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Articles 211 - 240 of 251
Full-Text Articles in Amino Acids, Peptides, and Proteins
Chikungunya Virus Infection Results In Higher And Persistent Viral Replication In Aged Rhesus Macaques Due To Defects In Anti-Viral Immunity, Ilhem Messaoudi, Jennifer Totonchy, Thomas Totonchy, Craig N. Kreklywich, Kristen Haberthur, Laura Springgay, James D. Brien, Michael S. Diamond, Victor R. Defilippis, Daniel N. Streblow
Chikungunya Virus Infection Results In Higher And Persistent Viral Replication In Aged Rhesus Macaques Due To Defects In Anti-Viral Immunity, Ilhem Messaoudi, Jennifer Totonchy, Thomas Totonchy, Craig N. Kreklywich, Kristen Haberthur, Laura Springgay, James D. Brien, Michael S. Diamond, Victor R. Defilippis, Daniel N. Streblow
Pharmacy Faculty Articles and Research
Chikungunya virus (CHIKV) is a re-emerging mosquito-borne Alphavirus that causes a clinical disease involving fever, myalgia, nausea and rash. The distinguishing feature of CHIKV infection is the severe debilitating poly-arthralgia that may persist for several months after viral clearance. Since its re-emergence in 2004, CHIKV has spread from the Indian Ocean region to new locations including metropolitan Europe, Japan, and even the United States. The risk of importing CHIKV to new areas of the world is increasing due to high levels of viremia in infected individuals as well as the recent adaptation of the virus to the mosquito species Aedes …
Aberrant Proliferation In Cxcr7+ Endothelial Cells Via Degradation Of The Retinoblastoma Protein, Jennifer Totonchy, Jessica M. Osborn, Sara Botto, Lisa Clepper, Ashlee V. Moses
Aberrant Proliferation In Cxcr7+ Endothelial Cells Via Degradation Of The Retinoblastoma Protein, Jennifer Totonchy, Jessica M. Osborn, Sara Botto, Lisa Clepper, Ashlee V. Moses
Pharmacy Faculty Articles and Research
Angiogenesis is a critical factor in the growth and dissemination of solid tumors. Indeed, tumor vasculature is abnormal and contributes to the development and spread of malignancies by creating a hostile microenvironment. The alternative SDF-1/CXCL12 receptor, CXCR7, is frequently and specifically expressed in tumor-associated vessels. In this study, we examine the role of endothelium-expressed CXCR7 in tumor vascular dysfunction by specifically examining the contribution of CXCR7 to endothelial cell (EC) proliferation. We demonstrate that CXCR7 expression is sufficient to drive post-confluent growth in EC cultures. Further, we provide a novel mechanism for CXCR7-mediated proliferation via proteasomal degradation of the tumor …
Novel Therapy For Nicotine Addiction In Alcohol Dependent Rats, Bethany Ann Stennett
Novel Therapy For Nicotine Addiction In Alcohol Dependent Rats, Bethany Ann Stennett
UNF Graduate Theses and Dissertations
The co-dependence of nicotine and alcohol addiction occurs at high rates, complicates treatment, and is often associated with significant morbidity and mortality. Treatment options of alcohol and tobacco co-dependence are limited. Currently, there are drugs available for nicotine dependence or alcohol dependence. However, there are no therapeutic drugs available on the market for the co-dependence of nicotine and alcohol. Therefore, and important opportunity of new therapeutic options and drug development has presented itself. NT69L, a non-selective neurotensin (NT) agonist, provides a potential novel therapy for nicotine addiction in alcoholics by interacting with the common neurotransmitter circuits supporting the rewarding process …
Selectivity Of The Ubiquitin-Binding Modules, Simin Rahighi, Ivan Dikic
Selectivity Of The Ubiquitin-Binding Modules, Simin Rahighi, Ivan Dikic
Pharmacy Faculty Articles and Research
Ubiquitin-binding modules are constituents of cellular proteins that mediate the effects of ubiquitylation by making transient, non-covalent interactions with ubiquitin molecules. While some ubiquitin- binding modules bind single ubiquitin moieties, others are selective for specific ubiquitin chains of different linkage types and lengths. In recent years, functions of ubiquitin chains that are polymerized through their Lys or N-terminal Met (i.e. linear chains) residues have been linked to a variety of cellular processes. Selectivity of ubiquitin-binding modules for different ubiquitin chain types appears as a key to the distinct regulatory consequences during protein quality control pathways, receptor endocytosis, gene transcription, signaling …
