Medical Pharmacology Commons^™

Differential Effects Of Endocannabinoid Catabolic Inhibitors On Opioid Withdrawal In Mice, Thomas Gamage

Theses and Dissertations

The effects of cannabinoids in reducing somatic signs of opioid withdrawal have been known for some time. In morphine dependent rodents, opioid withdrawal following precipitation with the mu opioid antagonist naloxone elicits robust withdrawal behaviors including jumps, paw flutters, head shakes, diarrhea and weight loss. Delta-9-tetrahydrocannabinol has been shown to reduce this opioid withdrawal in mice via activation of the cannabinoid type-1 (CB1) receptor and recently it has been shown that inhibition of the catabolic enzymes for endocannabinoids also reduce somatic signs of opioid withdrawal. Specifically, inhibition the enzyme fatty acid amide hydrolase (FAAH), the catabolic enzyme for the endocannabinoid …

Surface-Enhanced Raman Spectroscopy (Sers) Tracking Of Chelerythrine, A Na+ K+ Pump Inhibitor, Into Cytosol And Plasma Membrane Fractions Of Human Lens Epithelial Cell Cultures, Kevin M. Dorney, Ioana E.P. Sizemore, Tariq Alqahtani, Norma C. Adragna, Peter K. Lauf

Pharmacology and Toxicology Faculty Publications

Background/aims: The quaternary benzo-phenanthridine alkaloid (QBA) chelerythrine (CET) is a pro-apoptotic drug and Na(+)/K(+) pump (NKP) inhibitor in human lens epithelial cells (HLECs). In order to obtain further insight into the mechanism of NKP inhibition by CET, its sub-cellular distribution was quantified in cytosolic and membrane fractions of HLEC cultures by surface-enhanced Raman spectroscopy (SERS). Methods: Silver nanoparticles (AgNPs) prepared by the Creighton method were concentrated, and size-selected using a one-step tangential flow filtration approach. HLECs cultures were exposed to 50 μM CET in 300 mOsM phosphate-buffered NaCl for 30 min. A variety of cytosolic extracts, crude and purified membranes, …

Radiosensitization Of Head & Neck Carcinoma Cells By Linifanib, A Receptor Tyrosine Kinase Inhibitor, Heng-Wei Hsu

Loma Linda University Electronic Theses, Dissertations & Projects

Tumor angiogenesis is a hallmark of advanced cancers and promotes invasion and metastasis. Over 90% of head and neck squamous cell carcinomas (HNSCC) express angiogenic factors such as vascular endothelial growth factor (VEGF). Since radiotherapy is one of the most commonly used treatments for HNSCC, it is imperative to identify the interactions between antiangiogenic therapy and radiotherapy, and to develop combination therapy to improve clinical outcome. The mechanisms between antiangiogenic agents and ionizing radiation are complicated and involve many interactions between the vasculature, tumor stroma and tumor cells. The proliferation and metastasis of tumor cells rely on angiogenesis/blood vessel formation. …

Beta 2 Nicotinic Acetylcholine Receptor Contributions To Anxiety-Like Behavior, Shawn Anderson

Theses and Dissertations

Nicotine is a major psychoactive ingredient in tobacco that is thought to promote smoking behavior via nicotinic acetylcholine receptors (nAChRs) in the brain. Given reports that people smoke to relieve anxiety and that anxiety precipitates relapse, the overarching goal of this dissertation research is to assess beta 2 subunit containing nAChR (beta2*nAChR) contributions to anxiety-like behavior. Nicotine’s activity at beta2*nAChRs is concentration-dependent, with high concentrations facilitating activation followed by rapid desensitization and low concentrations preferentially desensitizing beta2*nAChRs; hence, activation or inhibition of beta2*nAChRs may support smoking behavior. Rodent studies reveal that nicotine affects anxiety-like behavior dose-dependently: low doses promote anxiolysis- …

