Medicine and Health Sciences Commons^™

Preclinical Evaluation Of Artesunate As An Antineoplastic Agent In Ovarian Cancer Treatment, Anthony Mcdowell Jr., Kristen S. Hill, Joseph Robert Mccorkle, Justin W. Gorski, Yilin Zhang, Ameen A. Salahudeen, Frederick R. Ueland, Jill M. Kolesar

Obstetrics and Gynecology Faculty Publications

BACKGROUND: Ovarian cancer is the deadliest gynecologic malignancy despite current first-line treatment with a platinum and taxane doublet. Artesunate has broad antineoplastic properties but has not been investigated in combination with carboplatin and paclitaxel for ovarian cancer treatment.

METHODS: Standard cell culture technique with commercially available ovarian cancer cell lines were utilized in cell viability, DNA damage, and cell cycle progression assays to qualify and quantify artesunate treatment effects. Additionally, the sequence of administering artesunate in combination with paclitaxel and carboplatin was determined. The activity of artesunate was also assessed in 3D organoid models of primary ovarian cancer and RNAseq …

Bacterial Vaccines Deficient In The 2-C-Methyl-D-Erythritol-4-Phosphate Pathway And Methods Of Preparation And Use Thereof, Keith Bahjat, Yoshinobu Koguchi, Alejandro F Alice

Technology Transfer - Patents

The present invention relates to the preparation and use in primates of whole organismvaccines in which the MEP pathway is disrupted such that synthesis of HMBPP by the bacterial cells is substantially blocked. The data provided demonstrates that, when bacteria or other vaccine vectors that comprise an active MEP pathway are used in vaccine methods, the .gamma..delta. T cell response dominates, potentially clearing the vaccine strain via .gamma..delta. T cell-mediated killing of vector infected antigen presenting cells and reducing its utility as a stimulator of a productive adaptive immune response, specifically priming or boosting of CD4.sup.+ and CD8.sup.+ .alpha..beta. T …

Stability Evaluation Of Extemporaneously Compounded Vancomycin Ophthalmic Drops: Effect Of Solvents And Storage Conditions, Christopher Ross, Basir Syed, Joanna Pak, Vishal Jhanji, Jason Yamaki, Ajay Sharma

Pharmacy Faculty Articles and Research

Vancomycin is the drug of choice for methicillin-resistant Staphylococcus aureus keratitis and other ocular infections. Vancomycin ophthalmic drops are not commercially available and require compounding. The present study was designed to investigate the stability of vancomycin ophthalmic drops in normal saline, phosphate-buffered saline (PBS), and balanced salt solution (BSS) while stored at room temperature or under refrigeration. Vancomycin ophthalmic drops (50 mg/mL) were aseptically prepared from commercially available intravenous powder using PBS, BSS, and saline. Solutions were stored at room temperature and in a refrigerator for 28 days. The vancomycin stability was tested by a microbiology assay and high-performance liquid …

Real World Clinicopathologic Observations Of Patients With Metastatic Solid Tumors Receiving Immune Checkpoint Inhibitor Therapy: Analysis From Kentucky Cancer Registry, Aasems Jacob, Jianrong Wu, Jill M. Kolesar, Eric B. Durbin, Aju Mathew, Susanne Arnold, Aman Chauhan

Biostatistics Faculty Publications

The state of Kentucky has the highest cancer incidence and mortality in the United States. High‐risk populations such as this are often underrepresented in clinical trials. The study aims to do a comprehensive analysis of molecular landscape of metastatic cancers among these patients with detailed evaluation of factors affecting response and outcomes to immune checkpoint inhibitor (ICI) therapy. We performed a retrospective analysis of metastatic solid tumor patients who received ICI and underwent molecular profiling at our institution.

