Pharmacy and Pharmaceutical Sciences Commons^™

Genetic Variants In Hsd17b3, Smad3, And Ipo11 Impact Circulating Lipids In Response To Fenofibrate In Individuals With Type 2 Diabetes, Daniel M. Rotroff, Sonja S. Pijut, Skylar W. Marvel, John R. Jack, Tammy M. Havener, Aurora Pujol, Agatha Schluter, Gregory A. Graf, Henry N. Ginsberg, Hetal S. Shah, He Gao, Mario-Luca Morieri, Alessandro Doria, Josyf C. Mychaleckyi, Howard L. Mcleod, John B. Buse, Michael J. Wagner, Alison A. Motsinger-Reif, Accord/Accordion Investigators

Pharmaceutical Sciences Faculty Publications

Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin‐treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed‐up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10^‐6). Rare variant and gene expression changes …

Phaeophleospora Vochysiae Savi & Glienke Sp. Nov. Isolated From Vochysia Divergens Found In The Pantanal, Brazil, Produces Bioactive Secondary Metabolites, Daiani C. Savi, Khaled A. Shaaban, Francielly M. W. Gos, Larissa V. Ponomareva, Jon S. Thorson, Chirlei Glienke, Jürgen Rohr

Pharmaceutical Sciences Faculty Publications

Microorganisms associated with plants are highly diverse and can produce a large number of secondary metabolites, with antimicrobial, anti-parasitic and cytotoxic activities. We are particularly interested in exploring endophytes from medicinal plants found in the Pantanal, a unique and widely unexplored wetland in Brazil. In a bio-prospecting study, strains LGMF1213 and LGMF1215 were isolated as endophytes from Vochysia divergens, and by morphological and molecular phylogenetic analyses were characterized as Phaeophleospora vochysiae sp. nov. The chemical assessment of this species reveals three major compounds with high biological activity, cercoscosporin (1), isocercosporin (2) and the new compound 3-(sec-butyl)-6-ethyl-4,5-dihydroxy-2-methoxy-6-methylcyclohex-2-enone (3). …

Novel Fluconazole Derivatives With Promising Antifungal Activity, Nishad Thamban Chandrika, Sanjib K. Shrestha, Huy X. Ngo, Kaitlind C. Howard, Sylvie Garneau-Tsodikova

Pharmaceutical Sciences Faculty Publications

The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activities of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against …

Amine Containing Analogs Of Sulindac For Cancer Prevention, Bini Mathew, Judith V. Hobrath, Michele C. Connelly, R. Kiplin Guy, Robert C. Reynolds

Pharmaceutical Sciences Faculty Publications

Background:

Sulindac belongs to the chemically diverse family of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) that effectively prevent adenomatous colorectal polyps and colon cancer, especially in patients with familial adenomatous polyposis. Sulindac sulfide amide (SSA), an amide analog of sulindac sulfide, shows insignificant COX-related activity and toxicity while enhancing anticancer activity in vitro and demonstrating in vivo xenograft activity.

Objective:

Develop structure-activity relationships in the sulindac amine series and identify analogs with promising anticancer activities.

Method:

A series of sulindac amine analogs were designed and synthesized and then further modified in a “libraries from libraries” approach to produce amide, sulfonamide and N,N-disubstituted …

Analytical High-Resolution Electron Microscopy Reveals Organ-Specific Nanoceria Bioprocessing, Uschi M. Graham, Robert A. Yokel, Alan K. Dozier, Lawrence Drummy, Krishnamurthy Mahalingam, Michael T. Tseng, Eileen Birch, Joseph Fernback

Pharmaceutical Sciences Faculty Publications

This is the first utilization of advanced analytical electron microscopy methods, including high-resolution transmission electron microscopy, high-angle annular dark field scanning transmission electron microscopy, electron energy loss spectroscopy, and energy-dispersive X-ray spectroscopy mapping to characterize the organ-specific bioprocessing of a relatively inert nanomaterial (nanoceria). Liver and spleen samples from rats given a single intravenous infusion of nanoceria were obtained after prolonged (90 days) in vivo exposure. These advanced analytical electron microscopy methods were applied to elucidate the organ-specific cellular and subcellular fate of nanoceria after its uptake. Nanoceria is bioprocessed differently in the spleen than in the liver.