Synthetic Peptides Derived From The Sequence Of A Lasso Peptide Microcin J25 Show Antibacterial Activity, Rania Soudy, Liru Wang, Kamaljit Kaur
Synthetic Peptides Derived From The Sequence Of A Lasso Peptide Microcin J25 Show Antibacterial Activity, Rania Soudy, Liru Wang, Kamaljit Kaur
Pharmacy Faculty Articles and Research
Microcin J25 (MccJ25) is a plasmid-encoded, ribosomally synthesized antibacterial peptide with a unique lasso structure. The lasso structure, produced with the aid of two processing enzymes, provides exceptional stability to MccJ25. We report the synthesis of six peptides (1–6), derived from the MccJ25 sequence, that are designed to form folded conformation by disulfide bond formation and electrostatic or hydrophobic interactions. Two peptides (1 and 6) display good activity against Salmonella newport, and are the first synthetic derivatives of MccJ25 that are bactericidal. Peptide 1 displays potent activity against several Salmonella strains including two …
N-Myristoylglutamic Acid Derivative Of 3′-Fluoro-3′- Deoxythymidine As An Organogel, Bhupender S. Chhikara, Rakesh Tiwari, Keykavous Parang
N-Myristoylglutamic Acid Derivative Of 3′-Fluoro-3′- Deoxythymidine As An Organogel, Bhupender S. Chhikara, Rakesh Tiwari, Keykavous Parang
Pharmacy Faculty Articles and Research
Designing microbicidal gels of anti-HIV drugs for local application to prevent HIV infection is a subject of major interest. 3′-Fluoro-3′-deoxythymidine (FLT), a nucleoside reverse transcriptase inhibitor (NRTI), was conjugated with a N-myristoylglutamate scaffold. The conjugate showed gelation at 1% (w/w) in different organic solvents, such as toluene, dichloromethane, and chloroform. The gels were opaque and stable at room temperature. The results indicate that myristoyl glutamate derivative of FLT can form an organogel. The gel could have potential application as a topical anti-HIV microbicidal agent.
Melatonin Membrane Receptors In Peripheral Tissues: Distribution And Functions, Radomir M. Slominski, Russel J. Reiter, Natalia Schlabritz-Loutsevich, Rennolds S. Ostrom, Andrzej T. Slominski
Melatonin Membrane Receptors In Peripheral Tissues: Distribution And Functions, Radomir M. Slominski, Russel J. Reiter, Natalia Schlabritz-Loutsevich, Rennolds S. Ostrom, Andrzej T. Slominski
Pharmacy Faculty Articles and Research
Many of melatonin’s actions are mediated through interaction with the G-protein coupled membrane bound melatonin receptors type 1 and type 2 (MT1 and MT2, respectively) or, indirectly with nuclear orphan receptors from the RORα/RZR family. Melatonin also binds to the quinone reductase II enzyme, previously defined the MT3 receptor. Melatonin receptors are widely distributed in the body; herein we summarize their expression and actions in non-neural tissues. Several controversies still exist regarding, for example, whether melatonin binds the RORα/RZR family. Studies of the peripheral distribution of melatonin receptors are important since they are attractive targets for immunomodulation, regulation of endocrine, …
Cytomegalovirus Cc Chemokine Promotes Immune Cell Migration, Jennifer Totonchy, Michael Denton, Craig N. Kreklywich, Takeshi Andoh, Jessica M. Osborn, Daniel Chen, Ilhem Messaoudi, Susan L. Orloff, Daniel N. Streblow
Cytomegalovirus Cc Chemokine Promotes Immune Cell Migration, Jennifer Totonchy, Michael Denton, Craig N. Kreklywich, Takeshi Andoh, Jessica M. Osborn, Daniel Chen, Ilhem Messaoudi, Susan L. Orloff, Daniel N. Streblow
Pharmacy Faculty Articles and Research
Cytomegaloviruses manipulate the host chemokine/receptor axis by altering cellular chemokine expression and by encoding multiple chemokines and chemokine receptors. Similar to human cytomegalovirus (HCMV), rat cytomegalovirus (RCMV) encodes multiple CC chemokine-analogous proteins, including r129 (HCMV UL128 homologue) and r131 (HCMV UL130 and MCMV m129/130 homologues). Although these proteins play a role in CMV entry, their function as chemotactic cytokines remains unknown. In the current study, we examined the role of the RCMV chemokine r129 in promoting cellular migration and in accelerating transplant vascular sclerosis (TVS) in our rat heart transplant model. We determined that r129 protein is released into culture …
A Thousand Tiny Pieces: The Federal Circuit’S Fractured Myriad Ruling, Lessons To Be Learned, And The Way Forward, Jonathan R. K. Stroud
A Thousand Tiny Pieces: The Federal Circuit’S Fractured Myriad Ruling, Lessons To Be Learned, And The Way Forward, Jonathan R. K. Stroud
IP Theory
No abstract provided.