Intestinal Gucy2c Prevents Tgf-Β Secretion Coordinating Desmoplasia And Hyperproliferation In Colorectal Cancer., Ahmara V Gibbons, Jieru Egeria Lin, Gilbert Won Kim, Glen P Marszalowicz, Peng Li, Brian Arthur Stoecker, Erik S Blomain, Satish Rattan, Adam E. Snook, Stephanie Schulz, Scott A Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Tumorigenesis is a multistep process that reflects intimate reciprocal interactions between epithelia and underlying stroma. However, tumor-initiating mechanisms coordinating transformation of both epithelial and stromal components are not defined. In humans and mice, initiation of colorectal cancer is universally associated with loss of guanylin and uroguanylin, the endogenous ligands for the tumor suppressor guanylyl cyclase C (GUCY2C), disrupting a network of homeostatic mechanisms along the crypt-surface axis. Here, we reveal that silencing GUCY2C in human colon cancer cells increases Akt-dependent TGF-β secretion, activating fibroblasts through TGF-β type I receptors and Smad3 phosphorylation. In turn, activating TGF-β signaling induces fibroblasts to …

Auditory Stimuli Mimicking Ambient Sounds Drive Temporal "Delta Brushes" In Premature Infants, Mathilde Chipaux, Matthew Colonnese, Audrey Mauguen, Laure Fellous, Mostafa Mokhtari, Oscar Lezcano, Mathieu Milh, Olivier Dulac, Catherine Chiron, Rustem Khazipov, Anna Kaminska

Pharmacology and Physiology Faculty Publications

In the premature infant, somatosensory and visual stimuli trigger an immature electroencephalographic (EEG) pattern, “delta-brushes,” in the corresponding sensory cortical areas. Whether auditory stimuli evoke delta-brushes in the premature auditory cortex has not been reported. Here, responses to auditory stimuli were studied in 46 premature infants without neurologic risk aged 31 to 38 postmenstrual weeks (PMW) during routine EEG recording. Stimuli consisted of either low-volume technogenic “clicks” near the background noise level of the neonatal care unit, or a human voice at conversational sound level. Stimuli were administrated pseudo-randomly during quiet and active sleep. In another protocol, the cortical response …

Behavioral And Genomic Characterization Of Scheduled Ethanol Deprivation, Jonathan Warner

Theses and Dissertations

Alcoholism is a persistent substance abuse disorder that is associated with negative health, social, and economic outcomes. Treatment strategies for alcohol use disorders are limited, and only three drugs have been approved by the FDA for treatment. Although behavioral therapy and drug combination strategies improve abstinence outcomes, the majority of those in treatment will not achieve long-term abstinence. Therefore, better treatment strategies are needed. While much progress has been made toward understanding the neurobiology of alcoholism, this knowledge has not been effectively translated into treatment strategies. Animal models of alcohol drinking have been crucial to this research effort, but until …

Microrna-142 Reduces Monoamine Oxidase A Expression And Activity In Neuronal Cells By Downregulating Sirt1, Amrita Datta Chaudhuri, Sowmya V. Yelamanchili, Howard S. Fox

Journal Articles: Pharmacology & Experimental Neuroscience

Aberrant expression of microRNAs (miRs) has been implicated in the pathogenesis of several neurodegenerative disorders. In HIV-associated neurocognitive disorders (HAND), miR-142 was found to be upregulated in neurons and myeloid cells in the brain. We investigated the downstream effects of chronic miR-142 upregulation in neuronal cells by comparing gene expression in stable clones of the human neuroblastoma cell line BE(2)M17 expressing miR-142 to controls. Microarray analysis revealed that miR-142 expression led to a reduction in monoamine oxidase (MAO) A mRNA, which was validated by qRT-PCR. In addition to the mRNA, the MAOA protein level and enzyme activity were also reduced. …

Mapping The Knowledge Economy Of Medicinal Plants In Northern Madagascar: Information And Resource Flow In Traditional Health Practices, Chanelle Adams

Independent Study Project (ISP) Collection

In the wake of pharmaceutical success with alkaloid compounds found in the Madagascar periwinkle (Catharanthus roseus), there has been increased attention towards identifying medicinal properties in the country’s rich flora. Both native and foreign companies seek profitable use of wild plant species found within Madagascar’s unique biodiversity. Many conservation organizations believe that the world’s forests in biological “hot spots” contain cures unknown to modern science and therefore, their preservation essential.

