Chemicals and Drugs Commons^™

Structural Basis For Earp-Mediated Arginine Glycosylation Of Translation Elongation Factor Ef-P, Ralph Krafczyk, Jakub Macošek, Pravin Kumar Ankush Jagtap, Daniel Gast, Swetlana Wunder, Prithiba Mitra, Amit Kumar Jha, Jürgen Rohr, Anja Hoffmann-Röder, Kirsten Jung, Janosch Hennig, Jürgen Lassak

Pharmaceutical Sciences Faculty Publications

Glycosylation is a universal strategy to posttranslationally modify proteins. The recently discovered arginine rhamnosylation activates the polyproline-specific bacterial translation elongation factor EF-P. EF-P is rhamnosylated on arginine 32 by the glycosyltransferase EarP. However, the enzymatic mechanism remains elusive. In the present study, we solved the crystal structure of EarP from Pseudomonas putida. The enzyme is composed of two opposing domains with Rossmann folds, thus constituting a B pattern-type glycosyltransferase (GT-B). While dTDP-β-L-rhamnose is located within a highly conserved pocket of the C-domain, EarP recognizes the KOW-like N-domain of EF-P. Based on our data, we propose a structural model for …

Age Drives Distortion Of Brain Metabolic, Vascular And Cognitive Functions, And The Gut Microbiome, Jared D. Hoffman, Ishita Parikh, Stefan J. Green, George Chlipala, Robert P. Mohney, Mignon Keaton, Bjoern Bauer, Anika M. S. Hartz, Ai-Ling Lin

Sanders-Brown Center on Aging Faculty Publications

Advancing age is the top risk factor for the development of neurodegenerative disorders, including Alzheimer’s disease (AD). However, the contribution of aging processes to AD etiology remains unclear. Emerging evidence shows that reduced brain metabolic and vascular functions occur decades before the onset of cognitive impairments, and these reductions are highly associated with low-grade, chronic inflammation developed in the brain over time. Interestingly, recent findings suggest that the gut microbiota may also play a critical role in modulating immune responses in the brain via the brain-gut axis. In this study, our goal was to identify associations between deleterious changes in …

Suppression Of Chrn Endocytosis By Carbonic Anhydrase Car3 In The Pathogenesis Of Myasthenia Gravis, Ailian Du, Shiqian Huang, Xiaonan Zhao, Kuan Fang, Shuangyan Zhang, Jiefang Huang, Xiang Miao, Fulvio Baggi, Rennolds S. Ostrom, Yanyun Zhang, Xiangjun Chen, Congfeng Xu

Pharmacy Faculty Articles and Research

Myasthenia gravis is an autoimmune disorder of the neuromuscular junction manifested as fatigable muscle weakness, which is typically caused by pathogenic autoantibodies against postsynaptic CHRN/ AChR (cholinergic receptor nicotinic) in the endplate of skeletal muscle. Our previous studies have identified CA3 (carbonic anhydrase 3) as a specific protein insufficient in skeletal muscle from myasthenia gravis patients. In this study, we investigated the underlying mechanism of how CA3 insufficiency might contribute to myasthenia gravis. Using an experimental autoimmune myasthenia gravis animal model and the skeletal muscle cell C2C12, we find that inhibition of CAR3 (the mouse homolog of CA3) promotes CHRN …

September 2017, Randy Curry, Cindy Brooks

RURAL ROCKS

Rural Rocks, the Rural Health Network newsletter by the SWOSU College of Pharmacy

Prevention Of Renal Apob Retention Is Protective Against Diabetic Nephropathy: Role Of Tgf-Β Inhibition, Patricia G. Wilson, Joel C. Thompson, Meghan S. Yoder, Richard Charnigo, Lisa R. Tannock

Internal Medicine Faculty Publications

Animal studies demonstrate that hyperlipidemia and renal lipid accumulation contribute to the pathogenesis of diabetic nephropathy (DN). We previously demonstrated that renal lipoproteins colocalize with biglycan, a renal proteoglycan. The purpose of this study was to determine whether prevention of renal lipid (apoB) accumulation attenuates DN. Biglycan-deficient and biglycan wild-type Ldlr^−/− mice were made diabetic via streptozotocin and fed a high cholesterol diet. As biglycan deficiency is associated with elevated transforming growth factor-β (TGF-β), in some experiments mice were injected with either the TGF-β-neutralizing antibody, 1D11, or with 13C4, an irrelevant control antibody. Biglycan deficiency had no significant effect …