Choreographing The Adenylyl Cyclase Signalosome: Sorting Out The Partners And The Steps, Rennolds S. Ostrom, Amy S. Bogard, Robert Gros
Choreographing The Adenylyl Cyclase Signalosome: Sorting Out The Partners And The Steps, Rennolds S. Ostrom, Amy S. Bogard, Robert Gros
Pharmacy Faculty Articles and Research
Adenylyl cyclases are a ubiquitous family of enzymes and are critical regulators of metabolic and cardiovascular function. Multiple isoforms of the enzyme are expressed in a range of tissues. However, for many processes, the adenylyl cyclase isoforms have been thought of as essentially interchangeable, with their impact more dependent on their common actions to increase intracellular cyclic adenosine monophosphate content regardless of the isoform involved. It has long been appreciated that each subfamily of isoforms demonstrate a specific pattern of “upstream” regulation, i.e., specific patterns of ion dependence (e.g., calcium-dependence) and specific patterns of regulation by kinases (protein kinase A …
Kshv Infection Of Endothelial Cells Manipulates Cxcr7-Mediated Signaling: Implications For Kaposi’S Sarcoma Progression And Intervention, Jennifer Totonchy, Lisa Clepper, Janet Douglas, Liron Pantanowitz, Klaus Fruh, Ashlee V. Moses
Kshv Infection Of Endothelial Cells Manipulates Cxcr7-Mediated Signaling: Implications For Kaposi’S Sarcoma Progression And Intervention, Jennifer Totonchy, Lisa Clepper, Janet Douglas, Liron Pantanowitz, Klaus Fruh, Ashlee V. Moses
Pharmacy Faculty Articles and Research
"CXCR7 was recently characterized as an alternative receptor for the chemokine CXCL12/SDF-1, previously thought to bind and signal exclusively through CXCR4.We recently identified CXCR7 as a key cellular factor in the endothelial cell (EC) dysfunction associated with KSHV infection. CXCL12 signaling is critically associated with tumor growth, angiogenesis and metastasis in several diverse tumors and is one of the most studied chemokine/chemokine receptor interactions in cancer systems. The tumorigenic activity of the CXCL12 signaling axis offers an attractive target for therapeutic intervention in multiple cancers including Kaposi’s Sarcoma (KS). However, most of the research to date was based on the …
Hepatic Immunosuppressive Effects Of Systemically- Administered Novel Dextran-Methylprednisolone Prodrugs With Peptide Linkers In Rats, Imam H. Shaik, Hitesh K. Agarwal, Keykavous Parang, Reza Mehvar
Hepatic Immunosuppressive Effects Of Systemically- Administered Novel Dextran-Methylprednisolone Prodrugs With Peptide Linkers In Rats, Imam H. Shaik, Hitesh K. Agarwal, Keykavous Parang, Reza Mehvar
Pharmacy Faculty Articles and Research
The hepatic immunosuppressive activities of two novel dextran prodrugs of methylprednisolone (MP) containing one (DMP1) or five (DMP5) amino acids as linkers were studied in rats. At various times (02 weeks) after intravenous administration of single 5 mg/kg (MP equivalent) doses of each prodrug or MP succinate (MPS), livers were isolated and immunologically stimulated ex vivo with lipopolysaccharide. The concentrations of tumor necrosis factor (TNF)-a in the outlet perfusate were then quantitated to assess immune response. Additionally, the concentrations of DMP1, DMP5, and/or MP were measured in the liver. MPS, DMP5, or DMP1 injections caused a maximum of 48.9%, 63.5%, …
Simulating Molecular Mechanisms Of The Mdm2-Mediated Regulatory Interactions: A Conformational Selection Model Of The Mdm2 Lid Dynamics, Gennady M. Verkhivker
Simulating Molecular Mechanisms Of The Mdm2-Mediated Regulatory Interactions: A Conformational Selection Model Of The Mdm2 Lid Dynamics, Gennady M. Verkhivker
Mathematics, Physics, and Computer Science Faculty Articles and Research