Sixty nine patients with metastatic solid tumors who received ICI were included in the study. Prevalence of smoking and secondhand tobacco exposure …

Interactions Of Neuroimmune Signaling And Glutamate Plasticity In Addiction, Cassandra D. Gipson, Scott Rawls, Michael D. Scofield, Benjamin M. Siemsen, Emma O. Bondy, Erin E. Maher

Family and Community Medicine Faculty Publications

Chronic use of drugs of abuse affects neuroimmune signaling; however, there are still many open questions regarding the interactions between neuroimmune mechanisms and substance use disorders (SUDs). Further, chronic use of drugs of abuse can induce glutamatergic changes in the brain, but the relationship between the glutamate system and neuroimmune signaling in addiction is not well understood. Therefore, the purpose of this review is to bring into focus the role of neuroimmune signaling and its interactions with the glutamate system following chronic drug use, and how this may guide pharmacotherapeutic treatment strategies for SUDs. In this review, we first describe …

Selecting An Anti-Malarial Clinical Candidate From Two Potent Dihydroisoquinolones, Yizhe Chen, Fangyi Zhu, Jared T. Hammill, Gloria Holbrook, Lei Yang, Burgess Freeman, Karen L. White, David M. Shackleford, Kathleen G. O'Loughlin, Susan A. Charman, Jon C. Mirsalis, R. Kiplin Guy

Pharmaceutical Sciences Faculty Publications

BACKGROUND: The ongoing global malaria eradication campaign requires development of potent, safe, and cost-effective drugs lacking cross-resistance with existing chemotherapies. One critical step in drug development is selecting a suitable clinical candidate from late leads. The process used to select the clinical candidate SJ733 from two potent dihydroisoquinolone (DHIQ) late leads, SJ733 and SJ311, based on their physicochemical, pharmacokinetic (PK), and toxicity profiles is described.

METHODS: The compounds were tested to define their physicochemical properties including kinetic and thermodynamic solubility, partition coefficient, permeability, ionization constant, and binding to plasma proteins. Metabolic stability was assessed in both microsomes and hepatocytes derived …

Anti-Inflammatory Effects Of Α7-Nicotinic Ach Receptors Are Exerted Through Interactions With Adenylyl Cyclase-6, Simeng Zhu, Shiqian Huang, Guofang Xia, Jin Wu, Yan Shen, Ying Wang, Rennolds S. Ostrom, Ailian Du, Chengxing Shen, Congfeng Xu

Pharmacy Faculty Articles and Research

Background and purpose

Alpha 7 nicotinic acetylcholine receptors (CHRNA7) suppress inflammation through diverse pathways in immune cells, so is potentially involved in a number of inflammatory diseases. However, the detailed mechanisms underlying CHRNA7’s anti‐inflammatory effects remain elusive.

Experimental approach

The anti‐inflammatory effects of CHRNA7 agonists in both murine macrophages (RAW 264.7) and bone marrow‐derived macrophages (BMDM) stimulated with LPS were examined. The role of adenylyl cyclase 6 (AC6) in Toll‐like Receptor 4 (TLR4) degradation was explored via overexpression and knockdown. A mouse model of chronic obstructive pulmonary disease was used to confirm key findings.

Results

Anti‐inflammatory effects of CHRNA7 were …

Pace Yourself: Impact Of Covid-19 On Patient-Centered Care Experience, Kristen Wilhite, Mikael D. Jones, Clark D. Kebodeaux

Pharmacy Practice and Science Faculty Publications

(1) Background: The outbreak of the novel coronavirus, COVID-19, forced colleges of pharmacy to implement new online learning methodologies to ensure that students could complete required courses. This transition was especially acute for laboratory simulation courses that require students to practice professional skills. This study aims to compare student assessment performance within a simulation-based laboratory course for students who completed the module prior to and after the online transition. (2) Methods: This study was a retrospective cohort comparison of student outcome performance with two distinct content delivery methods. Students were organized into two tracks at the beginning of the semester …

Valtoco® (Diazepam Nasal Spray) For The Acute Treatment Of Intermittent Stereotypic Episodes Of Frequent Seizure Activity, Elyse M. Cornett, Sam N. Amarasinghe, Alexis Angelette, Tunde Abubakar, Adam M. Kaye, Alan David Kaye, Elisa E. Neuchat, Ivan Urits, Omar Viswanath