While the protection of these natural resources is important to Western medicine, it is even more vital for local people who depend on the forest as their primary …

The Role Of Nitric Oxide Dysregulation In Tumor Maintenance, Christopher Rabender

Theses and Dissertations

The inflammatory nature of the tumor microenvironment provides a cytokine and chemokine rich proliferative environment. Much of the responsibility of this environment is due to the production of Reactive Oxygen Species (ROS). These studies examined the proliferative rich tumor environment from a new perspective of Nitric Oxide Synthase (NOS) dysregulation. NOS’s have the ability to become uncoupled and generate superoxide in lieu of nitric oxide (NO). A requirement of NOS for the production of NO is the cofactor tetrahydrobiopterin (BH4) and when it is missing NOS becomes uncoupled and turns into a peroxynitrite synthase. Here I demonstrate that NOS is …

Combined Fluorescent In Situ Hybridization For Detection Of Micrornas And Immunofluorescent Labeling For Cell-Type Markers, Amrita Datta Chaudhuri, Sowmya V. Yelamanchili, Howard S. Fox

Journal Articles: Pharmacology & Experimental Neuroscience

Identification of the cell type of origin for normal or aberrant gene expression is critical for many studies, and poses a significant problem for some regulatory RNAs such as microRNAs. MicroRNAs are small non-coding RNAs that regulate cellular function by targeting specific mRNAs and reducing the level of their protein product. Aberrant expression of miRNAs in cell-types where they are not normally expressed occurs in several disease conditions. Therefore, it is important to determine not only the expression level of microRNAs, but also where they are expressed. Here we describe a detailed method for fluorescent in situ hybridization (FISH) combined …

Functional Characterization Of Crip1a Knockout Mice, Joanna Jacob

Theses and Dissertations

CB1 cannabinoid receptors are G-protein-coupled receptors that mediate the central nervous system (CNS) effects of marijuana and endocannabinoids. Recently, cannabinoid receptor interacting protein 1a (CRIP1a) was discovered as a novel protein that binds to the CB1 receptor C-terminus and inhibits CB1 receptor activity without affecting CB1 expression. This thesis investigated the functions of CRIP1a by characterizing the first CRIP1a knockout (KO) mouse line. The absence of CRIP1a was confirmed in KO mice using quantitative PCR and immunoblotting. I hypothesized that CRIP1a KO mice would exhibit enhanced CB1 receptor-mediated G-protein activity in the CNS, as well as cannabimemetic phenotypes and enhanced …

The Drug Facts Box: Improving The Communication Of Prescription Drug Information, Lisa M. Schwartz, Steven Woloshin

Dartmouth Scholarship

Communication about prescription drugs ought to be a paragon of public science communication. Unfortunately, it is not. Consumers see $4 billion of direct-to-consumer advertising annually, which typically fails to present data about how well drugs work. The professional label—the Food and Drug Administration's (FDA) mechanism to get physicians information needed for appropriate prescribing—may also fail to present benefit data. FDA labeling guidance, in fact, suggests that industry omit bene

Beginner's Guide To Colorectal Cancer Research, Kayla M. Walker

Summer Training Program in Cancer Immunotherapy

Introduction

For a while now obesity has been a health care concern for people all over the world. In the many years that obesity research has been conducted, various things have been taken into consideration including diet, exercise and medical history. In relatively recent years, researchers have expanded their definition of physical activity levels to include both the amounts of occupational physical activity and leisure time activity that a person partakes in.

The 2002 census occupation system assigned a 4 digit Metabolic equivalent (MET) to 509 separate occupations. These codes are particularly helpful for statistics agencies that need to collect …

Prophylactic Vs. Therapeutic: Dna Vaccine To Metastatic Colorectal Cancer Using Molecular Marker Guanylyl Cyclase-C, Anmol Khurana, Msii

Summer Training Program in Cancer Immunotherapy

The role of heat-stable enterotoxin receptor guanylyl cyclase C (GCC) is well known for its aberrant chloride conductance in the intestinal epithelium in response to bacterial infection. Recently, its use as a molecular marker to detect metastatic colon cancer has grown, as has its use as oral hormone therapy for tumor suppression. This study investigates the preliminary stages of a DNA dendritic cell-based vaccine development specific to targeting guanylyl cyclase in systemic tissues. Construction of the plasmid as well as its transduction to Class I MHC molecules in antigen-presenting dendritic cells is examined. Future exploration includes a comparative assessment of …

Unraveling The Mechanism Of 2,4-Dinitrofluorobenzene-Associated Cell Death, Franklin Thelmo

