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Development Of A Suicide Inhibition-Based Protein Labeling Strategy For Nicotinamide N-Methyltransferase, Sudeshna Sen, Santanu Mondal, Li Zheng, Ari J. Salinger, Walter Fast, Eranthie Weerapana, Paul R. Thompson 2019 University of Massachusetts Medical School

Development Of A Suicide Inhibition-Based Protein Labeling Strategy For Nicotinamide N-Methyltransferase, Sudeshna Sen, Santanu Mondal, Li Zheng, Ari J. Salinger, Walter Fast, Eranthie Weerapana, Paul R. Thompson

University of Massachusetts Medical School Publications

Nicotinamide N-methyltransferase (NNMT) catalyzes the S-adenosyl-l-methionine-dependent methylation of nicotinamide to form N-methylnicotinamide. This enzyme detoxifies xenobiotics and regulates NAD+ biosynthesis. Additionally, NNMT is overexpressed in various cancers. Herein, we describe the first NNMT-targeted suicide substrates. These compounds, which include 4-chloropyridine and 4-chloronicotinamide, exploit the broad substrate scope of NNMT; methylation of the pyridine nitrogen enhances the electrophilicity of the C4 position, thereby promoting an aromatic nucleophilic substitution by C159, a noncatalytic cysteine. On the basis of this activity, we developed a suicide inhibition-based protein labeling strategy using an alkyne-substituted 4-chloropyridine that selectively labels NNMT in vitro and in cells. In ...


Amphiphilic Peptides For Efficient Sirna Delivery, Saghar Mozaffari, Emira Bousoik, Farideh Amirrad, Robert Lamboy, Melissa Coyle, Ryley Hall, Abdulaziz Alasmari, Parvin Mahdipoor, Keykavous Parang, Hamidreza Montazeri Aliabadi 2019 Chapman University

Amphiphilic Peptides For Efficient Sirna Delivery, Saghar Mozaffari, Emira Bousoik, Farideh Amirrad, Robert Lamboy, Melissa Coyle, Ryley Hall, Abdulaziz Alasmari, Parvin Mahdipoor, Keykavous Parang, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

A number of amphiphilic cyclic peptides—[FR]4, [WR]5, and [WK]5—containing hydrophobic and positively-charged amino acids were synthesized by Fmoc/tBu solid-phase peptide methods and evaluated for their efficiency in intracellular delivery of siRNA to triple-negative breast cancer cell lines, MDA-MB-231 and MDA-MB-468, in the presence and absence of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Among the peptides, [WR]5, which contains alternate tryptophan (W) and arginine (R) residues, was found to be the most efficient in the delivery of siRNA by improving the delivery by more than 3-fold when compared to other synthesized cyclic peptides that were not efficient ...


Iron-Containing Nanoparticles For The Treatment Of Chrionic Biofilm Infections In Cystic Fibrosis, Leisha M. A. Martin 2019 University of New Mexico - Main Campus

Iron-Containing Nanoparticles For The Treatment Of Chrionic Biofilm Infections In Cystic Fibrosis, Leisha M. A. Martin

Nanoscience and Microsystems ETDs

Cystic fibrosis (CF) is the most common genetic disease resulting in the morbidity and mortality of Caucasian children and adults worldwide. Due to a genetic mutation resulting in malfunction of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, CF patients produce highly viscous mucus in their respiratory tract. This leads to impairment of the mucociliary clearance of inhaled microbes. In addition to reduced microbial clearance, anoxic environmental conditions in the lungs promote biofilm-mode growth of the pathogenic bacterial species Pseudomonas aeruginosa. Chronic infections of P. aeruginosa begin in early childhood and typically persist until respiratory failure and death result. The ...