School of Pharmacy Faculty Articles

Valtoco® is a new FDA-approved nasal spray version of diazepam indicated for the treatment of acute, intermittent, and stereotypic episodes of frequent seizure activity in epilepsy patients six years of age and older. Although IV and rectal diazepam are already used to treat seizure clusters, Valtoco® has less variability in plasma concentration compared to rectal diazepam. Furthermore, the intranasal administration of Valtoco® is more convenient and less invasive than rectal or IV diazepam, making it ideal for self-administration outside of a hospital setting. Multiple clinical trials have taken place comparing Valtoco® to the oral, rectal, and IV forms of diazepam. …

Sars-Cov-2 Early Infection Signature Identified Potential Key Infection Mechanisms And Drug Targets, Yue Li, Ashley Duche, Michael R. Sayer, Don Roosan, Farid G. Khalafalla, Rennolds S. Ostrom, Jennifer Totonchy, Moom Roosan

Pharmacy Faculty Articles and Research

Background

The ongoing COVID-19 outbreak has caused devastating mortality and posed a significant threat to public health worldwide. Despite the severity of this illness and 2.3 million worldwide deaths, the disease mechanism is mostly unknown. Previous studies that characterized differential gene expression due to SARS-CoV-2 infection lacked robust validation. Although vaccines are now available, effective treatment options are still out of reach.

Results

To characterize the transcriptional activity of SARS-CoV-2 infection, a gene signature consisting of 25 genes was generated using a publicly available RNA-Sequencing (RNA-Seq) dataset of cultured cells infected with SARS-CoV-2. The signature estimated infection level accurately in …

Mapping Major Sars-Cov-2 Drug Targets And Assessment Of Druggability Using Computational Fragment Screening: Identification Of An Allosteric Small-Molecule Binding Site On The Nsp13 Helicase., Matthew R Freidel, Roger S Armen

College of Pharmacy Faculty Papers

The 2019 emergence of, SARS-CoV-2 has tragically taken an immense toll on human life and far reaching impacts on society. There is a need to identify effective antivirals with diverse mechanisms of action in order to accelerate preclinical development. This study focused on five of the most established drug target proteins for direct acting small molecule antivirals: Nsp5 Main Protease, Nsp12 RNA-dependent RNA polymerase, Nsp13 Helicase, Nsp16 2'-O methyltransferase and the S2 subunit of the Spike protein. A workflow of solvent mapping and free energy calculations was used to identify and characterize favorable small-molecule binding sites for an aromatic pharmacophore …

Immunomodulatory Effects Of Azithromycin Revisited: Potential Applications To Covid-19, Vincent J. Venditto, Dalia Haydar, Ahmed K. Abdel-Latif, John C. Gensel, Michael I. Anstead, Michelle G. Pitts, Jarrod W. Creameans, Timothy J. Kopper, Chi Peng, David J. Feola

Pharmaceutical Sciences Faculty Publications

The rapid advancement of the COVID-19 pandemic has prompted an accelerated pursuit to identify effective therapeutics. Stages of the disease course have been defined by viral burden, lung pathology, and progression through phases of the immune response. Immunological factors including inflammatory cell infiltration and cytokine storm have been associated with severe disease and death. Many immunomodulatory therapies for COVID-19 are currently being investigated, and preliminary results support the premise of targeting the immune response. However, because suppressing immune mechanisms could also impact the clearance of the virus in the early stages of infection, therapeutic success is likely to depend on …

Clinical Data Mining Reveals Analgesic Effects Of Lapatinib In Cancer Patients, Shuo Zhou, Fang Zheng, Chang-Guo Zhan

