, And Compositions Useful Therefore, Elaine L. Jacobson, Myron K. Jacobson, Hyuntae Kim, Donna L. Coyle, William R. Coyle

Graduate Center for Nutritional Sciences Faculty Patents

The invention relates to formulations useful in treating hair disorders, improving the health of hair, increasing hair growth, and in increasing the niacin content of hair follicles. Nicotinic acid alkyl esters having a straight chain alkyl group of from 1 to 22 methylene units, preferably from 6 to 16 methylene units, and most preferably from 8 to 14 methyl units, may be used, alone or in combinations for treating these conditions.

Dynamics Of Substrate Interactions In Trna (M1g37) Methyltransferase: Implications For Drug Discovery, Maria Kiouppis Palesis

Theses and Dissertations

The bacterial enzyme t-RNA (m1G37) methyltransferase (TrmD) is an ideal anti-microbial drug target since it is found in all eubacteria, serves an essential role during protein synthesis, and shares very little sequence or structural homology with its eukaryotic counterpart, Trm5. TrmD, a homodimeric protein, methylates the G37 nucleotide of tRNA using S-adenosyl-L-methionine (SAM) as the methyl donor and thus enables proper codon-anticodon alignment during translation. The two deeply buried binding sites for SAM seen in X-ray crystallography suggest that significant conformational changes must occur for substrate binding and catalytic turnover. Results from molecular dynamics simulations implicate a flexible loop region …

The Value Proposition Of Molecular Medicine., Scott A. Waldman, Andre Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Individualized patient management is rapidly evolving, driven by the emergence of insights in discovery, development, regulatory, and comparative effectiveness sciences.^1-4 The pace of discovery is accelerating, enabled by platforms, including “omics”, stem cell biology, network medicine, and medical and biological informatics that provide unanticipated insights into pathophysiology.^{2, 4-6} The integration of these paradigms has established a model for identifying the mechanistic underpinnings of disease, offering novel opportunities to individualize diagnostics that shape how modern therapies are deployed, including markers of disease prognosis, clinical predictors of therapeutic responses, and molecular determinants that optimize clinical management.^7-10 Importantly, deconvolution of …

Decorin Antagonizes The Angiogenic Network: Concurrent Inhibition Of Met, Hypoxia Inducible Factor 1Α, Vascular Endothelial Growth Factor A, And Induction Of Thrombospondin-1 And Timp3, Thomas Neill, Hannah Painter, Simone Buraschi, Rick T. Owens, Michael P. Lisanti, Liliana Schaefer, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Decorin, a small leucine-rich proteoglycan, inhibits tumor growth by antagonizing multiple receptor tyrosine kinases including EGFR and Met. Here, we investigated decorin during normoxic angiogenic signaling. An angiogenic PCR array revealed a profound decorin-evoked transcriptional inhibition of pro-angiogenic genes, such as HIF1A. Decorin evoked a reduction of hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor A (VEGFA) in MDA-231 breast carcinoma cells expressing constitutively-active HIF-1α. Suppression of Met with decorin or siRNA evoked a similar reduction of VEGFA by attenuating downstream β-catenin signaling. These data establish a noncanonical role for β-catenin in regulating VEGFA expression. We found that exogenous …

Y Chromosome Lineages In Men Of West African Descent, Jada Benn Torres, Menahem B. Doura, Shomarka O.Y. Keita, Rick A. Kittles

Pharmacology and Physiology Faculty Publications

The early African experience in the Americas is marked by the transatlantic slave trade from ~1619 to 1850 and the rise of the plantation system. The origins of enslaved Africans were largely dependent on European preferences as well as the availability of potential laborers within Africa. Rice production was a key industry of many colonial South Carolina low country plantations. Accordingly, rice plantations owners within South Carolina often requested enslaved Africans from the so-called “Grain Coast” of western Africa (Senegal to Sierra Leone). Studies on the African origins of the enslaved within other regions of the Americas have been limited. …

Uterine Dysfunction In Biglycan And Decorin Deficient Mice Leads To Dystocia During Parturition., Zhiping Wu, Abraham W Aron, Elyse E Macksoud, Renato V Iozzo, Chi-Ming Hai, Beatrice E Lechner

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Cesarean birth rates are rising. Uterine dysfunction, the exact mechanism of which is unknown, is a common indication for Cesarean delivery. Biglycan and decorin are two small leucine-rich proteoglycans expressed in the extracellular matrix of reproductive tissues and muscle. Mice deficient in biglycan display a mild muscular dystrophy, and, along with mice deficient in decorin, are models of Ehlers-Danlos Syndrome, a connective tissue anomaly associated with uterine rupture. As a variant of Ehlers-Danlos Syndrome is caused by a genetic mutation resulting in abnormal biglycan and decorin secretion, we hypothesized that biglycan and decorin play a role in uterine function. Thus, …

