Chemical and Pharmacologic Phenomena Commons^™

Natural Product Induction In Pencillium And Human Caspase Crystallography, Kelly J. Mcgrath

Graduate Student Theses, Dissertations, & Professional Papers

No abstract provided.

Epidermal Growth Factor Receptor (Egfr) Inhibition By Polychlorinated Biphenyls Contributes To Non-Alcoholic Fatty Liver Disease (Nafld)., Josiah Hardesty

Electronic Theses and Dissertations

This dissertation describes how poly-chlorinated biphenyls (PCBs) exacerbate the pathogenesis of non-alcoholic fatty liver disease (NAFLD). While PCBs were banned in 1979, they still persist in contaminated biota, including food, and are detected in human plasma and adipose. The body burden of PCBs is associated with elevation of liver enzymes and necrosis markers in humans, characteristic of NAFLD. PCB exposure in high-fat diet fed mice leads to steatohepatitis that recapitulate the findings seen in exposed humans. The global estimate of people diagnosed with NAFLD is up to 1 in 4 people, unrelated to dietary or genetic factors. The hepatic mechanisms …

Is Tpmt Testing A Predictor Of Duration Of Use Or Long-Term Benefit Of Thiopurine Agents?, Shatoya R. Wilson

Masters Theses

Background: Inflammatory Bowel Disease (IBD) affects as many as 1.3 million Americans and includes both ulcerative colitis (UC) and Crohn’s disease (CD). Recent practices have moved towards using immunomodulators early in the course of disease to prevent disease progression. Patients have shown improved outcomes on immunomodulators compared to aminosalicylates, and reduced risk for tachyphylaxis compared to corticosteroid treatment. Thiopurine agents such as azathioprine and 6-mercaptopurine are immunomodulators often used to treat IBD. Unfortunately, many patients experience cytotoxicity from thiopurine use. Recent studies have shown that patients deficient in thiopurine-S-methyltransferase (TMPT), produce an overabundance of the therapeutic end product, 6-thioguanine nucleotide …

Efficacy And Renal Outcomes Of Sglt2 Inhibitors In Patients With Type 2 Diabetes And Chronic Kidney Disease, Michael S. Kelly, Jelena Lewis, Ashley M. Huntsberry, Lauren Dea, Ivan Portillo

Pharmacy Faculty Articles and Research

Objective: To review glucose-lowering efficacy and changes in renal function associated with sodium-glucose co-transporter 2 (SGLT2) inhibitors among patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM).

Data sources: A literature search of MEDLINE and Cochrane databases was performed from 2000 to August 2018 using search terms: SGLT2 inhibitors, sodium glucose co-transporter 2, canagliflozin, empagliflozin, dapagliflozin, ertugliflozin, and chronic kidney disease. References of identified articles were also reviewed.

Study selection and data extraction: English-language studies investigating glucose-lowering endpoints and/or changes in renal function with one of four U.S. approved SGLT2 inhibitors were included. A …

Kinetics Of Dextromethorphan-O-Demethylase Activity And Distribution Of Cyp2d In Four Commonly-Used Subcellular Fractions Of Rat Brain, Barent N. Dubois, Farideh Amirrad, Reza Mehvar

Pharmacy Faculty Articles and Research

The purpose of this study was to compare the enzymatic kinetics and distribution of cytochrome P450 2D (CYP2D) among different rat brain subcellular fractions.

Rat brains were used to prepare total membrane, crude mitochondrial, purified mitochondrial, and microsomal fractions, in addition to total homogenate. Michaelis–Menten kinetics of the brain CYP2D activity was estimated based on the conversion of dextromethorphan (DXM) to dextrorphan using UPLC-MS/MS. Protein levels of CYP2D and subcellular markers were determined by Western blot.

