Pharmacology, Toxicology and Environmental Health Commons^™

The Effects Of Protein Kinase C Inhibitors On Blood Nitric Oxide And Hydrogen Peroxide Release In Ischemia And Reperfusion Injury, Kyle D. Bartol

PCOM Biomedical Studies Student Scholarship

Vascular endothelial dysfunction is a key component initiating oxidative stress in ischemia/reperfusion (I/R). Endothelial dysfunction is characterized by an increase in hydrogen peroxide (H2O2) and a decrease in the bioavailability of nitric oxide (NO). Previous studies using protein kinase C (PKC) inhibitor Gö 6983 or PKC Beta (β) II inhibitor improved cardiac function in myocardial I/R, decreased leukocyte-endothelial interactions and leukocyte superoxide (SO) release and increased endothelial-derived NO release in vitro. This study examined the effects of Gö 6983 or PKC β II inhibitor on realtime H2O2 and NO release in femoral vein I/R in vivo. NO or H2O2 microsensors …

Synthesis, Evaluation And Structural Studies Of Antiproliferative Tubulin-Targeting Azetidin-2-Ones, Niamh O'Boyle, Lisa M. Greene, Orla Bergin, Jean-Baptiste Fichet, Thomas Mccabe, David G. Lloyd, Daniela M. Zisterer, Mary J. Meegan

Articles

A series of azetidin-2-ones substituted at positions 2, 3 and 4 of the azetidinone ring scaffold were synthesised and evaluated for antiproliferative, cytotoxic and tubulin binding activity. In these compounds, the cis double bond of the vascular targeting agent combretastatin A-4 is replaced with the azetidinone ring in order to enhance the antiproliferative effects displayed by combretastatin A-4 and prevent the cis/trans isomerization that is associated with inactivation of combretastatin A-4. The series of azetidinones was synthetically accessible via the Staudinger and Reformatsky reactions. Of a diverse range of heterocyclic derivatives, 3-(2-thienyl) analogue 28 and 3-(3-thienyl) analogue 29 displayed the …

Feedback From Malaysian Pharmacists Who Underwent A 3-Year Period Of Compulsory Service With The Government, Ong Aik Liang, Thomas Paraidathathu

The Thai Journal of Pharmaceutical Sciences

Since 2004, it is mandatory for all new pharmacy graduates in Malaysia to serve the government for a period of 4 years, before they are free to work as registered pharmacists in a sector of their choice, either public or private. With the enactment of th...

Sensitive, Selective And Extraction-Free Spectrophotometric Determination Of Lamotrigine In Pharmaceuticals Using Two Sulphonthalein Dyes, K. B. Vinay, H. O., N. Rajendraprasad, K. Basavaiah

The Thai Journal of Pharmaceutical Sciences

Two direct, simple, sensitive and rapid extraction-free spectrophotometric methods have been developed for the determination of lamotrigine (LMT) in pure form and in its dosage forms. The methods are based on formation of ion-pair complex between the dru...

Pharmacotherapy Safety And Efficacy In Adolescent Smoking Cessation, Jennifer Lincoln

PCOM Physician Assistant Studies Student Scholarship

OBJECTIVE: To determine whether or not pharmacotherapy is a safe and effective treatment option for smoking cessation in adolescents

Small Gtp-Binding Proteins In Insulin Secretion, Bhavaani Jayaram

Wayne State University Dissertations

Type 2 diabetes mellitus is marked by a substantial beta-cell failure which is characterized by defective insulin secretion and resistance to insulin. Understanding the molecular events leading to Glucose-stimulated insulin secretion [GSIS] might serve as therapeutic potential towards diabetes. GSIS involves interplay between small G-proteins and their regulatory factors. Herein, I tested the hypothesis that Arf nucleotide binding site opener [ARNO], a guanine nucleotide exchange factor [GEF] for the small G-protein Arf6, mediates the activation of Arf6, and that ARNO/Arf6 signaling axis, in turn, controls the activation of downstream effectors. Salient features of my study are: [i] ARNO/Arf6 is expressed …