Trkb-Enhancer Facilitates Functional Recovery After Traumatic Brain Injury, John Marshall, Joanna Szmydynger-Chodobska, Mengia S. Rioult-Pedotti, Kara Lau, Andrea T. Chin, Siva K. Reddy Kotla, Rakesh Tiwari, Keykavous Parang, Steven W. Threlkeld, Adam Chodobski

Pharmacy Faculty Articles and Research

Brain-derived neurotrophic factor (BDNF), a key player in regulating synaptic strength and learning, is dysregulated following traumatic brain injury (TBI), suggesting that stimulation of BDNF signaling pathways may facilitate functional recovery. This study investigates whether CN2097, a peptidomimetic ligand which targets the synaptic scaffold protein, postsynaptic density protein 95, to enhance downstream signaling of tropomyosin-related kinase B, a receptor for BDNF, can improve neurological function after TBI. Moderate to severe TBI elicits neuroinflammation and c-Jun-N-terminal kinase (JNK) activation, which is associated with memory deficits. Here we demonstrate that CN2097 significantly reduces the post-traumatic synthesis of proinflammatory mediators and inhibits the …

Relationship Between Self-Efficacy And Patient Knowledge On Adherence To Oral Contraceptives Using The Morisky Medication Adherence Scale (Mmas-8), Daniel M. Tomaszewski, Benjamin D. Aronson, Margarette Kading, Donald Morisky

Pharmacy Faculty Articles and Research

Background: Preconception care, including family planning, is a vital component of healthcare for women of reproductive age. An average female spends the majority of her reproductive life trying to prevent a pregnancy. In order to prevent unintended pregnancy, women often rely on the use of hormonal contraceptives. In the United States, the majority of hormonal contraceptive users are prescribed oral contraceptive pills (OCPs). Reduced adherence to OCPs decreases their ability to prevent pregnancy. The study aimed to measure OCP adherence among female college students, and explore the relationship between OCP adherence, knowledge, and self-efficacy.

Methods: This cross-sectional study …

Plant-Expressed Cocaine Hydrolase Variants Of Butyrylcholinesterase Exhibit Altered Allosteric Effects Of Cholinesterase Activity And Increased Inhibitor Sensitivity, Katherine E. Larrimore, I. Can Kazan, Latha Kannan, R. Player Kendle, Tameem Jamal, Matthew Barcus, Ashini Bolia, Stephen Brimijoin, Chang-Guo Zhan, S. Banu Ozkan, Tsafrir S. Mor

Molecular Modeling and Biopharmaceutical Center Faculty Publications

Butyrylcholinesterase (BChE) is an enzyme with broad substrate and ligand specificities and may function as a generalized bioscavenger by binding and/or hydrolyzing various xenobiotic agents and toxicants, many of which target the central and peripheral nervous systems. Variants of BChE were rationally designed to increase the enzyme’s ability to hydrolyze the psychoactive enantiomer of cocaine. These variants were cloned, and then expressed using the magnICON transient expression system in plants and their enzymatic properties were investigated. In particular, we explored the effects that these site-directed mutations have over the enzyme kinetics with various substrates of BChE. We further compared the …

Celiprolol: A Unique Selective Adrenoceptor Modulator, James Nawarskas, Angela Cheng-Lai, William H. Frishman

NYMC Faculty Publications

Celiprolol is a β-blocker with a unique pharmacologic profile: it is a β1-andrenoceptor antagonist with partial β2 agonist activity. Given this combination of effects, celiprolol may be better described as a selective adrenoreceptor modulator. It has antihypertensive and antianginal properties and is indicated for those uses in various countries around the world. In the United States, however, the proposed indication for this drug will be for the treatment of vascular type Ehlers-Danlos syndrome, a rare connective tissue disorder characterized by fragile arterial structure and an increased risk of life-threatening vascular complications. By reducing heart rate and pulsatile pressure, celiprolol may …

Potential Modifications To Enzyme Replacement Therapy In Anderson-Fabry Disease, Mariam Meghdari