Molecular Modeling and Biopharmaceutical Center Faculty Publications

Microsomal prostaglandin E2 synthase 1 (mPGES-1) is recognized as a promising target for a next generation of anti-inflammatory drugs that are not expected to have the side effects of currently available anti-inflammatory drugs. Lapatinib, an FDA-approved drug for cancer treatment, has recently been identified as an mPGES-1 inhibitor. But the efficacy of lapatinib as an analgesic remains to be evaluated. In the present clinical data mining (CDM) study, we have collected and analyzed all lapatinib-related clinical data retrieved from clinicaltrials.gov. Our CDM utilized a meta-analysis protocol, but the clinical data analyzed were not limited to the primary and secondary outcomes …

Giving Pharmacists Provider Rights, Tanya E. Karwaki

Texas A&M Law Review

Changes to our health care system, robotics and health care mergers among them, are forcing pharmacists into expanded provider roles, yet federal policymakers are failing to act on these changes. State lawmakers are acting but not swiftly enough. A federal response, including recognizing pharmacists as health care providers and making them eligible for independent Medicare reimbursement, will be necessary to enable pharmacists to fill their role in our health care system. Policymakers have an opportunity now to respond proactively to a changing climate in health care by clarifying the boundaries on pharmacists’ services, particularly those boundaries regarding direct patient care …

Implementation Of A Teaching Electronic Medical Record Within Didactic Instruction Using A Drug Information Question Assignment., Jacqueline Wasynczuk, Amy H Sheehan

College of Pharmacy Faculty Papers

BACKGROUND: Pharmacy graduates are expected to be practice-ready to deliver quality patient care, which includes having comprehensive knowledge of health informatics and electronic medical records (EMRs). The purpose of this study was to (1) incorporate an EMR within a pharmacy student assignment, and (2) assess student perceptions of use of the EMR.

METHODS: Student pharmacists received a patient-specific drug-related question and were required to use an EMR to provide an accurate response. Following completion of the assignment, students were invited to complete a retrospective, pre-post survey instrument to collect their perceptions.

RESULTS: Only 28.8% of respondents reported prior experience using …

An Efficient Synthetic Route Tol-Γ-Methyleneglutamine And Its Amide Derivatives, And Their Selective Anticancer Activity, Md Imran Hossain, Ajit G. Thomas, Fakhri Mahdi, Amna T. Adam

Faculty and Student Publications

In cancer cells, glutaminolysis is the primary source of biosynthetic precursors, fueling the TCA cycle with glutamine-derived α-ketoglutarate. The enhanced production of α-ketoglutarate is critical to cancer cells as it provides carbons for the TCA cycle to produce glutathione, fatty acids, and nucleotides, and contributes nitrogens to produce hexosamines, nucleotides, and many nonessential amino acids. Efforts to inhibit glutamine metabolism in cancer using amino acid analogs have been extensive.l-γ-Methyleneglutamine was shown to be of considerable biochemical importance, playing a major role in nitrogen transport inArachisandAmorphaplants. Herein we report for the first time an efficient synthetic route tol-γ-methyleneglutamine and its amide …

Copper Oxide Nanoparticle Diameter Mediates Serum-Sensitive Toxicity In Beas-2b Cells, Angie S. Morris, Brittany E. Givens, Aaron Silva, Aliasger K. Salem

Chemical and Materials Engineering Faculty Publications

Copper oxide (CuO) nanoparticles (NPs) are abundant in manufacturing processes, but they are an airway irritant. In vitro pulmonary toxicity of CuO NPs has been modeled using cell lines such as human bronchial epithelial cell line BEAS-2B. In 2D in vitro culture, BEAS-2B undergoes squamous differentiation due to the presence of serum. Differentiation is part of the repair process of lung cells in vivo that helps to preserve the epithelial lining of the respiratory tract. Herein, the effects of serum on the hydrodynamic diameter, cellular viability, cellular differentiation, and cellular uptake of 5 and 35 nm CuO NPs are investigated, …

Virucidal Activity Of Chlorine Dioxide Gas For Reduction Of Coronavirus On Surfaces And Ppe, Jeffrey Driver, George Lukasik, Marie Bourgeois, Patricia Tam, Raymond Harbison