Synthesis And Antiproliferative Activities Of Conjugates Of Paclitaxel And Camptothecin With A Cyclic Cell-Penetrating Peptide, Naglaa Salem El-Sayed, Amir Nasrolahi Shirazi, Muhammad Imran Sajid, Shang Eun Park, Keykavous Parang, Rakesh Tiwari 2019 Chapman University

Synthesis And Antiproliferative Activities Of Conjugates Of Paclitaxel And Camptothecin With A Cyclic Cell-Penetrating Peptide, Naglaa Salem El-Sayed, Amir Nasrolahi Shirazi, Muhammad Imran Sajid, Shang Eun Park, Keykavous Parang, Rakesh Tiwari

Pharmacy Faculty Articles and Research

Cell-penetrating peptide [WR]5 has been previously shown to be an efficient molecular transporter for various hydrophilic and hydrophobic molecules. The peptide was synthesized using Fmoc/tBu solid-phase chemistry, and one arginine was replaced with one lysine to enable the conjugation with the anticancer drugs. Paclitaxel (PTX) was functionalized with an esterification reaction at the C20 hydroxyl group of PTX with glutaric anhydride and conjugated with the cyclic peptide [W(WR)4K(bAla)] in DMF to obtain the peptide-drug conjugate PTX1. Furthermore, camptothecin (CPT) was modified at the C(20)-hydroxyl group through the reaction with triphosgene. Then, it was ...


Fluorometholone Modulates Gene Expression Of Ocular Surface Mucins, Jonathan Taniguchi, Ajay Sharma 2019 Chapman University

Fluorometholone Modulates Gene Expression Of Ocular Surface Mucins, Jonathan Taniguchi, Ajay Sharma

Pharmacy Faculty Articles and Research

Purpose

Mucins are vital to keep the ocular surface hydrated. Genes encoding for mucins contain a glucocorticoid response element. The purpose of this study was to evaluate the effect of fluorometholone, a glucocorticoid receptor agonist used in the management of dry eye, on the gene expression of conjunctival and corneal epithelial cell mucins.

Methods

Stratified cultures of human conjunctival and corneal epithelial cells were exposed to 25, 50 and 100 nM of fluorometholone alone or in presence of mifepristone, a glucocorticoid receptor antagonist. The mRNA was isolated from the cells and reverse transcribed to cDNA. The cDNA was used for ...


The Influence Of Diabetes Mellitus On Glucuronidation And Sulphation Of Paracetamol In Patients With Febrile Neutropenia, Anna Stachowiak, Edyta Szałek, Agnieszka Karbownik, Anna Łojko, Joanna Porażka, Iwona Przewoźna, Tomasz Grabowski, Anna Wolc, Edmund Grześkowiak 2019 Medical University of Poznań

The Influence Of Diabetes Mellitus On Glucuronidation And Sulphation Of Paracetamol In Patients With Febrile Neutropenia, Anna Stachowiak, Edyta Szałek, Agnieszka Karbownik, Anna Łojko, Joanna Porażka, Iwona Przewoźna, Tomasz Grabowski, Anna Wolc, Edmund Grześkowiak

Animal Science Publications

Background and Objectives Numerous studies have confirmed the influence of diabetes mellitus on the pharmacokinetics of drugs. Paracetamol (APAP) is an antipyretic that is commonly used in febrile neutropenia (FN) therapy. APAP is chiefly metabolised by glucuronidation and sulphation. This study assessed the influence of diabetes on the pharmacokinetics of paracetamol and its metabolites: glucuronide (APAP-glu) and sulfate (APAP-sulfate) in FN patients.

Methods Patients with FN received single intravenous dose 1000 mg of APAP. The FN patients were allocated to one of two groups: diabetics (DG, n = 7) or non-diabetics (NDG, n = 11). The plasma concentrations of paracetamol and its ...