Low Dose Nicotine And Antagonism Of Β2 Subunit Containing Nicotinic Acetylcholine Receptors Have Similar Effects On Affective Behavior In Mice, Shawn M. Anderson, Darlene H. Brunzell

Pharmacology and Toxicology Publications

Nicotine leads to both activation and desensitization (inactivation) of nicotinic acetylcholine receptors (nAChRs). This study tested the hypothesis that nicotine and a selective antagonist of β2*nAChRs would have similar effects on affective behavior. Adult C57BL/6J male mice were tested in a conditioned emotional response (CER) assay which evaluates the ability of an aversive stimulus to inhibit goal-directed behavior. Mice lever-pressed for a saccharin reinforcer according to a variable schedule of reinforcement during sessions in which two presentations of a compound light/tone conditioned stimulus (CS) co-terminated with a 0.1 or 0.3 mA, 0.5 s footshock unconditioned stimulus (US). During testing in …

Mice Deficient In Gem Gtpase Show Abnormal Glucose Homeostasis Due To Defects In Beta-Cell Calcium Handling, Jenny E. Gunton, Mary Sisavanh, Rebecca A. Stokes, Jon Satin, Leslie S. Satin, Min Zhang, Sue M. Liu, Weikang Cai, Kim Cheng, Gregory J. Cooney, D. Ross Laybutt, Trina So, Juan-Carlos Molero, Shane T. Grey, Douglas A. Andres, Michael S. Rolph, Charles R. Mackay

Pharmacology and Toxicology Publications

Aims and Hypothesis

Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo.

Methods

Gem-deficient mice were generated and their metabolic phenotype characterised by …

Lipid Environment Modulates The Development Of Acute Tolerance To Ethanol In Caenorhabditis Elegans, Jill C. Bettinger, Kapo Leung, Mia H. Bolling, Andrew D. Goldsmith, Andrew G. Davies

Pharmacology and Toxicology Publications

The development of tolerance to a drug at the level of the neuron reflects a homeostatic mechanism by which neurons respond to perturbations of their function by external stimuli. Acute functional tolerance (AFT) to ethanol is a fast compensatory response that develops within a single drug session and normalizes neuronal function despite the continued presence of the drug. We performed a genetic screen to identify genes required for the development of acute functional tolerance to ethanol in the nematode C. elegans. We identified mutations affecting multiple genes in a genetic pathway known to regulate levels of triacylglycerols (TAGs) via …

Morphine Decreases Enteric Neuron Excitability Via Inhibition Of Sodium Channels, Tricia H. Smith, John R. Grider, William L. Dewey, Hamid I. Akbarali

Pharmacology and Toxicology Publications

Gastrointestinal peristalsis is significantly dependent on the enteric nervous system. Constipation due to reduced peristalsis is a major side-effect of morphine, which limits the chronic usefulness of this excellent pain reliever in man. The ionic basis for the inhibition of enteric neuron excitability by morphine is not well characterized as previous studies have mainly utilized microelectrode recordings from whole mount myenteric plexus preparations in guinea pigs. Here we have developed a Swiss-Webster mouse myenteric neuron culture and examined their electrophysiological properties by patch-clamp techniques and determined the mechanism for morphine-induced decrease in neuronal excitability. Isolated neurons in culture were confirmed …

The Use Of Cerium Oxide And Curcumin Nanoparticles As Therapeutic Agents For The Treatment Of Ventricular Hypertrophy Following Pulmonary Arterial Hypertension, Madhukar Babu Kolli

Theses, Dissertations and Capstones

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by inflammation, increased pulmonary vascular resistance, right ventricular failure and premature death. Monocrotaline (MCT) has been used to induce PAH in laboratory rats. Previous in vitro and in vivo work suggested that cerium oxide (CeO2)-and curcumin nanoparticles exhibit anti-inflammatory activity; however, it is unknown if these materials are effective for the treatment of PAH induced cardiac hypertrophy. To determine the efficacy of CeO2 nanoparticle treatment in preventing MCT-induced RV hypertrophy, male Sprague Dawley rats were divided into one of three groups (control, MCT, or MCT + CeO2 nanoparticle, n=6/group). …

Discovery Of Prostamide F2Α And Its Role In Inflammatory Pain And Dorsal Horn Nociceptive Neuron Hyperexcitability, Luisa Gatta, Fabiana Piscitelli, Catia Giordano, Serana Boccella, Aron H. Lichtman, Sebatino Maione, Vincenzo Di Marzo

