Pharmacology, Toxicology and Environmental Health Commons^™

Modelling Β2ar Regulation, Sharat J. Vayttaden

Dissertations & Theses (Open Access)

The β2 adrenergic receptor (β2AR) regulates smooth muscle relaxation in the vasculature and airways. Long- and Short-acting β-agonists (LABAs/SABAs) are widely used in treatment of chronic obstructive pulmonary disorder (COPD) and asthma. Despite their widespread clinical use we do not understand well the dominant β2AR regulatory pathways that are stimulated during therapy and bring about tachyphylaxis, which is the loss of drug effects. Thus, an understanding of how the β2AR responds to various β-agonists is crucial to their rational use. Towards that end we have developed deterministic models that explore the mechanism of drug- induced β2AR regulation. These mathematical models …

Store-Operated Calcium Channels In The Function Of Intracardiac Neurons, Timetria Bonds

USF Tampa Graduate Theses and Dissertations

Proper autonomic regulation of mammalian cardiac function is dependent upon very complex and precise communication among the intracardiac ganglia and individual neurons within the ganglia. An array of neuromodulators is found within the ganglia that direct neuronal activity by modulating the movement of calcium. The current study determines that opioidergic agonists, which have been found to contribute to severe cardiac disease states and intracellular calcium mobilization, are also responsible for changes in the function of the intracardiac neuron via their effects on store-operated calcium channels (SOCs).

Previous studies suggest that phosphorylation plays a role in SOC regulation. Using Fura-2 calcium …

Competition Between Ski And Creb-Binding Protein For Binding To Smad Proteins In Transforming Growth Factor-Beta Signaling, Weijun Chen, Suvana Lam, Hema Srinath, Celia Schiffer, William Royer, Kai Lin

Celia A. Schiffer

The family of Smad proteins mediates transforming growth factor-beta (TGF-beta) signaling in cell growth and differentiation. Smads repress or activate TGF-beta signaling by interacting with corepressors (e.g. Ski) or coactivators (e.g. CREB-binding protein (CBP)), respectively. Specifically, Ski has been shown to interfere with the interaction between Smad3 and CBP. However, it is unclear whether Ski competes with CBP for binding to Smads and whether they can interact with Smad3 at the same binding surface on Smad3. We investigated the interactions among purified constructs of Smad, Ski, and CBP in vitro by size-exclusion chromatography, isothermal titration calorimetry, and mutational studies. Here, …

Mass Spectrometry Analysis Of Hiv-1 Vif Reveals An Increase In Ordered Structure Upon Oligomerization In Regions Necessary For Viral Infectivity, Jared Auclair, Karin Green, Shivender Shandilya, James Evans, Mohan Somasundaran, Celia Schiffer

Celia A. Schiffer

HIV-1 Vif, an accessory protein in the viral genome, performs an important role in viral pathogenesis by facilitating the degradation of APOBEC3G, an endogenous cellular inhibitor of HIV-1 replication. In this study, intrinsically disordered regions are predicted in HIV-1 Vif using sequence-based algorithms. Intrinsic disorder may explain why traditional structure determination of HIV-1 Vif has been elusive, making structure-based drug design impossible. To characterize HIV-1 Vif's structural topology and to map the domains involved in oligomerization we used chemical cross-linking, proteolysis, and mass spectrometry. Cross-linking showed evidence of monomer, dimer, and trimer species via denaturing gel analysis and an additional …

Exploring The Role Of The Solvent In The Denaturation Of A Protein: A Molecular Dynamics Study Of The Dna Binding Domain Of The 434 Repressor, Celia Schiffer, Volker Dötsch, Kurt Wuthrich, Wilfred Van Gunsteren

Celia A. Schiffer

Molecular dynamics simulations of the DNA binding domain of 434 repressor are presented which aim at unraveling the role of solvent in protein denaturation. Four altered solvent models, each mimicking various possible aspects of the addition of a denaturant to the aqueous solvent, were used in the simulations to analyze their effects on the stability of the protein. The solvent was altered by selectively changing the Coulombic interaction between water and protein atoms and between different water molecules. The use of a modified solvent model has the advantage of mimicking the presence of denaturant without having denaturant molecules present in …

Structural Analysis Of Human Immunodeficiency Virus Type 1 Crf01_Ae Protease In Complex With The Substrate P1-P6., Rajintha Bandaranayake, Moses Prabu-Jeyabalan, Junko Kakizawa, Wataru Sugiura, Celia Schiffer

Celia A. Schiffer

The effect of amino acid variability between human immunodeficiency virus type 1 (HIV-1) clades on structure and the emergence of resistance mutations in HIV-1 protease has become an area of significant interest in recent years. We determined the first crystal structure of the HIV-1 CRF01_AE protease in complex with the p1-p6 substrate to a resolution of 2.8 A. Hydrogen bonding between the flap hinge and the protease core regions shows significant structural rearrangements in CRF01_AE protease compared to the clade B protease structure.