Meta-Analysis To Identify And Evaluate Factors Associated With Regulatory Approval Of Orphan Drugs (Od) To Develop An Algorithm For Predicting Regulatory Approval (Success) And To Develop A Standardized Tool To Improve Orphan Drug Portfolio Decision-Making, Milky C. Florent 2019 Seton Hall University

Meta-Analysis To Identify And Evaluate Factors Associated With Regulatory Approval Of Orphan Drugs (Od) To Develop An Algorithm For Predicting Regulatory Approval (Success) And To Develop A Standardized Tool To Improve Orphan Drug Portfolio Decision-Making, Milky C. Florent

Seton Hall University Dissertations and Theses (ETDs)

Background and Purpose of the Study: Developed an algorithm (AODI) for predicting probability of regulatory success (PRS) for new orphan drugs after phase II testing has been conductedwith the objective of providing a tool to improve drug portfolio decision-making.Methods: Examined 132 studies from recent publications (2005 onwards). Data on safety, efficacy, operational, market, and company characteristics were obtained from public sources. Meta-analysis and meta-regressions were used to provide an unbiased approach to assess overall predictability and to identify the most important individual predictors.Results: Found that a simple three-factor model (disease prevalence, clinical trial duration and clinical trial participation ...


Small Peptide Ligands For Targeting Egfr In Triple Negative Breast Cancer Cells, Hanieh Hossein-Nejad-Ariani, Emad Althagafi, Kamaljit Kaur 2019 Chapman University

Small Peptide Ligands For Targeting Egfr In Triple Negative Breast Cancer Cells, Hanieh Hossein-Nejad-Ariani, Emad Althagafi, Kamaljit Kaur

Pharmacy Faculty Articles and Research

The efficacy of chemotherapy for cancer treatment can be increased by targeted drug delivery to the cancer cells. This is particularly important for triple negative breast cancer (TNBC) for which chemotherapy is a major form of treatment. Here we designed and screened a library of 30 peptides starting with a previously reported epidermal growth factor receptor (EGFR) targeting peptide GE11 (YHWYGYTPQNVI). A direct peptide array-whole cell binding assay, where the peptides are conjugated to a cellulose membrane, was used to identify four peptides with enhanced binding to TNBC cells. Next, the four peptides were synthesized as FITC-labelled soluble peptides to ...


Synthesis Of Novel Library Of Cyanopyrrolidinyl Beta-Amino Alcohols And Matrine Alkaloids, Xiaotian Chen 2019 Rowan University

Synthesis Of Novel Library Of Cyanopyrrolidinyl Beta-Amino Alcohols And Matrine Alkaloids, Xiaotian Chen

Theses and Dissertations

Cyanopyrrolidines and beta-Amino alcohols are molecular scaffolds that are highly found in commercially available drugs. We developed a multi-step synthetic method to form a novel library of compounds as inhibitors that share both scaffolds toward potent and selective diabetes therapeutics. Despite the ease for the synthesis of Cyanopyrrolidines, the difficulty of forming high selective beta-Amino alcohols is challenging. We successfully find the best condition for the preference of highly selective mono-alkylation and double-alkylation products and produce them with high yield.

Matrine is an alkaloid found in plants from the genus Sophora and can produce some pharmacological effects such as anti-cancer ...


Src Family Kinase Inhibitors Block Translation Of Alphavirus Subgenomic Mrnas, Rebecca Broeckel, Sanjay Sarkar, Nicholas A. May, Jennifer Totonchy, Craig N. Kreklywich, Patricia Smith, Lee Graves, Victor R. DeFilippis, Mark T. Heise, Thomas E. Morrison, Nathaniel Moorman, Daniel N. Streblow 2019 Oregon Health and Science University

Src Family Kinase Inhibitors Block Translation Of Alphavirus Subgenomic Mrnas, Rebecca Broeckel, Sanjay Sarkar, Nicholas A. May, Jennifer Totonchy, Craig N. Kreklywich, Patricia Smith, Lee Graves, Victor R. Defilippis, Mark T. Heise, Thomas E. Morrison, Nathaniel Moorman, Daniel N. Streblow

Pharmacy Faculty Articles and Research

Alphaviruses are arthropod-transmitted RNA viruses that can cause arthralgia, myalgia, and encephalitis in humans. Since the role of cellular kinases in alphavirus replication is unknown, we profiled kinetic changes in host kinase abundance and phosphorylation following chikungunya virus (CHIKV) infection of fibroblasts. Based upon the results of this study, we treated CHIKV-infected cells with kinase inhibitors targeting the Src family kinase (SFK)–phosphatidylinositol 3-kinase (PI3K)–AKT–mTORC signaling pathways. Treatment of cells with SFK inhibitors blocked the replication of CHIKV as well as multiple other alphaviruses, including Mayaro virus, O’nyong-nyong virus, Ross River virus, and Venezuelan equine encephalitis virus ...