Discovery Of Novel, Orally Bioavailable, Antileishmanial Compounds Using Phenotypic Screening, Diana Ortiz, W. Armand Guiguemde, Jared T. Hammill, Angela K. Carrillo, Yizhe Chen, Michele Connelly, Kayla Stalheim, Carolyn Elya, Alex Johnson, Jaeki Min, Anang Shelat, David C. Smithson, Lei Yang, Fangyi Zhu, R. Kiplin Guy, Scott M. Landfear

Pharmaceutical Sciences Faculty Publications

Leishmaniasis is a parasitic infection that afflicts approximately 12 million people worldwide. There are several limitations to the approved drug therapies for leishmaniasis, including moderate to severe toxicity, growing drug resistance, and the need for extended dosing. Moreover, miltefosine is currently the only orally available drug therapy for this infection. We addressed the pressing need for new therapies by pursuing a two-step phenotypic screen to discover novel, potent, and orally bioavailable antileishmanials. First, we conducted a high-throughput screen (HTS) of roughly 600,000 small molecules for growth inhibition against the promastigote form of the parasite life cycle using the nucleic acid …

Computer-Aided Drug Design Of Capuramycin Analogues As Anti-Tuberculosis Antibiotics By 3d-Qsar And Molecular Docking, Yuanyuan Jin, Shuai Fan, Guangxin Lv, Haoyi Meng, Zhengyang Sun, Wei Jiang, Steven G. Van Lanen, Zhaoyong Yang

Pharmaceutical Sciences Faculty Publications

Capuramycin and a few semisynthetic derivatives have shown potential as anti-tuberculosis antibiotics.To understand their mechanism of action and structureactivity relationships a 3D-QSAR and molecular docking studies were performed. A set of 52 capuramycin derivatives for the training set and 13 for the validation set was used. A highly predictive MFA model was obtained with crossvalidated q² of 0.398, and non-cross validated partial least-squares (PLS) analysis showed a conventional r² of 0.976 and r²_pred of 0.839. The model has an excellent predictive ability. Combining the 3D-QSAR and molecular docking studies, a number of new capuramycin analogs with …

Type 2 Neural Progenitor Cell Activation Drives Reactive Neurogenesis After Binge-Like Alcohol Exposure In Adolescent Male Rats, Chelsea Rhea Geil Nickell, Hui Peng, Dayna M. Hayes, Kevin Y. Chen, Justin A. Mcclain, Kimberly Nixon

Pharmaceutical Sciences Faculty Publications

Excessive alcohol consumption during adolescence remains a significant health concern as alcohol drinking during adolescence increases the likelihood of an alcohol use disorder in adulthood by fourfold. Binge drinking in adolescence is a particular problem as binge-pattern consumption is the biggest predictor of neurodegeneration from alcohol and adolescents are particularly susceptible to the damaging effects of alcohol. The adolescent hippocampus, in particular, is highly susceptible to alcohol-induced structural and functional effects, including volume and neuron loss. However, hippocampal structure and function may recover with abstinence and, like in adults, a reactive burst in hippocampal neurogenesis in abstinence may contribute to …

Fluoroethoxy-1,4-Diphenethylpiperidine And Piperazine Derivatives: Potent And Selective Inhibitors Of [3H]Dopamine Uptake At The Vesicular Monoamine Transporter-2, Emily R. Hankosky, Shyam R. Joolakanti, Justin R. Nickell, Venumadhav Janganati, Linda P. Dwoskin, Peter A. Crooks

Pharmaceutical Sciences Faculty Publications

A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [³H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [³H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [³H]dofetilide binding at the human-ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [³H]DA uptake at VMAT2, with Ki values in the nanomolar range (K_i = 0.014–0.073 μM). Compound 15d exhibited the highest affinity (K_i = 0.014 μM) at VMAT2, and had 160-, 5-, …