Non-Viral Enos Gene Delivery And Transfection With Stents For The Treatment Of Restenosis, Luis A. Brito, Saradha Chandrasekhar, Steven R. Little, Mansoor M. Amiji

Mansoor M. Amiji

Background In this study, we have examined local non-viral gene delivery, transfection, and therapeutic efficacy of endothelial nitric oxide synthase (eNOS) encoding plasmid DNA administered using coated stents in a rabbit iliac artery restenosis model. Methods Lipopolyplexes (LPPs) with eNOS expressing plasmid DNA were immobilized on stainless steel stents using poly(D,L-lactide-co-glycolide) (PLGA) and type B gelatin coatings. The gene-eluting stents were implanted bilaterally in the denuded iliac arteries and eNOS transfection and therapeutic efficacy were examined 14 days after implantation. Results The results show that non-viral lipopolyplex-coated stents can efficiently tranfect eNOS locally in the arterial lumen assessed by PCR …

Phasic Activity Of Urinary Bladder Smooth Muscle In The Streptozotocin-Induced Diabetic Rat: Effect Of Potassium Channel Modulators, Bahareh Vahabi, Kim Lawson, Neil G. Mckay, Donna Sellers

Donna Sellers

Increased phasic activity in the bladder smooth muscle of animal models and patients with detrusor overactivity has been suggested to underlie the pathophysiology of overactive bladder. Potassium (K+) channels are key regulators of bladder smooth muscle tone and thus may play a role in this altered phasic activity. In this study the effects of K+ channel modulators on the phasic activity of bladder strips from the streptozotocin-induced diabetic rat model of bladder dysfunction were investigated. Bladder strips from rats 1 week following streptozotocin administration and age-matched controls were mounted in tissue baths at 37 °C and the effects of K+ …

The Growth Suppressing Effects Of Girinimbine On Hepg2 Involve Induction Of Apoptosis And Cell Cycle Arrest, Syam Mohan

Syam Mohan

Murraya koenigii is an edible herb widely used in folk medicine. Here we report that girinimbine, a carbazole alkaloid isolated from this plant, inhibited the growth and induced apoptosis in human hepatocellular carcinoma, HepG2 cells. The MTT and LDH assay results showed that girinimbine decreased cell viability and increased cytotoxicity in a dose-and time-dependent manner selectively. Girinimbine-treated HepG2 cells showed typical morphological features of apoptosis, as observed from normal inverted microscopy and Hoechst 33342 assay. Furthermore, girinimbine treatment resulted in DNA fragmentation and elevated levels of caspase-3 in HepG2 cells. Girinimbine treatment also displayed a time-dependent accumulation of the Sub-G(0)/G(1) …

Assessment Of Organic And Inorganic Phosphorus In Soils Derived From Cretaceous Sediments And Basement Complex Soils Of Guinea Savannah Of Kogi State, North Central Nigeria, Sunday I. Amhakhian, H H. Isitekhale, Charles I. Oyewole

Confluence Journal Environmental Studies (CJES), Kogi State University, Nigeria

A pot experiment was carried out using 20 surface soils (0-15cm depth) in 2008 to assess soil organic phosphorus and some fraction of inorganic phosphorus in other to know their availability in the soils of the studied area and also work have not been done in this areas in respect to organic and in-organic phosphorus. The experiment was conducted using 20 soils 10 from each geological formation (Cretaceous sediments and Basement complex soils), respectively. The mean organic phosphorus of 63.51 mgkg 1 soil was obtained for Cretaceous sediment soils and 158.54 mgkg 1 soil for the basement complex soils respectively. …

Development Of Functional Indices Of Facility Occurrence Towards The Distribution Of Social Services In Lagos Island Nigeria., Augustus O. Atubi