School of Pharmacy Faculty Articles

A coronavirus (SARS-CoV-2) has caused a global pandemic and associated morbidity and mortality resultant from COVID-19. As a result of efforts to control direct (person to person) and indirect (contaminated objects, surfaces, indoor air) transmission of the virus, various interventions have been evaluated. Studies were conducted to evaluate the efficacy of commercially available chlorine dioxide (CD) products to reduce viral loads on PPE (face masks) and surfaces using a novel dry gas release intervention. The efficacy of CD slow release 30-day sachets was tested on N95 face masks inoculated with human coronavirus OC43 in suspension. One sachet was placed with …

Dna Repair Pathways In Cancer Therapy And Resistance, Lan-Ya Li, Yi-Di Guan, Xi-Sha Chen, Jin-Ming Yang, Yan Cheng

Toxicology and Cancer Biology Faculty Publications

DNA repair pathways are triggered to maintain genetic stability and integrity when mammalian cells are exposed to endogenous or exogenous DNA-damaging agents. The deregulation of DNA repair pathways is associated with the initiation and progression of cancer. As the primary anti-cancer therapies, ionizing radiation and chemotherapeutic agents induce cell death by directly or indirectly causing DNA damage, dysregulation of the DNA damage response may contribute to hypersensitivity or resistance of cancer cells to genotoxic agents and targeting DNA repair pathway can increase the tumor sensitivity to cancer therapies. Therefore, targeting DNA repair pathways may be a potential therapeutic approach for …

Repurposing Of Omarigliptin As A Neuroprotective Agent Based On Docking With A2a Adenosine And Ache Receptors, Brain Glp-1 Response And Its Brain/Plasma Concentration Ratio After 28 Days Multiple Doses In Rats Using Lc-Ms/Ms, Bassam Ayoub, Haidy Michel, Shereen Mowaka, Moataz S. Hendy, Mariam M. Tadros

Pharmacy

Abstract: The authors in the current work suggested the potential repurposing of omarigliptin (OMR) for neurodegenerative diseases based on three new findings that support the preliminary finding of crossing BBB after a single dose study in the literature. The first finding is the positive results of the docking study with the crystal structures of A2A adenosine (A2AAR) and acetylcholine esterase (AChE) receptors. A2AAR is a member of non-dopaminergic GPCR superfamily receptor proteins and has essential role in regulation of glutamate and dopamine release in Parkinson’s disease while AChE plays a major role in Alzheimer’s disease as the primary enzyme responsible …

Application Of Standardized Antimicrobial Administration Ratio As A Motivational Tool Within A Multi-Hospital Healthcare System, Stephanie Shealy, Joseph Kohn, Emily Yongue, Casey Troficanto, P Brandon Bookstaver, Julie Ann Justo, Hana R. Winders, Sangita Dash, Majdi N. Al-Hasan

Faculty Publications

The standardized antimicrobial administration ratio (SAAR) is a novel antimicrobial stewardship metric that compares actual to expected antimicrobial use (AU). This prospective cohort study examines the utility of SAAR reporting and inter-facility comparisons as a motivational tool to improve overall and broad-spectrum AU within a three-hospital healthcare system. Transparent inter-facility comparisons were deployed during system-wide antimicrobial stewardship meetings beginning in October 2017. Stakeholders were advised to interpret the results to foster competition and incorporate SAAR data into focused antimicrobial stewardship interventions. Student's -test was used to compare mean SAARs in the pre- (July 2017 through October 2017) and post-intervention periods …

Sexually Transmitted Neisseria Gonorrhoeae Infections—Update On Drug Treatment And Vaccine Development, A. Jefferson, A. Smith, P. S. Fasinu, D. K. Thompson

Pharmaceutical Sciences

No abstract provided.