Diversity and complexity of MDM2 mechanisms govern its principal function as the cellular antagonist of the p53 tumor suppressor. Structural and biophysical studies have demonstrated that MDM2 binding could be regulated by the dynamics of a pseudo-substrate lid motif. However, these experiments and subsequent computational studies have produced conflicting mechanistic models of MDM2 function and dynamics. We propose a unifying conformational selection model that can reconcile experimental findings and reveal a fundamental role of the lid as a dynamic regulator of MDM2-mediated binding. In this work, structure, dynamics and energetics of apo-MDM2 are studied as a function of posttranslational modifications …
Antivirulence Potential Of Tr-700 And Clindamycin On Clinical Isolates Of Staphylococcus Aureus Producing Phenol-Soluble Modulins, Jason Yamaki, Timothy Synold, Annie Wong-Beringer
Antivirulence Potential Of Tr-700 And Clindamycin On Clinical Isolates Of Staphylococcus Aureus Producing Phenol-Soluble Modulins, Jason Yamaki, Timothy Synold, Annie Wong-Beringer
Pharmacy Faculty Articles and Research
Staphylococcus aureus strains (n = 50) causing complicated skin and skin structure infections produced various levels of phenol-soluble modulin alpha-type (PSMα) peptides; some produced more than twice that produced by the control strain (LAC USA300). TR-700 (oxazolidinone) and clindamycin strongly inhibited PSM production at one-half the MIC but exhibited weak to modest induction at one-fourth and one-eighth the MICs, primarily in low producers. Adequate dosing of these agents is emphasized to minimize the potential for paradoxical induction of virulence.
Thiazolyl N-Benzyl-Substituted Acetamide Derivatives: Synthesis, Src Kinase Inhibitory And Anticancer Activities, Asal Fallah-Tafti, Alireza Foroumadi, Rakesh Tiwari, Amir Nasrolahi Shirazi, David G. Hangauer, Yahao Bu, Tahmineh Akbarzadeh, Keykavous Parang, Abbas Shafiee
Thiazolyl N-Benzyl-Substituted Acetamide Derivatives: Synthesis, Src Kinase Inhibitory And Anticancer Activities, Asal Fallah-Tafti, Alireza Foroumadi, Rakesh Tiwari, Amir Nasrolahi Shirazi, David G. Hangauer, Yahao Bu, Tahmineh Akbarzadeh, Keykavous Parang, Abbas Shafiee
Pharmacy Faculty Articles and Research
KX2-391 (KX-01/Kinex Pharmaceuticals), N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide, is a highly selective Src substrate binding site inhibitor. To understand better the role of pyridine ring and N-benzylsubstitution in KX2-391 and establish the structure-activity relationship, a number of N-benzyl substituted (2-morpholinoethoxy)phenyl)thiazol-4-yl)acetamide derivatives containing thiazole instead of pyridine were synthesized and evaluated for Src kinase inhibitory activities. The unsubstituted N-benzyl derivative (8a) showed the inhibition of c-Src kinase with GI50 values of 1.34 μM and 2.30 M in NIH3T3/c-Src527F and SYF/c-Src527F cells, respectively. All the synthesized compounds were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29), breast carcinoma (BT-20), and leukemia (CCRF-CEM) cells. …
Fatty Acyl Amide Dderivatives Of Doxorubicin: Synthesis And In Vitro Anticancer Activities, Bhupender S. Chhikara, Nicole St. Jean, Deendayal Mandal, Anil Kumar, Keykavous Parang
Fatty Acyl Amide Dderivatives Of Doxorubicin: Synthesis And In Vitro Anticancer Activities, Bhupender S. Chhikara, Nicole St. Jean, Deendayal Mandal, Anil Kumar, Keykavous Parang
Pharmacy Faculty Articles and Research
Doxorubicin is an anticancer drug extensively used in anticancer therapy. Doxorubicin is highly hydrophilic, has short half-life, and its use is associated with severe side effects at high doses. Fatty acyl amide derivatives of doxorubicin were synthesized with the expectation to improve the lipophilicity and anticancer activity of the drug. The lipophilicity was enhanced with the increase in chain length of fatty acyl moiety. Conjugation of 4-amino group with fatty acids through an amide bond reduced the anticancer activity in leukemia, breast, ovarian, and colon cancer cell lines, suggesting that the presence of free amino group is required for anticancer …