Confluence Journal Environmental Studies (CJES), Kogi State University, Nigeria

Proper coordination of transport and public facilities provision is vital to any balanced regional development strategy. The central aim of this study, therefore, is to find out what the relationship is between access to the transport network and the provision of functional indices of facility occurrence towards the distribution of social services in Lagos Island, Nigeria. In particular it seeks to find out areas that have below or above average level of facility occurrences relative to the level of accessibility. However, a pair wise correlation matrix of the eleven (11) variables employed in the index construction was carried out. The …

A Geospatial Based Decision Framework For Extending Marssim Regulatory Principles Into The Subsurface, Robert Nathan Stewart

Doctoral Dissertations

The Multi-Agency Radiological Site Survey Investigation Manual (MARSSIM) is a regulatory guidance document regarding compliance evaluation of radiologically contaminated soils and buildings (USNRC, 2000). Compliance is determined by comparing radiological measurements to established limits using a combination of hypothesis testing and scanning measurements. Scanning allows investigators to identify localized pockets of contamination missed during sampling and allows investigators to assess radiological exposure at different spatial scales. Scale is important in radiological dose assessment as regulatory limits can vary with the size of the contaminated area and sites are often evaluated at more than one scale (USNRC, 2000). Unfortunately, scanning is …

Urban Climate And Challenges Of Tropical Cities, B E. Omogbai

Confluence Journal Environmental Studies (CJES), Kogi State University, Nigeria

This study examines the nature of urban climate, features and the challenges on the developing tropical cities in the 21st century. It argues that the use of principles of urban climate would help in providing comfortable living conditions and problem immune working environments for the inhabitants of tropical cities. The findings reveal that owing to poor environmental planning, inadequate geotechnical landscape surveys prior to the development of urban infrastructures, and non-adherence to the principles of urban climate, challenges of landscape degradation, excessive flooding of the built infrastructures, heat-island effects, and collapse of buildings have emerged. Suggested measures to avert these …

Sr-A Ligand And M-Csf Dynamically Regulate Sr-A Expression And Function In Primary Macrophages Via P38 Mapk Activation, Dejan Nikolic, Lindsay Calderon, Liqin Du, Steven R. Post

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Inflammation is characterized by dynamic changes in the expression of cytokines, such as M-CSF, and modifications of lipids and proteins that result in the formation of ligands for Class A Scavenger Receptors (SR-A). These changes are associated with altered SR-A expression in macrophages; however, the intracellular signal pathways involved and the extent to which SR-A ligands regulate SR-A expression are not well defined. To address these questions, SR-A expression and function were examined in resident mouse peritoneal macrophages incubated with M-CSF or the selective SR-A ligand acetylated-LDL (AcLDL).

RESULTS: M-CSF increased SR-A expression and function, and required the specific …

Detecting Changes In Landuse/Cover Of Umuahia, South-Eastern Nigeria Using Remote Sensing And Gis Techniques, Fanan Ujoh, Olarewaju Oluseyi Ifatimehin, Adams Ndalai Baba

Confluence Journal Environmental Studies (CJES), Kogi State University, Nigeria

Since 1991 when it became the capital city of Abia State, Umuahia has undergone tremendous transformation in its land use and land cover due to rapid urbanization. The main materials employed for this study are a land use map (1991) and Landsat ETM+satellite image (2007) of the study area. These, combined with field survey/checks, were brought into a GIS environment using ILWIS 3.2 Academic image classification software to map the land use/land cover and to estimate the rate of urban expansion and loss of rural land at the peri-urban fringes of Umuahia between 1991 and 2007. The study revealed significant …

Formulation And Characterization Of Lipid-Based Drug Delivery System Of Raloxifene-Microemulsion And Self-Microemulsifying Drug Delivery System, Hetal Thakkar, Jitesh Nangesh, Mayur Parmar, Divyakant Patel

HPD Articles

BACKGROUND: Raloxifene, a second-generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women is administered orally in the form of a tablet. The absolute bioavailability of the drug is only 2% because of extensive hepatic first-pass metabolism. Lipid-based formulations are reported to reduce the first-pass metabolism by promoting its lymphatic uptake. MATERIALS AND METHODS: In the present investigation, microemulsion and Self-Microemulsifying Drug Delivery System (SMEDDS) formulations of Raloxifene were prepared. The prepared formulations were characterized for drug loading, size, transparency, zeta potential, Transmission Electron Microscopy (TEM) and in vitro intestinal permeability. RESULTS: The results indicated that high …

Gender Participation In The Management Of Tricycle Transport For Youth Empowerment And Sustainable Development In Kano State, Nigeria, Nuratu Muhammed