Summer Training Program in Cancer Immunotherapy

The mechanism by which the hapten 2,4-dinitrophenyl (DNP) mediates cell death is unclear according to current literature. To determine how DNP mediates death in the B16F10 murine melanoma cell line in vitro, cells were modified with 2,4-dinitro-1-fluorobenzene (DNFB). Following modification, cell lysates were collected and analyzed via Western blottings with known apoptotic or necrotic markers. Our results indicated that DNFB treated cells do not express the apoptotic marker Cleaved Caspase-3 and have no change in levels of the necrotic marker Cyclophilin A. We conclude that DNFB is not inducing apoptosis in B16F10 cells. Future research will further examine the …

Anticuerpos Contra El Virus De La Parainfluenza 3 En Cerdos De Crianza Tecnificada Y De Traspatio Beneficiados En Mataderos De Lima, Milagros P. Montesinos, Hermelinda G. Rivera, Mariluz Araínga

Journal Articles: Pharmacology & Experimental Neuroscience

Parainfluenza 3 antibodies against (PI3) virus in pigs were determined from commercial (n = 192) and backyard farms (n = 192). Blood samples were collected at the slaughter house from pigs of 2 to 6 months of age of any sex for detecting antibodies against the PI3 virus by viral neutralization test. The 5.5 ± 2.3% (21/384) of the pigs had antibodies against PI3 virus, where 5.2 ± 1.1% (10/192) and 5.7 ± 1.2% (11/192) were from commercial and backyard farms respectively. The antibody titres ranged from 4 to 64 and were detected in pigs older than 3 months of …

Poor Positive Predictive Value Of Mcconnell’S Sign On Transthoracic Echocardiography For The Diagnosis Of Acute Pulmonary Embolism, Urvashi Vaid, Md, Ms, Esme Singer, Md, Gregary D. Marhefka, Md, Walter K. Kraft, Md, Michael Baram, Md, Fccm

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Abstract: Background: Acute pulmonary embolism (PE) is a life-threatening condition. Making a definitive diagnosis with radiologic studies may delay therapy or be unsafe for the patient. Echocardiography is readily available and can suggest PE by demonstrating right ventricular (RV) dysfunction. McConnell’s sign on echocardiogram (ECHO-CG) (RV dysfunction with characteristic sparing of the apex) has been reported to have high sensitivity and specificity for the diagnosis of acute PE. It is hypothesized that McConnell’s sign on ECHO-CG in patients hospitalized with suspected acute PE would have a high positive predictive value (PPV).

Methods: Data, from 2005 to 2010, were retrospectively collected …

The Minimum M3-M4 Loop Length Of Neurotransmitter-Activated Pentameric Receptors Is Critical For The Structural Integrity Of Cytoplasmic Portals, Daniel T. Baptista-Hon, Tarek Z. Deeb, Jeremy J. Lambert, John A. Peters, Tim G. Hales

Pharmacology and Physiology Faculty Publications

The 5-HT₃A receptor homology model, based on the partial structure of the nicotinic acetylcholine receptor from Torpedo marmorata, reveals an asymmetric ion channel with five portals framed by adjacent helical amphipathic (HA) stretches within the 114-residue loop between the M3 and M4 membrane-spanning domains. The positive charge of Arg-436, located within the HA stretch, is a rate-limiting determinant of single channel conductance (γ). Further analysis reveals that positive charge and volume of residue 436 are determinants of 5-HT₃A receptor inward rectification, exposing an additional role for portals. A structurally unresolved stretch of 85 residues constitutes …

Genetic Dissection Of Quantitative Trait Loci For Substances Of Abuse, Jo Lynne Harenza

Theses and Dissertations

It has been reported that an individual’s initial level of response to a drug might be predictive of his or her future risk of becoming dependent, thus basal gene expression profiles underlying those drug responses may be informative for both predicting addiction susceptibility and determining targets for intervention. This dissertation research aims to elucidate genetic risk factors underlying acute alcohol and nicotine dependence phenotypes using mouse genetic models of addiction. Phenotyping, brain region-specific mRNA expression profiling, and genetic mapping of a recombinant inbred panel of over 25 mouse strains were performed in order to identify quantitative trait loci (QTL) harboring …