Impaired M3 And Enhanced M2 Muscarinic Receptor Contractile Function In A Streptozotocin Model Of Mouse Diabetic Urinary Bladder, K. J. Pak, Rennolds S. Ostrom, M. Matsui, F. J. Ehlert
Impaired M3 And Enhanced M2 Muscarinic Receptor Contractile Function In A Streptozotocin Model Of Mouse Diabetic Urinary Bladder, K. J. Pak, Rennolds S. Ostrom, M. Matsui, F. J. Ehlert
Pharmacy Faculty Articles and Research
We investigated the contractile roles of M2 and M3 muscarinic receptors in urinary bladder from streptozotocin-treated mice. Wild-type and M2 muscarinic receptor knockout (M2 KO) mice were given a single injection of vehicle or streptozotocin (125 mg kg−1) 2–24 weeks prior to bladder assays. The effect of forskolin on contractions elicited to the muscarinic agonist, oxotremorine-M, was measured in isolated urinary bladder (intact or denuded of urothelium). Denuded urinary bladder from vehicle-treated wild-type and M2 KO mice exhibited similar contractile responses to oxotremorine-M, when contraction was normalized relative to that elicited by KCl (50 mM). Eight to 9 weeks after …
Hcmv Pus28 Initiates Pro-Migratory Signaling Via Activation Of Pyk2 Kinase, Jennifer Totonchy, Susan Varnum, Ryan Melnychuk, Patricia Smith, Ljiliana Pasa-Tolic, Janani I. Shutthanadan, Daniel N. Streblow
Hcmv Pus28 Initiates Pro-Migratory Signaling Via Activation Of Pyk2 Kinase, Jennifer Totonchy, Susan Varnum, Ryan Melnychuk, Patricia Smith, Ljiliana Pasa-Tolic, Janani I. Shutthanadan, Daniel N. Streblow
Pharmacy Faculty Articles and Research
Background: Human Cytomegalovirus (HCMV) has been implicated in the acceleration of vascular disease and chronic allograft rejection. Recently, the virus has been associated with glioblastoma and other tumors. We have previously shown that the HCMV-encoded chemokine receptor pUS28 mediates smooth muscle cell (SMC) and macrophage motility and this activity has been implicated in the acceleration of vascular disease. pUS28 induced SMC migration involves the activation of the protein tyrosine kinases (PTKs) Src and Focal adhesion kinase as well as the small GTPase RhoA. The PTK Pyk2 has been shown to play a role in cellular migration and formation of cancer, …
Pk/Pd Modelling Of Comb-Shaped Pegylated Salmon Calcitonin Conjugates Of Differing Molecular Weights, Sinead Ryan, Jesus Maria Frias, David H. Haddleton, David J. Brayden
Pk/Pd Modelling Of Comb-Shaped Pegylated Salmon Calcitonin Conjugates Of Differing Molecular Weights, Sinead Ryan, Jesus Maria Frias, David H. Haddleton, David J. Brayden
Articles
Salmon calcitonin (sCT) was conjugated via cysteine-1 to novel combed-shaped end-functionalised poly(PEG) methyl ether methacrylate) (sCT-P) comb-shaped polymers, to yield conjugates of total molecular weights (MW) inclusive of sCT: 6.5, 9.5, 23 and 40 kDa. The conjugates were characterised by HPLC and their in vitro and in vivo bioactivity was measured by cAMP assay on human T47D cells and following intravenous (i.v.) injection to rats, respectively. Stability against endopeptidases, rat serum and liver homogenates was assessed. There were linear and exponential relationships between conjugate MW with potency and efficacy respectively, however the largest MW conjugate still retained 70% of E …
The Proteolytic Stability And Cytotoxicity Studies Of L‐Aspartic Acid And L‐Diaminopropionic Acid Derived Β‐Peptides And A Mixed Α/Β‐Peptide, Sahar Ahmed, Kamaljit Kaur
The Proteolytic Stability And Cytotoxicity Studies Of L‐Aspartic Acid And L‐Diaminopropionic Acid Derived Β‐Peptides And A Mixed Α/Β‐Peptide, Sahar Ahmed, Kamaljit Kaur
Pharmacy Faculty Articles and Research