Mechanisms Of Regulation Of Islet Function By Nadph Oxidase, Ismail Syed

Wayne State University Dissertations

Glucose stimulated insulin secretion (GSIS) involves a series of metabolic and cationic events, leading to translocation of insulin-laden secretory granules from a distal site toward the plasma membrane for fusion and release of insulin into circulation. Vesicular transport and fusion events are tightly regulated by signals which coordinate between vesicle- and membrane-associated docking proteins. It is now being accepted that reactive oxygen species [ROS] plays a second messenger role in islet â-cell function. Further, evidence from multiple laboratories suggests a tonic increase in ROS generation is necessary for GSIS and fatty acid-induced insulin secretion. On the other hand, excessive ROS …

Response Of Monovalent Cation Transporters To Pro-Apoptotic Protein Kinase C Modulators In Human Lens Epithelial Cells, Michael Anthony Lepera

Browse all Theses and Dissertations

Protein kinase inhibition by staurosporine causes apoptotic volume decrease involving potassium (K) channels in immortalized human B3 lens epithelial cells (LECs). Here, the effect of two pro-apoptotic protein kinase C (PKC) inhibitors [12-O-tetradecanoyl-phorbol-13-acetate (TPA) and chelerythrine (CET)] were studied on membrane K transport in a fetal human LEC line (FHL124) by western blotting, immunofluorescence, ion flux, ATP, apoptosis, and biotinylation assays. Long term TPA exposure (0-6 h) inhibited 75% of Na-K-2Cl cotransport (NKCC). In contrast, short term (0-20 min) exposure to 50 μM CET reduced Na/K pump and NKCC by >90% and >70%, respectively, without retrieval from the membrane into …

Differentiation Of Megakaryocytes/Platelets And Neurons From Human Endometrial Stromal Progenitor Cells, Jinju Wang

Browse all Theses and Dissertations

Human endometrium is a high dynamic tissue that contains stem/progenitor cells. These endometrial stromal progenitor cells (hESCs) have been differentiated into a number of mesodermal lineages. There is limited information on differentiating hESCs into neurons, and no information on differentiating hESCs into megakaryocytes (MKs) and platelets (PLTs). The aim of this work was to investigate the possibility of differentiating hESCs into two distinct lineages: MKs, with subsequent PLT formation, and neurons.

We isolated hESCs from human endometrial tissue and cultured the cells for 4-6 passages. Before each differentiation experiment, the purity of hESCs was confirmed by flow cytometry analysis which …

Role Of Hyperglycemia And Aldosterone On Renal Ace2 And Albuminuria In Db/Db Mice, Harshita Chodavarapu

Browse all Theses and Dissertations

Diabetic nephropathy (DN) is one of the microvascular complications of type II diabetes and a leading cause for the development of end stage renal disease. Renin angiotensin system (RAS) plays a pivotal role in the development and progression of diabetic nephropathy. Hyperglycemia activates RAS and increases tissue and circulating levels of angiotensin II (Ang II) and aldosterone. A new component of RAS, angiotensin converting enzyme 2 (ACE2), has been shown to be renoprotective in early stages of diabetes. The aim of this study is to test the hypothesis that strict glycemic control using rosiglitazone or treatment with mineralocorticoid receptor (MR) …

Analysis Of Archived Dried Blood Spots By Mass Spectrometry For Vitamin D And Real-Time Pcr For Its Enzymes And Receptor, Amod N. Joshi

Browse all Theses and Dissertations

Vitamin D is an essential micronutrient required for maintenance of the skeletal system and its deficiency leads to diminished availability of calcium for maintaining bone mineralization. Vitamin D deficiency (VDD) during pregnancy and/or in early infancy can lead to rickets and a fragile bone state resulting in fractures with minimal forces. Such multiple unexplained fractures (MUF) present in infants at less than 6 months of age are often misdiagnosed as cases of child abuse. Therefore, it is important to evaluate the status of vitamin D in early infancy. The analysis of dried blood spots (DBS) provides a unique screening method …

Response Of Neuroinflammatory And Neurodegenerative Markers Following Sub-Lethal Sarin Exposure And Subsequent Treatment Via An In-Vivo Caspase Inhibitor, Douglas F. Chmura