Confluence Journal Environmental Studies (CJES), Kogi State University, Nigeria

The research examined gender participation in the management of tricycle for youth empowerment and sustainable development in Kano state, Nigeria. Stratified random sampling technique was used to select samples of drivers(150), passengers (150) and owners/managers the female tricycle owners fell under this category and they numbered(65).All together a total of 365 samples were selected for the study. Data obtained from the primary data was analyzed using simple statistical techniques and chi square test to ascertain whether there was any significant differences in some of the variables tested. The results of the analysis revealed that the main difference was found in …

An Exploration Of Pharmacognosy And Its Potential In The Multi-Faceted Solution Required To Address Hiv/Aids In Sub-Saharan Africa, Alexandra Sassi

Pell Scholars and Senior Theses

This work has both both biological and anthropoligcal foci. It addresses research done on the medicinal properties of plants and how this research could make positive contributions to the current social and biological issues surrounding the HIV/AIDS epidemic in sub-Saharan Africa.

Comparison Of Subcellular Responses For The Evaluation And Prediction Of The Chemotherapeutic Response To Cisplatin In Lung Adenocarcinoma Using Raman Spectroscopy, Haq Nawaz, Franck Bonnier, Aidan Meade, Fiona Lyng, Hugh Byrne

Articles

Confocal Raman Micro spectroscopy (CRM) is employed to examine the chemical and physiological effects of anticancer agents, using cisplatin and A549 adenocarcinoma cells as a model compound and test system respectively. Spectral responses of the membrane and cytoplasm of the cell are analysed independently and the results are compared to previously reported spectroscopic studies of the nucleus. Moreover, Raman spectra from the proteins extracted from the control and exposed samples are acquired and analysed to confirm the origin of the molecular changes of the cell membrane and cytoplasm of the A549 cells. Multivariate data analysis techniques including Principal Component Analysis …

Environmental Problems Of Industrialization And Sustainable Development In Nigeria - A Review, Adejoh Iyaji

Confluence Journal Environmental Studies (CJES), Kogi State University, Nigeria

The main objective of this paper is to examine the impact of the quest for industrialization on the environment in Nigeria; others include, the identification of the objectives of sustainable development as well as making recommendations that will lead to the much needed sustainable environment both for the present generation and generations yet unborn. The researcher relied principally on secondary sources of data for this paper which is theoretical in approach. Findings revealed the emergence of a host of environmental problems such as air pollution, deforestation, desertification, solid and hazardous waste problems in the wake of the quest for industrialization. …

Eschar-Associated Spotted Fever Rickettsiosis, Bahia, Brazil, Nanci Silva, Marina Eremeeva, Tatiana Rozental, Guilherme S. Ribeiro, Christopher D. Paddock, Eduardo Antonio G. Ramos, Alexsandra R.M. Favacho, Mitermayer G. Reis, Gregory A. Dasch,, Elba R.S. De Lemos, Albert I. Ko

Marina E. Eremeeva

In Brazil, Brazilian spotted fever was once considered the only tick-borne rickettsial disease. We report eschar-associated rickettsial disease that occurred after a tick bite. The etiologic agent is most related to Rickettsia parkeri, R. africae, and R. sibirica and probably widely distributed from São Paulo to Bahia in the Atlantic Forest.

Specific Thiazolidinediones Inhibit Ovarian Cancer Cell Line Proliferation And Cause Cell Cycle Arrest In A Pparγ Independent Manner, Linah Al-Alem, R. Chase Southard, Michael W. Kilgore, Thomas E. Curry

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Peroxisome Proliferator Activated Receptor gamma (PPARγ) agonists, such as the thiazolinediones (TZDs), have been studied for their potential use as cancer therapeutic agents. We investigated the effect of four TZDs--Rosiglitazone (Rosi), Ciglitazone (CGZ), Troglitazone (TGZ), and Pioglitazone (Pio)--on ovarian cancer cell proliferation, PPARγ expression and PPAR luciferase reporter activity. We explored whether TZDs act in a PPARγ dependent or independent manner by utilizing molecular approaches to inhibit or overexpress PPARγ activity.

PRINCIPAL FINDINGS: Treatment with CGZ or TGZ for 24 hours decreased proliferation in three ovarian cancer cell lines, Ovcar3, CaOv3, and Skov3, whereas Rosi and Pio had no …

Comparison Of Renal Effects Of Ibuprofen Versus Indomethacin During Treatment Of Patent Ductus Arteriosus In Contiguous Historical Cohorts, Alla Kushnir, Joaquim Mb Pinheiro

Alla Kushnir

No abstract provided.