Dissertations, Theses, and Capstone Projects

Mutations in the GLA gene that encodes the lysosomal enzyme α-galactosidase A (αGal) result in the sphingolipidoses named Fabry disease. This enzymatic defect is inherited as an X-linked recessive disorder and is associated with a progressive deposition of glycosphingolipids, including globotriaosylceramide (GB3), galabioasylceramide, and blood group B substance in the cell. In affected males, and in some females, this leads to early death due to occlusive disease of the heart, kidney, and brain. This disease is currently treated by infusions of αGal, prolonging patients’ lives but producing antibodies against the enzyme reducing the treatment efficacy. Treatment also causes numerous and …

Roles Of Gabab, Muscarinic And Nicotinic Receptor Signaling In The Acquisition And Expression Of Fructose And Fat-Conditioned Flavor Preferences And Acquisition Of Quinine-Conditioned Flavor Avoidances In Rats, Francis M. Rotella

Dissertations, Theses, and Capstone Projects

In addition to increased intake of sweet solutions by mammals, learning, particularly classically-conditioned “Pavlovian-like” learning, also plays an important role. An orosensory conditioned flavor preference (CFP) can be elicited by pairing one novel flavor (conditioned stimulus, CS+) with a fructose solution and a second novel flavor (CS-) with a saccharin solution. Rats will prefer the CS+ flavor in a subsequent 2-bottle choice test with both flavors mixed in saccharin. Previous pharmacological analyses revealed that systemic administration of dopamine (DA) D1 and D2 as well as NMDA, but not opioid, receptor antagonists eliminated the acquisition (learning) of fructose-CFP. Further, expression of …

Improving The Thermal Stability Of Cellobiohydrolase Cel7a From Hypocrea Jecorina By Directed Evolution, Frits Goedegebuur, Lydia Dankmeyer, Peter Gualfetti, Saeid Karkehabadi, Henrik Hansson, Suvamay Jana, Vicky Huynh, Bradley R. Kelemen, Paulien Kruithof, Edmund A. Larenas, Pauline J. M. Teunissen, Jerry Ståhlberg, Christina M. Payne, Colin Mitchinson, Mats Sandgren

Chemical and Materials Engineering Faculty Publications

Secreted mixtures of Hypocrea jecorina cellulases are able to efficiently degrade cellulosic biomass to fermentable sugars at large, commercially relevant scales. H. jecorina Cel7A, cellobiohydrolase I, from glycoside hydrolase family 7, is the workhorse enzyme of the process. However, the thermal stability of Cel7A limits its use to processes where temperatures are no higher than 50 °C. Enhanced thermal stability is desirable to enable the use of higher processing temperatures and to improve the economic feasibility of industrial biomass conversion. Here, we enhanced the thermal stability of Cel7A through directed evolution. Sites with increased thermal stability properties were combined, and …

Analyzing The Effectiviness Of A Prescription Drug Monitoring Program Targeting At-Risk Opioid Abuse Patients, Treadway Childs

Public Administration ETDs

The effectiveness of a prescription drug monitoring program in coordination with a prescription opioid recidivism program was examined at a semi-rural community hospital. Patients were identified by a multi-disciplinary committee to be at-risk for opioid misuse or abuse, and were denied prescription opioids. Patients were considered eligible for the program if they had over 12 emergency department visits in the previous 12 months, or 6 visits in the previous 6 months, depending on how long the hospital had records on a patient. Patients who were placed in the prescription opioid recidivism program could not receive opioids at this hospital. The …

Translational Fidelity, Mistranslation, And The Cellular Responses To Stress, Kyle Mohler, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Faithful translation of mRNA into the corresponding polypeptide is a complex multistep process, requiring accurate amino acid selection, transfer RNA (tRNA) charging and mRNA decoding on the ribosome. Key players in this process are aminoacyl-tRNA synthetases (aaRSs), which not only catalyse the attachment of cognate amino acids to their respective tRNAs, but also selectively hydrolyse incorrectly activated non-cognate amino acids and/or misaminoacylated tRNAs. This aaRS proofreading provides quality control checkpoints that exclude non-cognate amino acids during translation, and in so doing helps to prevent the formation of an aberrant proteome. However, despite the intrinsic need for high accuracy during translation, …

Aligning Opioid Prescribing Pathways, Andrea Lai, Outpatient Pharmacy, Haley Pelletier, Suneela Nayak, Stephen Tyzik, Ruth Hanselman

MaineHealth Maine Medical Center

There is a drug epidemic sweeping the State of Maine and it continues to worsen each passing year. In 2017, the Maine legislature passed Public Law Chapter 488 to strengthen the controlled substance prescription monitoring program. An outpatient pharmacy, located in a large acute care hospital, created a performance improvement project to clarify opioid prescription and resolve any non-compliance with Chapter 488.