Browse all Theses and Dissertations

Organophosphorus nerve agents are amongst the most deadly chemical compounds ever synthesized. Sarin is an organophosphate (OP) ester that irreversibly forms a phosphoester bond at the active site of acetylcholinesterase and thereby induces a rapid and lethal cholinergic crisis. It remains an active threat to vulnerable civilian populations due to its ease of synthesis and known use by rogue nations and terrorist groups. Death is the most extreme consequence of sarin toxicity. Current treatments fail to provide protection against progressive cognitive impairments years after mild exposure. Q-VD-OPh is an in-vivo caspase inhibitor with potent anti-apoptotic and anti-inflammatory properties. In this …

Synthesis, Characterization And Manipulation Of Creighton Silver Nanoparticles For Future Cytotoxicity Studies, Sesha Lakshmi Paluri

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Nowadays, 24% of the nanomaterial-based consumer products contain silver nanoparticles (AgNPs) and exploit the well-known antimicrobial properties of silver. Although AgNPs have a wide range of biomedical research and industrial applications, very little is known about their toxicity. The main goal of this study is to synthesize, characterize and manipulate Creighton colloidal AgNPs for future cytotoxicity studies. These "naked" AgNPs were free from chemically aggressive capping/stabilizing agents, reaction byproducts or organic solvents. To achieve this goal, colloidal AgNPs were successfully: a) synthesized in large volumes (5L) using a slightly modified Creighton method by the reduction of silver nitrate with sodium …

Low Dose Nerve Agent Sarin Causes Dilated Cardiomyopathy And Autonomic Imbalance In Mice, Swapnil Vijay Shewale

Browse all Theses and Dissertations

Sarin, a lethal chemical nerve agent, may be a causative factor in multifactorial syndrome implicated in the Gulf War and Tokyo terrorist attacks. While high dose results in seizure and death, low dose exposure may lead to autonomic imbalance and chronic cardiac pathologies. In the present study, echocardiography and electrocardiography were used to examine the late onset effects of a low dose sarin on cardiac structure and function in mice. Stress responsiveness of the hypothalamic pituitary adrenal (HPA) axis was also tested. Findings demonstrate changes consistent with a dilated cardiomyopathy, including left ventricular dilatation, reduced contractility, and altered electrophysiological and …

Synthesis And Cytotoxicity Study Of Magnetoliposomes Loaded Doxorubicin, Surachai Ngamratanapaiboon, Issara Sramala, Wichet Leelamanit

The Thai Journal of Pharmaceutical Sciences

The limitation of clinical use of doxorubicin is its side effects especially a cumulative dose-dependent cardiotoxicity. To overcome this, doxorubicin can be targeted to accumulate on the site of action and limit dispersion in healthy tissue. Magnetic li...

Overuse Of Antibiotics In Children For Upper Respiratory Infections (Uris): A Dilemma, Malika Taufiq, Rukhsana Wamiq Zuberi

Department for Educational Development

No abstract provided.

Secreted Factors From Human Umbilical Cord Blood Cells Protect Oligodendrocytes From Ischemic Insult, Derrick Rowe

USF Tampa Graduate Theses and Dissertations

Oligodendrocytes (OL)s are the dominant cell type in the white matter and are integral for synaptic transmission essential for proper neuronal communication between brain areas. Previous studies have shown that intravenous administration of the mononuclear fraction of human umbilical cord blood (HUCB) cells in rat models of stroke reduced white matter injury, gray matter injury and behavioral deficits. Yet the mechanisms used by HUCB cells remain unknown in ischemic injury. These studies will investigate both in vitro and in vivo approaches to elucidate this mechanism in OLs. When mature primary OLs were coincubated with HUCB cells, HUCB cells secreted soluble …

Lead Identification Of Β-Lactam And Related Imine Inhibitors Of The Molecular Caperone Heat Shock Protein 90, Niamh O'Boyle, Andrew Js Knox, Trevor P. Price, D. Clive Williams, Daniela M. Zisterer, David G. Lloyd, Mary J. Meegan

Articles

Heat shock protein 90 is an emerging target for oncology therapeutics. Inhibitors of this molecular chaperone, which is responsible for the maintenance of a number of oncogenic proteins, have shown promise in clinical trials and represent a new and exciting area in the treatment of cancer. Heat shock protein 90 inhibitors have huge structural diversity, and here we present the identification of inhibitors based on β-lactam and imine templates. β-Lactam 5 and imines 12 and 18 exhibit binding to heat shock protein 90-α with IC₅₀ values of 5.6 μM, 14.5 μM and 22.1 μM respectively. The binding affinity displayed …