Pharmacology and Toxicology Publications

It was suggested that endocannabinoids are metabolized by cyclooxygenase (COX)-2 in the spinal cord of rats with kaolin/λ-carrageenan-induced knee inflammation, and that this mechanism contributes to the analgesic effects of COX-2 inhibitors in this experimental model. We report the development of a specific method for the identification of endocannabinoid COX-2 metabolites, its application to measure the levels of these compounds in tissues, and the finding of prostamide F2α (PMF2α) in mice with knee inflammation. Whereas the levels of spinal endocannabinoids were not significantly altered by kaolin/λ-carrageenan-induced knee inflammation, those of the COX-2 metabolite of AEA, PMF2α, were strongly elevated. The …

Retrospective Comparison Of The Incidence Of Acute Kidney Injury In Patients Treated With Intravenous Polymyxin B Or Intravenous Colistimethate Sodium, Rebecca A. Sumner Pharmd, Jarrod W. Kile Rph, Bcps

Department of Pharmacy

No abstract provided.

Retrospective Evaluation Of Admissions For Chemotherapy-Inducednausea, Vomiting, And Dehydration, Katelin Van Leer Pharmad, Janine Barnaby Rph, Bcop

Department of Pharmacy

No abstract provided.

Acid Sphingomyelinase Gene Knockout Ameliorates Hyperhomocysteinemic Glomerular Injury In Mice Lacking Cystathionine-Β-Synthase, Krishna M. Boini, Min Xia, Justine M. Abais, Ming Xu, Cai-Xia Li, Pin-Lan Li

Pharmacology and Toxicology Publications

Acid sphingomyelinase (ASM) has been implicated in the development of hyperhomocysteinemia (hHcys)-induced glomerular oxidative stress and injury. However, it remains unknown whether genetically engineering of ASM gene produces beneficial or detrimental action on hHcys-induced glomerular injury. The present study generated and characterized the mice lacking cystathionine β-synthase (Cbs) and Asm mouse gene by cross breeding Cbs+/− and Asm+/− mice. Given that the homozygotes of Cbs−/−/Asm−/− mice could not survive for 3 weeks. Cbs+/−/Asm+/+, Cbs+/−/Asm+/− and Cbs+/−/Asm−/− as well as their Cbs wild type littermates were used to study the role of Asm−/− under a background of Cbs+/− with hHcys. HPLC …

The Fit-Hansa Demonstrates Reliability And Convergent Validity Of Functional Performance In Patients With Shoulder Disorders, Prajyot Kumta, Joy C. Macdermid, Saurabh Mehta, Paul W. Stratford

Physical Therapy Faculty Research

Study

DesignPsychometric study design.

Objectives

To assess the test-retest reliability and convergent validity of the Functional Impairment Test-Hand and Neck/Shoulder/Arm (FIT-HaNSA) in patients with shoulder disorders.

Background

Performance tests that assess functional ability of patients with shoulder disorders can provide useful information for making clinical or return-to-activity decisions. No performance-based shoulder test has yet demonstrated sufficient relevance or clinical measurement properties. The FIT-HaNSA examines upper extremity performance during repetitive tasks that emphasize shoulder reaching and static postures and, therefore, has greater relevance for assessing performance.

Methods

Thirty-six patients with shoulder disorders and 65 healthy controls were recruited for the study. …

Vascular Inflammatory Cells In Hypertension., David G Harrison, Paul J. Marvar, Jens M Titze

Pharmacology and Physiology Faculty Publications

Hypertension is a common disorder with uncertain etiology. In the last several years, it has become evident that components of both the innate and adaptive immune system play an essential role in hypertension. Macrophages and T cells accumulate in the perivascular fat, the heart and the kidney of hypertensive patients, and in animals with experimental hypertension. Various immunosuppressive agents lower blood pressure and prevent end-organ damage. Mice lacking lymphocytes are protected against hypertension, and adoptive transfer of T cells, but not B cells in the animals restores their blood pressure response to stimuli such as angiotensin II or high salt. …

Interferon-Α Regulates Glutaminase 1 Promoter Through Stat1 Phosphorylation: Relevance To Hiv-1 Associated Neurocognitive Disorders., Lixia Zhao, Yunlong Huang, Changhai Tian, Lynn Taylor, Norman Curthoys, Yi Wang, Hamilton Vernon, Jialin C. Zheng

Journal Articles: Pharmacology & Experimental Neuroscience

HIV-1 associated neurocognitive disorders (HAND) develop during progressive HIV-1 infection and affect up to 50% of infected individuals. Activated microglia and macrophages are critical cell populations that are involved in the pathogenesis of HAND, which is specifically related to the production and release of various soluble neurotoxic factors including glutamate. In the central nervous system (CNS), glutamate is typically derived from glutamine by mitochondrial enzyme glutaminase. Our previous study has shown that glutaminase is upregulated in HIV-1 infected monocyte-derived-macrophages (MDM) and microglia. However, how HIV-1 leads to glutaminase upregulation, or how glutaminase expression is regulated in general, remains unclear. In …