Buspirone Maintenance Does Not Alter The Reinforcing, Subjective, And Cardiovascular Effects Of Intranasal Methamphetamine, Anna R. Reynolds, Justin Charles Strickland, William W. Stoops, Joshua A. Lile, Craig R. Rush

Pharmaceutical Sciences Faculty Publications

Background—Medications development efforts for methamphetamine-use disorder have targeted central monoamines because these systems are directly involved in the effects of methamphetamine. Buspirone is a dopamine autoreceptor and D3 receptor antagonist and partial agonist at serotonin 1A receptors, making it a logical candidate medication for methamphetamine-use disorder. Buspirone effects on abuse-related behaviors of methamphetamine have been mixed in clinical and preclinical studies. Experimental research using maintenance dosing, which models therapeutic use, is limited. This study evaluated the influence of buspirone maintenance on the reinforcing effects of methamphetamine using a self-administration procedure, which has predictive validity for clinical efficacy. The impact …

Binge Alcohol Exposure Transiently Changes The Endocannabinoid System: A Potential Target To Prevent Alcohol-Induced Neurodegeneration, Daniel J. Liput, James R. Pauly, Audra L. Stinchcomb, Kimberly Nixon

Pharmaceutical Sciences Faculty Publications

Excessive alcohol consumption leads to neurodegeneration, which contributes to cognitive decline that is associated with alcohol use disorders (AUDs). The endocannabinoid system has been implicated in the development of AUDs, but little is known about how the neurotoxic effects of alcohol impact the endocannabinoid system. Therefore, the current study investigated the effects of neurotoxic, binge-like alcohol exposure on components of the endocannabinoid system and related N-acylethanolamines (NAEs), and then evaluated the efficacy of fatty acid amide hydrolase (FAAH) inhibition on attenuating alcohol-induced neurodegeneration. Male rats were administered alcohol according to a binge model, which resulted in a transient decrease in …

Challenges In Characterizing The Environmental Fate And Effects Of Carbon Nanotubes And Inorganic Nanomaterials In Aquatic Systems, Peter Laux, Christian Riebeling, Andy M. Booth, Joseph D. Brain, Josephine Brunner, Cristina Cerrillo, Otto Creutzenberg, Irina Estrela-Lopis, Thomas Gebel, Gunnar Johanson, Harald Jungnickel, Heiko Kock, Jutta Tentschert, Ahmed Tlili, Andreas Schäffer, Adriënne J. A. M. Sips, Robert A. Yokel, Andreas Luch

Pharmaceutical Sciences Faculty Publications

The current lack of commonly used protocols for dispersion, characterization, and aquatic toxicity testing of nanomaterials (NMs) has resulted in inconsistent results, which make meaningful comparisons difficult. The need for standardized sample preparation procedures that allow the reproducible generation of relevant test conditions remains a key challenge for studies of the environmental fate and aquatic toxicity of NMs. Together with the further development of optimized and cost-effective analytical techniques for physicochemical characterization that depend on reproducible sample preparation, such methods have the potential to overcome the current uncertainties with regard to NM dispersion properties, effective dose, and particle dissolution. In …

Tobacco's Minor Alkaloids: Effects On Place Conditioning And Nucleus Accumbens Dopamine Release In Adult And Adolescent Rats, Julie A. Marusich, Mahesh Darna, A. George Wilson, Emily D. Denehy, Amanda Ebben, Agripina G. Deaciuc, Linda P. Dwoskin, Michael T. Bardo, Timothy W. Lefever, Jenny L. Wiley, Chad J. Reissig, Kia J Jackson

Pharmaceutical Sciences Faculty Publications

Tobacco products are some of the most commonly used psychoactive drugs worldwide. Besides nicotine, alkaloids in tobacco include cotinine, myosmine, and anatabine. Scientific investigation of these constituents and their contribution to tobacco dependence is less well developed than for nicotine. The present study evaluated the nucleus accumbens dopamine-releasing properties and rewarding and/or aversive properties of nicotine (0.2-0.8 mg/kg), cotinine (0.5-5.0 mg/kg), anatabine (0.5-5.0 mg/kg), and myosmine (5.0-20.0 mg/kg) through in vivo microdialysis and place conditioning, respectively, in adult and adolescent male rats. Nicotine increased dopamine release at both ages, and anatabine and myosmine increased dopamine release in adults, but not …