Microsomal CYP2D exhibited high affinity and low capacity, compared with the mitochondrial CYP2D that had a much lower (∼50-fold) affinity but a higher (∼six-fold) …

Synthesis And Antiproliferative Activities Of Doxorubicin Thiol Conjugates And Doxorubicin-Ss-Cyclic Peptide, Shaban Darwish, Neda Sadeghiani, Shirley Fong, Saghar Mozaffari, Parinaz Hamidi, Thimanthi Withana, Sun Yang, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

Myocardial toxicity and drug resistance caused by drug efflux are major limitations of doxorubicin (Dox)-based chemotherapy. Dox structure modification could be used to develop conjugates with an improved biological profile, such as antiproliferative activity and higher cellular retention. Thus, Dox thiol conjugates, Dox thiol (Dox-SH), thiol-reactive Dox-SS-pyridine (SS = disulfide), and a Dox-SS-cell-penetrating cyclic peptide, Dox-SS-[C(WR)4K], were synthesized. Dox was reacted with Traut's reagent to generate Dox-SH. The thiol group was activated by the reaction with dithiodipyridine to afford the corresponding Dox-SS-Pyridine (Dox-SS-Pyr). A cyclic cell-penetrating peptide containing a cysteine residue [C(WR)4K] was prepared using Fmoc solid-phase strategy. Dox-SS-Py was …

Correcting Glucose-6-Phosphate Dehydrogenase Deficiency With A Small-Molecule Activator, Sunhee Hwang, Karen Mruk, Simin Rahighi, Andrew G. Raub, Che-Hong Chen, Lisa E. Dorn, Naoki Horikoshi, Soichi Wakatsuki, James K. Chen, Daria Mochly-Rosen

Pharmacy Faculty Articles and Research

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, one of the most common human genetic enzymopathies, is caused by over 160 different point mutations and contributes to the severity of many acute and chronic diseases associated with oxidative stress, including hemolytic anemia and bilirubin-induced neurological damage particularly in newborns. As no medications are available to treat G6PD deficiency, here we seek to identify a small molecule that corrects it. Crystallographic study and mutagenesis analysis identify the structural and functional defect of one common mutant (Canton, R459L). Using high-throughput screening, we subsequently identify AG1, a small molecule that increases the activity of the wild-type, the …

Iron-Dependent Cleavage Of Ribosomal Rna During Oxidative Stress In The Yeast Saccharomyces Cerevisiae, Jessica A Zinskie, Arnab Ghosh, Brandon M Trainor, Daniel Shedlovskiy, Dimitri G Pestov, Natalia Shcherbik

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Stress-induced strand breaks in rRNA have been observed in many organisms, but the mechanisms by which they originate are not well-understood. Here we show that a chemical rather than an enzymatic mechanism initiates rRNA cleavages during oxidative stress in yeast (Saccharomyces cerevisiae). We used cells lacking the mitochondrial glutaredoxin Grx5 to demonstrate that oxidant-induced cleavage formation in 25S rRNA correlates with intracellular iron levels. Sequestering free iron by chemical or genetic means decreased the extent of rRNA degradation and relieved the hypersensitivity of grx5Δ cells to the oxidants. Importantly, subjecting purified ribosomes to an in vitro iron/ascorbate …

Uplc-Ms/Ms Analysis Of Dextromethorphan-O-Demethylation Kinetics In Rat Brain Microsomes, Barent N. Dubois, Reza Mehvar

Pharmacy Faculty Articles and Research

Formation of dextrorphan (DXT) from dextromethorphan (DXM) has been widely used to assess cytochrome P450 2D (CYP2D) activity. Additionally, the kinetics of CYP2D activity have been well characterized in the liver microsomes. However, studies in brain microsomes are limited due to the lower microsomal content and abundance of CYP2D in the brain relative to the liver. In the present study, we developed a micro-scale enzymatic incubation method, coupled with a sensitive UPLC-MS/MS assay for the quantitation of the rate of DXT formation from DXM in brain microsomes. Rat brain microsomes were incubated with different concentrations of DXM for various times. …

30-Day Oral Acetaminophen Tolerance In Adult Horses, Sarah E. Foreman

Celebration of Learning

There are no controlled studies of acetaminophen toxicity in horses. The objective was to test the hypotheses that oral acetaminophen administered at a dosage 25% higher than that sometimes used in horses would result in measurable hepatic toxicity as seen in humans and other species. Six healthy adult horses were administered 25 mg/kg acetaminophen powder in corn syrup twice daily for 30 days. Three other horses served as negative controls receiving only corn syrup. Jugular venous blood samples were obtained on days 7 and 1 before treatment; on treatment days 1, 2, 5, 8, 12, 15, 19, 22, 26 and …