Synthesis, Biochemical And Molecular Modelling Studies Of Antiproliferative Azetidinones Causing Microtubule Disruption And Mitotic Catastrophe, Niamh O'Boyle, Miriam Carr, Lisa M. Greene, Niall O. Keely, Andrew Js Knox, Thomas Mccabe, David G. Lloyd, Daniela M. Zisterer, Mary J. Meegan

Articles

The structure-activity relationships of antiproliferative β-lactams, focusing on modifications at the 4-position of the β-lactam ring, is described. Synthesis of this series of compounds was achieved utilizing the Staudinger and Reformatsky reactions. The antiproliferative activity was assessed in MCF-7 cells, where the 4-(4-ethoxy)phenyl substituted compound 26 displayed the most potent activity with an IC₅₀ value of 0.22 μM. The mechanism of action was demonstrated to be by inhibition of tubulin. Cell exposure to combretastatin A-4 and 26 led to arrest of MCF-7 cells in the G2/M phase of the cell cycle and induction of apoptosis. Additionally, mitotic catastrophe for …

Anaplasmataceae As Human Pathogens : Biology, Ecology And Epidemiology, Marina E. Eremeeva, Gregory A. Dasch

Environmental Health Sciences: Faculty Publications

This review describes the biology, ecology, and epidemiology of known human pathogens in the family Anaplasmataceae that are transmitted by ticks and belong to the genus Anaplasma and genus Ehrlichia. We discuss the current status of diagnosis and surveillance of the diseases they cause, and address the challenges and new perspectives raised due to continuous recognition of new emerging human pathogens in the family Anaplasmataceae.

Biologically Active Alkaloids From Kopsia., Yap Wai Sum

Student Works (2010-2019)

Two Malaysian plants viz., Kopsia pauciflora and Kopsia grandifolia were investigated for their alkaloidal constituents. A total of 40 alkaloids were isolated and characterized from K. pauciflora, of which 12 are new alkaloids. The new alkaloids isolated include seven aspidofractinine alkaloids (1, 2, 3, 4, 5, 6, 7), and five eburnane alkaloids (8, 9, 10, 11, 12). K. grandifolia yielded a total of eight alkaloids. Of these, three are new. The new alkaloids are grandilodine A (41), grandilodine B (42), and grandilodine C (43). Grandilodine A (41), grandilodine C (43), and lapidilectine B (47) were found to reverse multidrug resistance …

Genotoxin-Induced Acetylation Of The Werner Syndrome Protein (Wrn) And Effect On Its Dna Metabolic Function, Enerlyn Meliza Lozada Santiago

University of Kentucky Doctoral Dissertations

Loss of function of the WRN protein causes the genetic disorder Werner Syndrome that is characterized by increased cancer and premature aging. WRN belongs to the RecQ helicase family that plays key roles in preventing genome instability. In response to treatment with genotoxins, WRN is subject to post-translational modification. The relationship of post-translational modification of WRN with its function in DNA metabolism is unknown. There is accumulating evidence suggesting that WRN contributes to the maintenance of genomic integrity through its involvement in DNA replication. Consistent with this notion, WS cells are sensitive to DNA replication inhibitors and DNA damaging agents …

Identification Of Activities Involved In Cag/Ctg Repeat Instability, Nelson Lap Shun Chan

University of Kentucky Doctoral Dissertations

CAG/CTG repeat instability is associated with at least 14 neurological disorders, including Huntington’s disease and Myotonic dystrophy type 1. In vitro and in vivo studies have showed that CAG/CTG repeats form a stable hairpin that is believed to be the intermediate for repeat expansion and contraction.