Development Of Halofluorochromic Polymer Nanoassemblies For The Potential Detection Of Liver Metastatic Colorectal Cancer Tumors Using Experimental And Computational Approaches, Derek Alexander Reichel, Louis T. Curtis, Elizabeth Ehlman, B. Mark Evers, Piotr G. Rychahou, Hermann B. Frieboes, Younsoo Bae

Pharmaceutical Sciences Faculty Publications

Purpose—To develop polymer nanoassemblies (PNAs) modified with halofluorochromic dyes to allow for the detection of liver metastatic colorectal cancer (CRC) to improve therapeutic outcomes.

Methods—We combine experimental and computational approaches to evaluate macroscopic and microscopic PNA distributions in patient-derived xenograft primary and orthotropic liver metastatic CRC tumors. Halofluorochromic and non-halofluorochromic PNAs (hfPNAs and n-hfPNAs) were prepared from poly(ethylene glycol), fluorescent dyes (Nile blue, Alexa546, and IR820), and hydrophobic groups (palmitate), all of which were covalently tethered to a cationic polymer scaffold [poly(ethylene imine) or poly(lysine)] forming particles with an average diameter < 30 nm.

Results—Dye-conjugated PNAs showed no aggregation under …

Diverse Amide Analogs Of Sulindac For Cancer Treatment And Prevention, Bini Mathew, Judith V. Hobrath, Michele C. Connelly, R. Kiplin Guy, Robert C. Reynolds

Pharmaceutical Sciences Faculty Publications

Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivoantitumor activity that was comparable to sulindac in a human colon tumorxenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good …

Statin Use And Venous Thromboembolism In Cancer: A Large, Active Comparator, Propensity Score Matched Cohort Study, Sherif M. El-Refai, Esther P. Black, Val R. Adams, Jeffery C. Talbert, Joshua D. Brown

Pharmaceutical Sciences Faculty Publications

Background—Statins have been shown to have a protective effect for venous thromboembolism (VTE) in the general population. This study sought to assess the association between statins and the risk for cancer-associated deep vein thrombosis (DVT) and pulmonary embolism (PE).

Methods—Patients with newly diagnosed cancer were followed for up to one year in a healthcare claims database (2010–2013). Three treatment groups included statin users, non-statin cholesterol lowering medication users, and an untreated group with pre-existing indications for statin therapy (hyperlipidemia, diabetes, or heart disease). Propensity score matched groups were compared using competing risks survival models for DVT and PE …

Blockade Of Α2-Adrenergic Receptors In Prelimbic Cortex: Impact On Cocaine Self-Administration In Adult Spontaneously Hypertensive Rats Following Adolescent Atomoxetine Treatment, Britahny M. Baskin, Bríd Á. Nic Dhonnchadha, Linda P. Dwoskin, Kathleen M. Kantak

Pharmaceutical Sciences Faculty Publications

Rationale

Research with the spontaneously hypertensive rat (SHR) model of attention deficit/hyperactivity disorder demonstrated that chronic methylphenidate treatment during adolescence increased cocaine self-administration established during adulthood under a progressive ratio (PR) schedule. Compared to vehicle, chronic atomoxetine treatment during adolescence failed to increase cocaine self-administration under a PR schedule in adult SHR.

Objectives

We determined if enhanced noradrenergic transmission at α2-adrenergic receptors within prefrontal cortex contributes to this neutral effect of adolescent atomoxetine treatment in adult SHR.