After a root cause analysis, several KPIs were established to include tracking the number of phone calls made by pharmacists to non-compliant providers to clarify scripts, provide one on one education and ultimately resolve non-compliance. Repeat offenders were …

August 2017, Randy Curry, Cindy Brooks

RURAL ROCKS

Rural Rocks, the Rural Health Network newsletter by the SWOSU College of Pharmacy

Carbonyl Reduction By Ymfi Completes The Modification Of Ef-P In Bacillus Subtilis To Prevent Accumulation Of An Inhibitory Modification State, Katherine R. Hummels, Anne Witzky, Andrei Rajkovic, Rodney Tollerson Ii, Lisa A. Jones, Michael Ibba, Daniel B. Kearns

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Translation elongation factor P (EF‐P) in Bacillus subtilis is required for a form of surface migration called swarming motility. Furthermore, B. subtilis EF‐P is post‐translationally modified with a 5‐aminopentanol group but the pathway necessary for the synthesis and ligation of the modification is unknown. Here we determine that the protein YmfI catalyzes the reduction of EF‐P‐5 aminopentanone to EF‐P‐5 aminopentanol. In the absence of YmfI, accumulation of 5‐aminopentanonated EF‐P is inhibitory to swarming motility. Suppressor mutations that enhanced swarming in the absence of YmfI were found at two positions on EF‐P, including one that changed the conserved modification site (Lys …

Synthesis Of Hydroxybenzylidene-Indolinones, Schiff Bases And N-Substituted Analogs And Their Effects On Bacterial Physiology., Catherine Eliana Cabrera, Neetu Dayal, Moloud Aflaki, Herman Sintim

The Summer Undergraduate Research Fellowship (SURF) Symposium

c-di-AMP is a global stress response regulator involved in some processes of biofilm formation and antibiotic resistance. It has become a candidate target for the development of new antibacterial treatments. Previous studies have shown that hydroxybenzylidene-indolinones can act as c-di-AMP synthase inhibitors. They also act as antibacterial and anti-biofilm inhibitors and re-sensitize resistant bacteria to methicillin and vancomycin. In this project, potent analogs of these compounds, including Schiff bases and N-substituted compounds, have been synthetized. The objective of this work is to explore the effect of these modifications on their biological activity. Base-catalyzed condensation and acid-catalyzed reactions were performed in …

Development Of Self-Assembling Nanoparticles For Drug Delivery Applications, Young Chan Kim, Craig Sweet, Helen Margaret Flynn, David H. Thompson

The Summer Undergraduate Research Fellowship (SURF) Symposium

Bladder cancer is the ninth most common cancer in the world, and occurs in nearly four percent of all men. Although many cases are diagnosed as early stage cancer and the tumor can be removed by surgery, reoccurrence rates are high making treatment difficult and thus one of the most expensive cancers. To address this problem, drugs are injected intravesically after tumor removal to kill any residual cancer that may cause reoccurrence. While this was a significant improvement over surgery alone, high toxicity along with short residence times in the bladder limited its effectiveness. To combat these shortcomings, we will …

Fret Biosensors: Engineering Fluorescent Proteins As Biological Tools For Studying Parkinson’S Disease, Nathan J. Leroy, Jacob R. Norley, Saranya Radhakrishnan, Mathew Tantama

The Summer Undergraduate Research Fellowship (SURF) Symposium

Parkinson’s Disease (PD) is a common neurodegenerative disease with over 200,000 new cases each year. In general, the cause of the disease is unknown, but oxidative stress inside of neurons has been associated with the disease’s pathology for some time. Currently, techniques to study the onset of PD inside of neurons are limited. This makes treatments and causes difficult to discover. One solution to this has been fluorescent protein biosensors. In short, these proteins can be engineered to glow when a certain state is achieved inside a cell. The present research discusses the engineering of a genetically-encoded fluorescent protein (FP) …