Addition of extra DNA is essential for repeat expansion, so DNA synthesis is one of the keys for repeat expansion. In vivo studies reveal that 3’ CTG slippage with subsequent hairpin formation (henceforth called the 3’ CTG slippage hairpin) occurs during DNA synthesis. It is proposed that hairpin tolerance machinery is activated because prolonged …

When Curiosity Kills More Than The Cat: The Perils Of Unchecked Scientific Inquiry, Jamie Shannon

Pomona Senior Theses

This work analyzes the ecological, physical, emotional and health impacts of the US nuclear testing done in the Marshall Islands in the mid-20th century.

Mycotoxins In Grains – Causes, Prevention And Control, Hester F. Vismer

INTSORMIL Presentations

Discusses mycotoxins, their effect on grain, mitigation considerations, and resulting human toxicology.

Exhausted Or Unlicensed: Can Field-Of-Use Restrictions In Biotech License Agreements Still Prevent Off-Label Use Promotion After Quanta Computer?, Kristal M. Wicks

The University of New Hampshire Law Review

[Excerpt] “In the biotechnology (biotech) industry, companies must be increasingly aware of their intellectual property and how their licensing strategies can impact their rights. When licensing patented technology, it is common practice for biotech companies to include restricted field-of-use provisions in their license agreements. Such provisions permit a licensee to only use licensed technology in a defined field and restrict use or development in another field. This licensing strategy plays an important role within the biotech industry because it allows companies to more effectively control their intellectual property and to more efficiently research and develop pharmaceutical products.

A problem that …

Pharmacokinetic Evaluation Of The Blood: Tissue Relationship In Poultry: Screening For Antibiotic Residues In Chicken Muscle, Ixchel Reyes Herrera

Graduate Theses and Dissertations

During their life, humans are exposed to numerous substances that are naturally present in the environment or that are the result of man made processes, including heavy metals, persistent organic pollutants, pesticides and veterinary drugs. Some of these substances can leave residues in food products and possibly expose consumers to their potential toxic effects. To address these problems extensive regulatory efforts are devoted to prevent, detect and control these substances from reaching the food supply. However, given the vast diversity of food products that requires monitoring and the immense diversity of potential chemical contaminants, the need for an efficient and …

Chloroquine Susceptibility And Reversibility In A Plasmodium Falciparum Genetic Cross, Jigar J. Patel, Drew Thacker, Jon C. Tan, Perri Pleeter, Lisa Checkley, Joseph M. Gonzales, Bingbing Deng, Paul D. Roepe, Roland A. Cooper, Michael T. Ferdig

Collected Faculty Scholarship

Mutations in the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT), are major determinants of verapamil (VP)-reversible CQ resistance (CQR). In the presence of mutant PfCRT, additional genes contribute to the wide range of CQ susceptibilities observed. It is not known if these genes influence mechanisms of chemosensitization by CQR reversal agents. Using quantitative trait locus (QTL) mapping of progeny clones from the HB3 × Dd2 cross, we show that the P. falciparum multidrug resistance gene 1 (pfmdr1) interacts with the Southeast Asiaderived mutant pfcrt haplotype to modulate CQR levels. A novel chromosome 7 locus is predicted to contribute with the …

Anticancer And Antifungal Activity Of Copper(Ii) Complexes Of Quinolin-2(1h)-One-Derived Schiff Bases, Bernadette S. Creaven, Brian Duff, Denise A. Egan, Kevin Kavanagh, Georgina Rosair, Venkat Reddy Thangella, Maureen Walsh

Articles

The condensation of substituted aromatic aldehydes with 7-amino-4-methyl-quinolin-2(1H)-one (1) has lead to the isolation of quinolin-2(1H)-one derived Schiff bases (2–14). The copper(II) complexes (2a–14a) of the ligands were also prepared, and together with their corresponding free ligands were fully characterised by elemental analyses, spectral methods (IR, ¹H and ¹³C NMR, AAS, UV–Vis), magnetic and conductance measurements. The bidentate ligands coordinated to the copper(II) ion through the deprotonated phenolic oxygen and the azomethine nitrogen of the ligands in almost all cases. X-ray crystal structures of two of the complexes, 5a and 8a, confirmed the bidentate …

Comparison Of Bacteroides Human Markers For Pollution Diagnostics In Recreational Waters, Asli Aslan, Joan B. Rose

Environmental Health Sciences: Faculty Presentations (2010-2017)

This presentation was given during the Great Lakes Beach Association Annual Conference.