The Beta-Catenin/Muc1.Ct Interaction In Pancreatic Cancer, Edwin Wiest

Theses & Dissertations

MUC1 is overexpressed in over 90% of pancreatic cancer cases, and its interaction with beta-catenin promotes progression of the disease. Various in vitro and in vivo methods show that beta-catenin and MUC1 interact by way of the cytoplasmic tail of MUC1 (MUC1.CT). This interaction occurs in the membrane of pancreatic cancer cells but is found to a smaller extent in the nucleus as well. Biophysical methods suggest that MUC1 interacts with beta-catenin through a sequence of amino acids in the tail of MUC1 that sit very near the transmembrane domain of MUC1. In pancreatic ductal adenocarcinoma cells, it appears that …

Linear Ubiquitin Chain-Binding Domains, Lilian Fennell, Simin Rahighi, Fumiyo Ikeda

Pharmacy Faculty Articles and Research

Ubiquitin modification (ubiquitination) of target proteins can vary with respect to chain lengths, linkage type, and chain forms, such as homologous, mixed, and branched ubiquitin chains. Thus, ubiquitination can generate multiple unique surfaces on a target protein substrate. Ubiquitin‐binding domains (UBDs) recognize ubiquitinated substrates, by specifically binding to these unique surfaces, modulate the formation of cellular signaling complexes and regulate downstream signaling cascades. Among the eight different homotypic chain types, Met1‐linked (also termed linear) chains are the only chains in which linkage occurs on a non‐Lys residue of ubiquitin. Linear ubiquitin chains have been implicated in immune responses, cell death …

Factors Involved In Suppression Of Human Vγ9vδ2 T-Lymphocytes And Impact Of Checkpoint Blockades On The Effector Functions Of Vγ9vδ2 T-Lymphocytes, Minji Choi, Andrew Wiemer, Andrea Hubbard, Brian Aneskievich

University Scholar Projects

Chronic antigenic stimulation leads to T cell exhaustion, which drastically dampens T cell effector functions. Upon exhaustion, T cells progressively lose their proliferative capacity, cytokine production, and cytotoxic effector functions against tumors. T cell exhaustion involves programmed cell death-1 (PD-1), which is an inhibitory co-stimulation receptor. Limited scope of studies has been done regarding impact of PD-1 expression on the effector functions of γδ T cells. In this study, we investigated expression of PD-1 and its impact on effector functions of human γδ T cells. When γδ T cells were stimulated with phosphoantigens (HMBPP and POM₂-C-HMBP) and analyzed …

Ferrocenylchalcone-Uracil Conjugates: Synthesis And Cytotoxic Evaluation, Amandeep Singh, Vishu Mehra, Neda Sadeghiani, Saghar Mozaffari, Keykavous Parang, Vipan Kumar

Pharmacy Faculty Articles and Research

Huisgen’s azide-alkyne cycloaddition reaction was employed to synthesize a series of 1H-1,2,3-triazole-tethered uracil-ferrocenyl chalcone conjugates with the aim of evaluating their in vitro anti-proliferative efficacy on human leukemia (CCRF-CEM) and human breast adenocarcinoma (MDA-MB-468) cell lines. Cytotoxic evaluation studies identified a number of synthesized conjugates that inhibited the proliferation of leukemia cancer cells by ~70% after 72 h. The selected synthesized conjugates were found to be significantly less cytotoxic against normal kidney cell line (LLC-PK1) when compared with CCRF-CEM cancer cells.