Methods

Following treatment from postnatal days 28–55 with atomoxetine (0.3 mg/kg) or vehicle, adult male SHR and control rats from Wistar-Kyoto (WKY) and …

Defining The Epichromatin Epitope, Travis J. Gould, Katalin Tóth, Norbert Mücke, Jörg Langowski, Alexandra S. Hakusui, Ada L. Olins, Donald E. Olins

Pharmaceutical Sciences Faculty Publications

Epichromatin is identified by immunostaining fixed and permeabilized cells with particular bivalent anti-nucleosome antibodies (mAbs PL2-6 and 1H6). During interphase, epichromatin resides adjacent to the inner nuclear membrane; during mitosis, at the outer surface of mitotic chromosomes. By STED (stimulated emission depletion) microscopy, PL2-6 stained interphase epichromatin is ∼76 nm thick and quite uniform; mitotic epichromatin is more variable in thickness, exhibiting a “wrinkled” surface with an average thickness of ∼78 nm. Co-immunostaining with anti-Ki-67 demonstrates Ki-67 deposition between the PL2-6 “ridges” of mitotic epichromatin. Monovalent papain-derived Fab fragments of PL2-6 yield a strikingly different punctate “chromomeric” immunostaining pattern throughout …

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 …

Design, Synthesis, And Biological Activity Of 5'-Phenyl-1,2,5,6-Tetrahydro-3,3'-Bipyridine Analogues As Potential Antagonists Of Nicotinic Acetylcholine Receptors, Yafei Jin, Xiaoqin Huang, Roger L. Papke, Emily M. Jutkiewicz, Hollis D Showalter, Chang-Guo Zhan

Pharmaceutical Sciences Faculty Publications

Starting from a known non-specific agonist (1) of nicotinic acetylcholine receptors (nAChRs), rationally guided structural-based design resulted in the discovery of a small series of 5′-phenyl-1,2,5,6-tetrahydro-3,3′-bipyridines (3a – 3e) incorporating a phenyl ring off the pyridine core of 1. The compounds were synthesized via successive Suzuki couplings on a suitably functionalized pyridine starting monomer 4 to append phenyl and pyridyl substituents off the 3- and 5-positions, respectively, and then make subsequent modifications on the flanking pyridyl ring to provide target compounds. Compound 3a is a novel antagonist which is highly selective for α3β4 nAChR (K_i = 123 nM) …

Antibacterial Activity Of Endophytic Actinomycetes Isolated From The Medicinal Plant Vochysia Divergens (Pantanal, Brazil), Francielly M. W. Gos, Daiani C. Savi, Khaled A. Shaaban, Jon S. Thorson, Rodrigo Aluizio, Yvelise M. Possiede, Jürgen Rohr, Chirlei Glienke

Pharmaceutical Sciences Faculty Publications

Endophytic actinomycetes from medicinal plants produce a wide diversity of secondary metabolites (SM). However, to date, the knowledge about endophytes from Brazil remains scarce. Thus, we analyzed the antimicrobial potential of 10 actinomycetes isolated from the medicinal plant Vochysia divergens located in the Pantanal sul-mato-grossense, an unexplored wetland in Brazil. Strains were classified as belonging to the Aeromicrobium, Actinomadura, Microbacterium, Microbispora, Micrococcus, Sphaerisporangium, Streptomyces, and Williamsia genera, through morphological and 16S rRNA phylogenetic analyzes. A susceptibility analysis demonstrated that the strains were largely resistant to the antibiotics oxacillin and nalidixic acid. Additionally, different culture media (SG and R5A), and …

A New Approach To Synthesize Of 4-Phenacylideneflavene Derivatives And To Evaluate Their Cytotoxic Effects On Hepg2 Cell Line, Hongbin Chen, Yang Xu, Yinan Zhang, Zongping Zheng

Pharmaceutical Sciences Faculty Publications

In this study, a convenient approach and green procedure for the synthesis of 4-phenacylideneflavenes has been developed from the reaction between 2,4-dihydroxybenzaldehyde and substituted acetophenones using boric acid as a catalyst in polyethylene glycol 400. Seven 4-phenacylideneflavenes were synthetized and their structures were confirmed by NMR and mass spectral analyses. Meanwhile, their possible mechanism of formation was also discussed. These products were found to have potential cytotoxic effect on HepG2 cell line with IC₅₀ values from 12.5 to 50 µM.