The use of peptides as drugs in pharmaceutical applications is hindered by their susceptibility to proteolysis and therefore low bioavailability. β‐Peptides that contain an additional methylene group in the backbone, are gaining recognition from a pharmaceutical stand point as they are considerably more resilient to proteolysis and metabolism. Recently, we reported two new classes of β‐peptides, β3‐ and β2‐peptides derived from l‐aspartic acid and l‐diaminopropionic acid, respectively. Here, we report the proteolytic stability of these β‐peptidic compounds and a mixed α /β‐peptide against three enzymes (pronase, trypsin and elastase), as well as, human serum. The …
Human Cytomegalovirus Us28: A Functionally Selective Chemokine Binding Receptor, Jennifer Totonchy, Jay A. Nelson, Daniel N. Streblow
Human Cytomegalovirus Us28: A Functionally Selective Chemokine Binding Receptor, Jennifer Totonchy, Jay A. Nelson, Daniel N. Streblow
Pharmacy Faculty Articles and Research
The Human Cytomegalovirus (HCMV)-encoded chemokine receptor US28 is the most well-characterized of the four chemokine receptor-like molecules found in the HCMV genome. US28 been studied as an important virulence factor for HCMV-mediated vascular disease and, more recently, in models of HCMV-associated malignancy. US28 is a rare multi-chemokine family binding receptor with the ability to bind ligands from two distinct chemokine classes. Ligand binding to US28 activates cell-type and ligand-specific signaling pathways leading to cellular migration, an example receptor functional selectivity. Additionally, US28 has been demonstrated to constitutively activate PLC and NFkB. Understanding the structure/function relationships between US28, its ligands and …
The Guinea Pig Ileum Lacks The Direct, High-Potency, M2-Muscarinic, Contractile Mechanism Of The Mouse Ileum, Michael T. Griffin, Minoru Matsui, Rennolds S. Ostrom, Frederick J. Ehlert
The Guinea Pig Ileum Lacks The Direct, High-Potency, M2-Muscarinic, Contractile Mechanism Of The Mouse Ileum, Michael T. Griffin, Minoru Matsui, Rennolds S. Ostrom, Frederick J. Ehlert
Pharmacy Faculty Articles and Research
We explored whether the M2 muscarinic receptor in the guinea pig ileum elicits a highly potent, direct-contractile response, like that from the M3 muscarinic receptor knockout mouse. First, we characterized the irreversible receptor-blocking activity of 4-DAMP mustard in ileum from muscarinic receptor knockout mice to verify its M3 selectivity. Then, we used 4-DAMP mustard to inactivate M3 responses in the guinea pig ileum to attempt to reveal direct, M2 receptor-mediated contractions. The muscarinic agonist, oxotremorine-M, elicited potent contractions in ileum from wild-type, M2 receptor knockout, and M3 receptor knockout mice characterized by negative log EC50 (pEC50) values ± SEM of …
Rat Cytomegalovirus Infection Depletes Mhc Ii In Bone Marrow Derived Dendritic Cells, Carmen C. Baca Jones, Craig N. Kreklywich, Ilhem Messaoudi, Jennifer Totonchy, Erin Mccartney, Susan L. Orloff, Jay A. Nelson, Daniel N. Streblow
Rat Cytomegalovirus Infection Depletes Mhc Ii In Bone Marrow Derived Dendritic Cells, Carmen C. Baca Jones, Craig N. Kreklywich, Ilhem Messaoudi, Jennifer Totonchy, Erin Mccartney, Susan L. Orloff, Jay A. Nelson, Daniel N. Streblow
Pharmacy Faculty Articles and Research
While cytomegalovirus (CMV) infects and replicates in a multitude of cell types, the ability of the virus to replicate in antigen presenting cells (APCs) is believed to play a critical role in the viral dissemination and latency. CMV infection of APCs and manipulation of their function is an important area of investigation. CMV down regulation of MHC II is reportedly mediated by the HCMV proteins US2, US3, UL83, UL111a (vIL10) or through the induction of cellular IL10. In this study, we demonstrate that rat CMV (RCMV) significantly reduces MHC II expression by mechanisms that do not involve orthologues of the …