Spatial Distribution Of Commercial Banks In Ilorin Metropolis, Kwara State, Nigeria, I B. Abdullahi, M A. Ijaiya, A Abdulraheem, R I. Abdulkadir, R O. Ibrahim

Confluence Journal of Environmental Studies (CJES), Kogi State University, Nigeria

The spatial distribution of banks in any geographic entity determines the level of accessibility to its services by the public. This study examined the pattern of banks distribution in Ilorin metropolis. Field survey was employed in determining the number of available commercial banks and their respective distances between each other. The spatial analysis technique such as the nearest neighbour analysis as used ascertain the degree of clustering, density and the average distance taken to access these services. The study revealed that about 96% of the total number of banks are situated in the Central Business District which exhibited a very …

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 …

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.

The Impact Of Tricaine Methanesulfonate, 2-Phenoxyethanol, And Carvone-Methyl Salicylate On The Innate Immune Response Of Zebrafish (Danio Rerio), Charles R. Wulff

Honors Theses

Anesthesia plays a vital role in the maintenance of aquaculture species, where it is used to minimize stress during complex handling tasks such as transport, assessment, and harvesting. However, anesthetics have been shown to suppress the innate immune response, which could impact immunity and increase risk of infection. Tricaine methanesulfonate (MS-222) and 2-Phenoxyethanol (2-PE) represent two of the most commonly used anesthetics in aquaculture, with R-(+)-carvone, in the form of carvone-methyl salicylate (CMS) has recently been proposed as an alternative anesthetic for food fish. These three anesthetics were used to assess the influence of anesthetics on the immune system of …

Emergence Of A Novel Human Ehrlichia-Muris Like Organism In North America – Wisconsin And Minnesota, Bobbi S. Pritt, Lynne M. Sloan, Diep K. Hoang-Johnson, Ulrike G. Munderloh, Susan M. Paskewitz, Kristina M. Mcelroy, Jevon D. Mcfadden, Matthew J. Binnicker, David F. Neitzel, Gongping Liu, William L. Nicholson, Curtis M. Nelson, Joni J. Franson, Scott A. Martin, Scott A. Cunningham, Christopher R. Steward, Kay Bogumill, Mary E. Bjorgaard, Jeffrey P. Davis, Jennifer H. Mcquiston, David M. Warshauer, Mark P. Wilhelm, Robin Patel, Vipul A. Trivedi, Marina Eremeeva

Marina E. Eremeeva

Background: Ehrlichiosis is a clinically important, emerging zoonosis. Only Ehrlichia chaffeensis and E. ewingii have been thought to cause ehrlichiosis in humans in the United States. Patients with suspected ehrlichiosis routinely undergo testing to ensure proper diagnosis and to ascertain the cause.

Methods: We used molecular methods, culturing, and serologic testing to diagnose and ascertain the cause of cases of ehrlichiosis.

Results: On testing, four cases of ehrlichiosis in Minnesota or Wisconsin were found not to be from E. chaffeensis or E. ewingii and instead to be caused by a newly discovered ehrlichia species.

All patients had fever, …

Estrogen Sulfotransferase (Sult1e1) Expression And Function In Mcf10a-Series Breast Epithelial Cells: Role As A Modifier Of Breast Carcinogenesis And Regulation By Proliferation State, Jiaqi Fu

Wayne State University Dissertations

Estrogen sulfotransferase (SULT1E1) catalyzes the sulfonation of estrogens, which limits estrogen mitogenicity. TaqMan Gene Expression assays were used to profile the mRNA expression of estrogen receptor (ERα and ERβ) and estrogen metabolism enzymes including cytosolic sulfotransferases (SULT1E1, SULT1A1, SULT2A1, and SULT2B1), steroid sulfatase (STS), aromatase (CYP19), 17β-hydroxysteroid dehydrogenases (17βHSD1 and 2), CYP1B1, and catechol-O-methyltransferase (COMT) in an MCF10A-derived lineage cell culture model for basal-like human breast cancer progression and in ERα-positive luminal MCF7 breast cancer cells. Low levels of ERα and ERβ mRNA were present in MCF10A-derived cell lines. SULT1E1 mRNA was more abundant in confluent relative to subconfluent MCF10A …