Polymer Nanoassemblies With Hydrophobic Pendant Groups In The Core Induce False Positive Sirna Transfection In Luciferase Reporter Assays, Steven Rheiner, Derek Alexander Reichel, Piotr G. Rychahou, Tadahide Izumi, Hsin-Sheng Yang, Younsoo Bae

Pharmaceutical Sciences Faculty Publications

Poly(ethylene glycol)-conjugated polyethylenimine (PEG-PEI) is a widely studied cationic polymer used to develop non-viral vectors for siRNA therapy of genetic disorders including cancer. Cell lines stably expressing luciferase reporter protein typically evaluate the transfection efficacy of siRNA/PEG-PEI complexes, however recent findings revealed that PEG-PEI can reduce luciferase expression independent of siRNA. This study elucidates a cause of the false positive effect in luciferase assays by using polymer nanoassemblies (PNAs) made from PEG, PEI, poly-(L-lysine) (PLL), palmitate (PAL), and deoxycholate (DOC): PEG-PEI (2P), PEG-PEI-PAL (3P), PEG-PLL (2P′), PEG-PLL-PAL (3P′), and PEG-PEI-DOC (2PD). In vitro transfection and western blot assays of luciferase …

Increased Expression Of M1 And M2 Phenotypic Markers In Isolated Microglia After Four-Day Binge Alcohol Exposure In Male Rats, Hui Peng, Chelsea Rhea Geil Nickell, Kevin Y. Chen, Justin A. Mcclain, Kimberly Nixon

Pharmaceutical Sciences Faculty Publications

Microglia activation and neuroinflammation are common features of neurodegenerative conditions, including alcohol use disorders (AUDs). When activated, microglia span a continuum of diverse phenotypes ranging from classically activated, pro-inflammatory (M1) microglia/macrophages to alternatively activated, growth-promoting (M2) microglia/macrophages. Identifying microglia phenotypes is critical for understanding the role of microglia in the pathogenesis of AUDs. Therefore, male rats were gavaged with 25% (w/v) ethanol or isocaloric control diet every 8 h for 4 days and sacrificed at 0, 2, 4, and 7 days after alcohol exposure (e.g., T0, T2, etc.). Microglia were isolated from hippocampus and entorhinal cortices by Percoll density gradient …

Blocking An N-Terminal Acetylation-Dependent Protein Interaction Inhibits An E3 Ligase, Daniel C. Scott, Jared T. Hammill, Jaeki Min, David Y. Rhee, Michele Connelly, Vladislav O. Sviderskiy, Deepak Bhasin, Yizhe Chen, Su-Sien Ong, Sergio C. Chai, Asli N. Goktug, Guochang Huang, Julie K. Monda, Jonathan Low, Ho Shin Kim, Joao A. Paulo, Joe R. Cannon, Anang A. Shelat, Taosheng Chen, Ian R. Kelsall, Arno F. Alpi, Vishwajeeth Pagala, Xusheng Wang, Junmin Peng, Bhuvanesh Singh, J. Wade Harper, Brenda A. Schulman, R. Kiplin Guy

Pharmaceutical Sciences Faculty Publications

N-terminal acetylation is an abundant modification influencing protein functions. Because ∼80% of mammalian cytosolic proteins are N-terminally acetylated, this modification is potentially an untapped target for chemical control of their functions. Structural studies have revealed that, like lysine acetylation, N-terminal acetylation converts a positively charged amine into a hydrophobic handle that mediates protein interactions; hence, this modification may be a druggable target. We report the development of chemical probes targeting the N-terminal acetylation–dependent interaction between an E2 conjugating enzyme (UBE2M or UBC12) and DCN1 (DCUN1D1), a subunit of a multiprotein E3 ligase for the ubiquitin-like protein NEDD8. The inhibitors are …

Drug-Resistant Epilepsy: Multiple Hypotheses, Few Answers, Fei Tang, Anika M. S. Hartz, Björn Bauer