Evaluation Of Triclosan Exposures On Secretion Of Pro-Inflammatory Cytokines From Human Immune Cells, Wendy J. Wilburn, Sara Jamal, Farah Ismail, Dylan Brooks, Margaret Whalen

Chemistry Faculty Research

Triclosan (TCS) is widely used in personal hygiene products, such as mouthwash and toothpaste, and is found in human tissues. Interleukin (IL)-1 beta (IL-1β), IL-6, tumor necrosis factor alpha (TNFα), and interferon gamma (IFNγ) are pro-inflammatory cytokines and inappropriately elevated levels of each have been associated with pathologies including rheumatoid arthritis and certain cancers. Here we examine effects of TCS on the secretion of the pro-inflammatory cytokines from human immune cell preparations. TCS at concentrations between 0.05–5 μM consistently increased the secretion of IL-1β, IL-6, and TNFα within 24 h of exposure and the increases often maintained out to 6 …

Discovery Of Molecular Interactions Of The Human Melanocortin-4 Receptor (Hmc4r) Asp189 (D189) Amino Acid With The Endogenous G-Protein-Coupled Receptor (Gpcr) Antagonist Agouti-Related Protein (Agrp) Provides Insights To Agrp's Inverse Agonist Pharmacology At The Hmc4r, Mark D. Ericson, Erica M. Haslach, Sathya M. Schnell, Katie T. Freeman, Zhimin M. Xiang, Frederico P. Portillo, Robert Speth, Sally A. Litherland, Carrie Haskell-Luevano

HPD Articles

The melanocortin receptors (MCRs) are important for numerous biological pathways, including feeding behavior and energy homeostasis. In addition to endogenous peptide agonists, this receptor family has two naturally occurring endogenous antagonists, agouti and agouti-related protein (AGRP). At the melanocortin-4 receptor (MC4R), the AGRP ligand functions as an endogenous inverse agonist in the absence of agonist and as a competitive antagonist in the presence of agonist. At the melanocortin-3 receptor (MC3R), AGRP functions solely as a competitive antagonist in the presence of agonist. The molecular interactions that differentiate AGRP's inverse agonist activity at the MC4R have remained elusive until the findings …

Proposed Mechanism For The Antitrypanosomal Activity Of Quercetin And Myricetin Isolated From Hypericum Afrum Lam: Phytochemistry, In Vitro Testing And Modeling Studies, Farida Larit, Khaled M. Elokely, Manal A. Nael, Samira Benyahia

Faculty and Student Publications

The in vitro activity of L. donovani (promastigotes, axenic amastigotes and intracellular amastigotes in THP1 cells) and T. brucei, from the fractions obtained from the hydroalcoholic extract of the aerial part of Hypericum afrum and the isolated compounds, has been evaluated. The chloroform, ethyl acetate and n-butanol extracts showed significant antitrypanosomal activity towards T. brucei, with IC50 values of 12.35, 13.53 and 12.93 µg/mL and with IC90 values of 14.94, 19.31 and 18.67 µg/mL, respectively. The phytochemical investigation of the fractions led to the isolation and identification of quercetin (1), myricitrin (2), biapigenin (3), myricetin (4), hyperoside (5), myricetin-3-O-β-D-galactopyranoside (6) …

Crosstalk Of Cancer Signaling Pathways By Cyclic Hexapeptides And Anthraquinones From Rubia Cordifolia, Premalatha Balachandran, Mohamed Ali Ibrahim, Jin Zhang, Mei Wang

Faculty and Student Publications

The anticancer activities of Rubia cordifolia and its constituents have been reported earlier, but their influence on the crosstalk of complex cancer-related signaling metabolic pathways (i.e., transcription factors; TF) has not yet been fully investigated. In this study, R. cordifolia root extract was subjected to the cancer signaling assay based bioactivity-guided fractionation, which yielded the following compounds viz., three anthraquinones, namely alizarin (1), purpurin (2), and emodin (3); two lignans, namely eudesmin (4) and compound 5; and two cyclic hexapeptides, namely deoxybouvardin RA-V (6), and a mixture of 6+9 (RA-XXI). The structures of the isolated compounds were determined by NMR …