Novel Insights Into The Contribution Of Cellular Senescence To Cancer Therapy: Reversibility, Dormancy And Senolysis., Tareq Saleh

Theses and Dissertations

Cellular senescence a specialized form of growth arrest that contributes to the pathogenesis of several aging-related disorders including cancer. While by definition tumor cells are considered immortalized, they can undergo senescence when exposed to conventional and targeted cancer therapy. Therapy-Induced Senescence (TIS) represents a fundamental response to therapy and impacts its outcomes. However, TIS has been considered a positive therapeutic goal since senescent tumor cells are expected to enter a state of permanent growth abrogation. In this work we examined the hypothesis that a subpopulation of senescent cells can re-acquire proliferative potential after a state of senescent dormancy, indicating that …

Study Of Low Dose Nitrite Stress On Human Mononuclear Cells: An In-Vitro Case-Control Study On Osteoarthritis, Junu Shrestha

Dissertations and Theses @ UNI

Nitrate, (NOR 3RP - P) is an oxidized form of nitrogen and it is an integral part of the nitrogen cycle in the natural environment. Nitrates are extensively used in agricultural practices as fertilizers, applied as either animal manures or derived slurries or as chemical fertilizers in the form of ammonium nitrate. Most of the toxicologically relevant nitrate enters the human body through consumption of vegetables, fruits, processed food products, and drinking water. In the ground water system, nitrates are a problematic and widespread contaminant, especially in agricultural areas such as the Midwest, South, and Northeastern U.S. Low-levels of nitrate …

Targeting Ribosome Assembly Factors Selectively Protects P53 Positive Cells From Chemotherapeutic Agents, Russell T. Sapio, Anastasiya Nezdyur, Matthew Krevetski, Leonid Anikin, Vincent J. Manna, N. Minkovsky, Dimitri G Pestov

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Many chemotherapeutic agents act in a nondiscriminatory fashion, targeting both cancerous and noncancerous cells in Sphase and Mphase. One approach to reduce the toxic side effects in normal tissue is to exploit the differences in p53 functionality between cancerous and noncancerous cells. For example, activating p53 signaling by nongenotoxic means can transiently arrest noncancerous p53 positive cells in G1 phase and protect them from the cytotoxic effects of chemotherapeutic drugs. However, since most cancerous cells have faulty p53 signaling, they will proceed to cycle, and continue to be affected by the drug. In this study we asked if this G1‐phase …

Harmonizing Lipidomics: Nist Interlaboratory Comparison Exercise For Lipidomics Using Srm 1950-Metabolites In Frozen Human Plasma, J Bowden, C Ulmer, C Jones, J Koelmel, L Abdullah, Houli Jiang, Michal Schwartzman, Amaury Cazenave-Gassiot, Antonio Checa, Michelle Cinel, Romain Colas, Serge Cremers, Edward Dennis, James Evans, Alexander Fauland, Jun Han, Houli Jiang, Michal Schwartzman

NYMC Faculty Publications

As the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950-Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each laboratory using a different lipidomics workflow. A total of 1,527 unique lipids were measured across all laboratories and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks …

Analysis Of The Proposed Tpp-Related Patent Linkage System In Taiwan, Ping-Hsun Chen

Journal of Law and Health

The Trans-Pacific Partnership (TPP) Agreement mandates member states to implement a patent linkage system vested in Article 18.53. To successfully join the TPP Agreement, Taiwan has begun the legislation of a patent linkage system by proposing an amendment for the Pharmaceutical Affairs Act. Article 18.53 requires a member either to adopt a notification mechanism under Paragraph 1 or to stay the issuance of marketing approval under Paragraph 2. But, Taiwan’s proposal includes both measures. Taiwan’s patent linkage system allows a pioneer drug company to register patents claiming (a) a material, (b) a combination or formula, or (c) pharmaceutical use. The …

Cytotoxicity Of Platinum Anticancer Drugs In Mammalian Cell Lines Of Metastatic Cancer, Hosannah Evie

Mahurin Honors College Capstone Experience/Thesis Projects

With the invention of advanced technology, focus has been put on understanding and looking for potential cures for many diseases, one of which is cancer. The difference in the leaving and non-leaving ligands of the FDA approved cancer drugs contributes to the differential cell specific cytotoxic effects. These drugs such as oxaliplatin approved for colorectal cancer, cisplatin approved for testicular cancer, and their analogs were used to treat different cancer cell lines in an MTT assay. This project aims to determine how changing the molecular shape of these compounds affects their uptake and toxicity into different cell lines. The assay …