Pharmaceutical Sciences Faculty Publications

Epilepsy is a common neurological disorder that affects over 70 million people worldwide. Despite the recent introduction of new antiseizure drugs (ASDs), about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Early identification of patients who will become refractory to ASDs could help direct such patients to appropriate non-pharmacological treatment, but the complexity in the temporal patterns of epilepsy could make such identification difficult. The target hypothesis and transporter hypothesis are the most cited theories trying to explain refractory epilepsy, but neither theory alone fully explains the neurobiological basis of pharmacoresistance. This review summarizes evidence for and against …

A Microrna Signature Of Response To Erlotinib Is Descriptive Of Tgfβ Behaviour In Nsclc, Madeline J. Krentz Gober, James P. Collard, Katherine L. Thompson, Esther P. Black

Pharmaceutical Sciences Faculty Publications

Our previous work identified a 13-gene miRNA signature predictive of response to the epidermal growth factor receptor (EGFR) inhibitor, erlotinib, in Non-Small Cell Lung Cancer cell lines. Bioinformatic analysis of the signature showed a functional convergence on TGFβ canonical signalling. We hypothesized that TGFβ signalling controls expression of the miRNA genes comprising an erlotinib response signature in NSCLC. Western analysis revealed that TGFβ signalling via Smad2/3/4 occurred differently between erlotinib-resistant A549 and erlotinib- sensitive PC9 cells. We showed that TGFβ induced an interaction between Smad4 and putative Smad Binding Elements in PC9. However, qRT-PCR analysis showed that endogenous miR-140/141/200c expression …

Data-Driven Design Of An Ebola Therapeutic, Robert A. Lodder

Pharmaceutical Sciences Faculty Publications

Formulation is very important in drug delivery. The wrong formulation can render a drug product useless. The amount of preclinical (animal and in vitro) work that must be done before a new drug candidate can be tested in humans can be a problem. The cost of these cGxP studies is typically $3-$5 million. If the wrong drug product formulation is tested, new iterations of the formulation must be tested with additional costs.

Data-driven computational science can help reduce this cost. In the absence of existing human exposure, a battery of preclinical tests must be performed in at least two species …

Immune Checkpoint Inhibition And The Prevalence Of Autoimmune Disorders Among Patients With Lung And Renal Cancer, Sherif M. El-Refai

Pharmaceutical Sciences Faculty Publications

PURPOSE: Immune checkpoint inhibition reactivates the immune response against cancer cells in multiple tissue types and has been shown to induce durable responses. However, for patients with autoimmune disorders, their conditions can worsen with this reactivation. We sought to identify, among patients with lung and renal cancer, how many harbor a comorbid autoimmune condition and may be at risk of worsening their condition while on immune checkpoint inhibitors such as nivolumab and pembrolizumab.

METHODS: An administrative health care claims database, Truven MarketScan, was used to identify patients diagnosed with lung and renal cancer from 2010 to 2013. We assessed patients …

The Effects Of Nicotine In The Neonatal Quinpirole Rodent Model Of Psychosis: Neural Plasticity Mechanisms And Nicotinic Receptor Changes, Daniel J. Peterson, W. Drew Gill, John M. Dose, Donald B. Hoover, James R. Pauly, Elizabeth D. Cummins, Katherine C. Burgess, Russell W. Brown

Pharmaceutical Sciences Faculty Publications

Neonatal quinpirole (NQ) treatment to rats increases dopamine D2 receptor sensitivity persistent throughout the animal’s lifetime. In Experiment 1, we analyzed the role of α7 and α4β2 nicotinic receptors (nAChRs) in nicotine behavioral sensitization and on the brain-derived neurotrophic factor (BDNF) response to nicotine in NQ- and neonatally saline (NS)-treated rats. In Experiment 2, we analyzed changes in α7 and α4β2 nAChR density in the nucleus accumbens (NAcc) and dorsal striatum in NQ and NS animals sensitized to nicotine. Male and female Sprague-Dawley rats were neonatally treated with quinpirole (1 mg/kg) or saline from postnatal days (P)1–21. Animals were given …