Differential Ligand Binding To A Human Cytomegalovirus Chemokine Receptor Determines Cell Type-Specific Motility, Jennifer Totonchy, Ryan Melnychuk, Patricia P. Smith, Joshua Powell, Laurel Hall, Victor R. Defilippis, Klaus Fruh, Martine Smit, David D. Schlaepfer, Jay A. Nelson, Daniel N. Streblow
Differential Ligand Binding To A Human Cytomegalovirus Chemokine Receptor Determines Cell Type-Specific Motility, Jennifer Totonchy, Ryan Melnychuk, Patricia P. Smith, Joshua Powell, Laurel Hall, Victor R. Defilippis, Klaus Fruh, Martine Smit, David D. Schlaepfer, Jay A. Nelson, Daniel N. Streblow
Pharmacy Faculty Articles and Research
While most chemokine receptors fail to cross the chemokine class boundary with respect to the ligands that they bind, the human cytomegalovirus (HCMV)-encoded chemokine receptor US28 binds multiple CC-chemokines and the CX3Cchemokine Fractalkine. US28 binding to CC-chemokines is both necessary and sufficient to induce vascular smooth muscle cell (SMC) migration in response to HCMV infection. However, the function of Fractalkine binding to US28 is unknown. In this report, we demonstrate that Fractalkine binding to US28 not only induces migration of macrophages but also acts to inhibit RANTES-mediated SMC migration. Similarly, RANTES inhibits Fractalkine-mediated US28 migration in macrophages. While US28 binding …
The C1 And C2 Domains Target Human Type 6 Adenylyl Cyclase To Lipid Rafts And Caveolae, Muthusamy Thangavel, Xiaoqiu Liu, Shu Qiang Sun, Joseph Kaminsky, Rennolds S. Ostrom
The C1 And C2 Domains Target Human Type 6 Adenylyl Cyclase To Lipid Rafts And Caveolae, Muthusamy Thangavel, Xiaoqiu Liu, Shu Qiang Sun, Joseph Kaminsky, Rennolds S. Ostrom
Pharmacy Faculty Articles and Research
Previous data has shown that adenylyl cyclase type 6 (AC6) is expressed principally in lipid rafts or caveolae of cardiac myocytes and other cell types while certain other isoforms of AC are excluded from these microdomains. The mechanism by which AC6 is localized to lipid rafts or caveolae is unknown. In this study, we show AC6 is localized in lipid rafts of COS-7 cells (expressing caveolin-1) and in HEK-293 cells or cardiac fibroblasts isolated from caveolin-1 knock-out mice (both of which lack prototypical caveolins). To determine the region of AC6 that confers raft localization, we independently expressed each of the …
Helical Peptides Derived From Lactoferrin Bind Hepatitis C Virus Envelope Protein E2, Reem Beleid, Donna Douglas, Norman Kneteman, Kamaljit Kaur
Helical Peptides Derived From Lactoferrin Bind Hepatitis C Virus Envelope Protein E2, Reem Beleid, Donna Douglas, Norman Kneteman, Kamaljit Kaur
Pharmacy Faculty Articles and Research
Hepatitis C virus is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma infecting more than 170 million people. Hepatitis C virus envelope 2 glycoprotein (E2) binds several cell‐surface molecules that act as receptor candidates mediating hepatitis C virus entry into hepatocytes. Peptides derived from human lactoferrin have been shown to bind hepatitis C virus‐E2 protein thereby preventing hepatitis C virus entry in cultured hepatocytes. In this study, starting from a 33‐residue human lactoferrin‐derived peptide, a number of biotin‐linked α‐peptides were synthesized and investigated for their E2 protein binding activity. E2 protein from hepatitis C virus genotype 1b …
Right-Handed 14-Helix In Β3-Peptides From L-Aspartic Acid Monomers, Kamaljit Kaur, Tara Sprules, Wael Soliman, Reem Beleid, Sahar Ahmed
Right-Handed 14-Helix In Β3-Peptides From L-Aspartic Acid Monomers, Kamaljit Kaur, Tara Sprules, Wael Soliman, Reem Beleid, Sahar Ahmed
Pharmacy Faculty Articles and Research