Development And Characterization Of Sustained-Released Donepezil Hydrochloride Solid Dispersions Using Hot Melt Extrusion Technology, Abdullah Alshetaili, Bjad K. Almutairy, Sultan M. Alshehri, Michael A. Repka

Faculty and Student Publications

The aim of this work was to develop the sustained release formulation of donepezil hydrochloride (DH) using the hot-melt extruded solid dispersion technique via the rational screening of hydrophobic carriers. Hydrophobic carriers with different physicochemical properties such as pH-independent swellability, low-permeability (Eudragit® RS PO (E-RS)), pH-independent non-swellability (ethyl cellulose N7 (EC-N7)), and the presence of lipids (Compritol® 888 ATO (C-888)) with or without pore-forming agents were used to achieve the sustained release profile of DH. Mannitol (MNT) was chosen as the temporary pore-forming agent. The thermal analysis showed that both the drug and C-888 preserved their crystallinity within a solid …

Nsu Cop Students On Rotations Contribute To The Vaccination Efforts, Silverman College Of Pharmacy

Archived News and Events

Broward Health Medical Center began administering the COVID19 vaccine to healthcare workers, EMS and patients aged 65 and over in January 2021. They opened a community vaccination site at Inter Miami CF Stadium in Fort Lauderdale. NSU students taking introductory and advanced pharmacy practice rotations within a Broward Health Hospital or Clinic had an opportunity to contribute to the vaccination effort.

NSU P4 student Angela Sanichar immunized her preceptor and alumni, Dr. Kaleed Mohammed ('09), Regional Manager of Pharmacy Services at Broward Health. Dr. Mohammed said, "Vaccine dose number 2 done! How cool is it to have your student give …

Leucine Carboxyl Methyltransferase 1 Overexpression Protects Against Cognitive And Electrophysiological Impairments In Tg2576 App Transgenic Mice, Madhumathi Gnanaprakash, Agnieszka Staniszewski, Hong Zhang, Rose Pitstick, Michael P. Kavanaugh, Ottavio Arancio, Russell E. Nicholls

Biomedical and Pharmaceutical Sciences Faculty Publications

Background: The serine/threonine protein phosphatase, PP2A, is thought to play a central role in the molecular pathogenesis of Alzheimer’s disease (AD), and the activity and substrate specificity of PP2A is regulated, in part, through methylation and demethylation of its catalytic subunit. Previously, we found that transgenic overexpression of the PP2A methyltransferase, LCMT-1, or the PP2A methylesterase, PME-1, altered the sensitivity of mice to impairments caused by acute exposure to synthetic oligomeric amyloid-β (Aβ).

Objective: Here we sought to test the possibility that these molecules also controlled sensitivity to impairments caused by chronically elevated levels of Aβ produced in vivo. …

Supplemental Ascorbate Diminishes Dna Damage Yet Depletes Glutathione And Increases Acute Liver Failure In A Mouse Model Of Hepatic Antioxidant System Disruption, Colin G. Miller, Jean A. Kundert, Justin R. Prigge, Julie A. Amato, Allison E. Perez, Lucia Coppo, Gabrielle N. Rizzo, Michael P. Kavanaugh, David J. Orlicky, Colin T. Shearn, Edward E. Schmidt

Biomedical and Pharmaceutical Sciences Faculty Publications

Cellular oxidants are primarily managed by the thioredoxin reductase-1 (TrxR1)- and glutathione reductase (Gsr)-driven antioxidant systems. In mice having hepatocyte-specific codisruption of TrxR1 and Gsr (TrxR1/Gsr-null livers), methionine catabolism sustains hepatic levels of reduced glutathione (GSH). Although most mice with TrxR1/Gsr-null livers exhibit long-term survival, ~25% die from spontaneous liver failure between 4- and 7-weeks of age. Here we tested whether liver failure was ameliorated by ascorbate supplementation. Following ascorbate, dehydroascorbate, or mock treatment, we assessed survival, liver histology, or hepatic redox markers including GSH and GSSG, redox enzyme activities, and oxidative damage markers. Unexpectedly, rather than providing protection, ascorbate …