β-Peptides made from L-aspartic acid monomers form a new class of β3-peptides. Here we report the first three-dimensional NMR solution structure of a β3-hexapeptide (1) from L-aspartic acid monomers in 2,2,2-trifluoroethanol (TFE). We show that 1 forms a right-handed 14-helical structure in TFE. α-peptides from naturally occurring L-amino acids adopt a right-handed α-helix whereas β3-peptides formed from β3-amino acids derived from naturally occurring L-amino acids form left-handed 14-helices. The right-handed 14-helical conformation of 1 is a better mimic of α-peptide conformations. Using the NMR structure of 1 in TFE, we …
Adenylyl Cyclase Type 6 Overexpression Selectively Enhances Ss-Adrenergic And Prostacyclin Receptor Mediated Inhibition Of Rat Cardiac Fibroblast Function Due To Co-Localization In Lipid Rafts, Xiaoqiu Liu, Muthusamy Thangavel, Shu Qiang Sun, Joseph Kaminsky, Penden Mahautmr, Jeremiah Stitham, John Hwa, Rennolds S. Ostrom
Adenylyl Cyclase Type 6 Overexpression Selectively Enhances Ss-Adrenergic And Prostacyclin Receptor Mediated Inhibition Of Rat Cardiac Fibroblast Function Due To Co-Localization In Lipid Rafts, Xiaoqiu Liu, Muthusamy Thangavel, Shu Qiang Sun, Joseph Kaminsky, Penden Mahautmr, Jeremiah Stitham, John Hwa, Rennolds S. Ostrom
Pharmacy Faculty Articles and Research
Cardiac fibroblasts produce and degrade extracellular matrix and are critical in regulating cardiac remodeling and hypertrophy. Fibroblasts are activated by factors such as transforming growth factor β and inhibited by agents that elevate 3′,5′-cyclic adenosine monophosphate (cAMP) levels. cAMP signal generation and response is known to be compartmentalized in many cell types in part through the colocalization of receptors and specific adenylyl cyclase isoforms in lipid rafts and caveolae. The present study sought to define the localization of key G protein-coupled receptors with adenylyl cyclase type 6 (AC6) in lipid rafts of rat cardiac fibroblasts and to determine if this …
The Role Of Multi-Drug Resistance Associated Protein 4 And P-Glycoprotein In Resistance Of Neuroblastoma To Topotecan And Irinotecan, Patricia Kellie Turner
The Role Of Multi-Drug Resistance Associated Protein 4 And P-Glycoprotein In Resistance Of Neuroblastoma To Topotecan And Irinotecan, Patricia Kellie Turner
Theses and Dissertations (ETD)
High-risk neuroblastoma presents a significant therapeutic challenge because the 5-year survival rate remains less than 30% despite the use of surgery, multi-agent chemotherapy, radiation, and autologous bone marrow transplant. Novel therapeutic modalities are under development. The camptothecin analogs topotecan and irinotecan have been identified as successful cytotoxic agents. For topotecan, pharmacokinetically guided dosing to achieve a systemic exposure associated with preclinical anti-tumor activity in neuroblastoma xenograft models is feasible and has elicited favorable responses in children with high-risk neuroblastoma. However, some children with high-risk disease did not respond to the putatively effective topotecan systemic exposure. These children represent a subset …
Methods For The Study Of Signaling Molecules In Membrane Lipid Rafts And Caveolae, Rennolds S. Ostrom, Paul A. Insel
Methods For The Study Of Signaling Molecules In Membrane Lipid Rafts And Caveolae, Rennolds S. Ostrom, Paul A. Insel
Pharmacy Faculty Articles and Research
Lipid rafts and caveolae are cholesterol- and sphingolipid-rich microdomains of the plasma membrane that concentrate components of certain signal transduction pathways. Interest in and exploration of these microdomains has grown in recent years, especially after the discovery of the biochemical marker of caveolae, caveolin, and the recognition that caveolin interacts with many different signaling molecules via its scaffolding domain. There are three major types of caveolins (1, 2, and 3), with some selectivity in their expression in different tissues. Results assessing lipid raft/caveolae co-localization of molecules in signal transduction pathways have provided support for the idea that signaling components are …