I3: Isomerization Of Isomer Ions, Krisztián Gabor Torma 2019 University of the Pacific

I3: Isomerization Of Isomer Ions, Krisztián Gabor Torma

University of the Pacific Theses and Dissertations

Photoelectron Photoion Coincidence (PEPICO) spectroscopy is a robust tool for elucidating complex unimolecular dissociation mechanisms and for determining thermochemical and kinetic data of gas-phase ion dissociations with high accuracy. In this work, the dissociative photoionization of two sets of isomeric systems were analyzed with PEPICO: 1) C7H7+ ions of toluene (Tol) and 1,3,5-cycloheptatriene (CHT), and 2) two butyl alcohol isomers, 1-butanol and isobutanol. Threshold dissociative photoionization data on these four molecules of interest were collected on the imaging PEPICO apparatus at the VUV beamline of the Swiss Light Source. Data analysis was aided by ab initio calculations and ...


Development And Characterization Of Ldv Peptide Targeted Nanocarriers For Paclitaxel Delivery: A Comparative Study Of Micelles, Liposomes And Solid Lipid Nanoparticles, Poonam Dattani 2019 University of the Pacific

Development And Characterization Of Ldv Peptide Targeted Nanocarriers For Paclitaxel Delivery: A Comparative Study Of Micelles, Liposomes And Solid Lipid Nanoparticles, Poonam Dattani

University of the Pacific Theses and Dissertations

Nanocarriers have been established as delivery vehicles to target cancer tumors. However, premature drug leakage is one of the major reasons for inefficient drug delivery of nanocarriers to the tumor. Drug diffusion out of the nanocarriers or destabilization of drug loaded nanocarriers by physiological interactions with blood cells, serum proteins, and cell membranes upon systemic administration contribute to premature drug release. In this study, targeted micelles, liposomes and solid lipid nanoparticles (SLNs) of similar composition were prepared and characterized to compare physicochemical characteristics, in vitro stability, in vitro release rates in release media and in vivo performance. Peptide Amphiphiles (PAs ...


Structure-Activity Relationship Studies Of Synthetic Cathinones And Related Agents, Rachel A. Davies 2019 Virginia Commonwealth University

Structure-Activity Relationship Studies Of Synthetic Cathinones And Related Agents, Rachel A. Davies

Theses and Dissertations

Synthetic cathinones and related agents represent an international drug abuse problem, and at the same time an important class of clinically useful compounds. Structure-activity relationship studies are needed to elucidate molecular features underlying the pharmacology of these agents. Illicit methcathinone (i.e., MCAT), the prototype of the synthetic cathinone class, exists as a racemic mixture. Though the differences in potency and target selectivity between the positional and optical isomers of synthetic cathinones and related agents have been demonstrated to have important implications for abuse and therapeutic potential, the two MCAT isomers have never been directly compared at their molecular targets ...


Intrapulmonary Inoculation Of Multicellular Tumor Spheroids To Construct An Orthotopic Lung Cancer Xenograft Model That Mimics Four Clinical Stages Of Non-Small Cell Lung Cancer, Yingbo Huang 2019 University of the Pacific

Intrapulmonary Inoculation Of Multicellular Tumor Spheroids To Construct An Orthotopic Lung Cancer Xenograft Model That Mimics Four Clinical Stages Of Non-Small Cell Lung Cancer, Yingbo Huang

University of the Pacific Theses and Dissertations

Lung cancer leads in mortality among all types of cancer in the US and Non-small cell lung cancer (NSCLC) is the major type of lung cancer. Immuno-compromised mice bearing xenografts of human lung cancer cells represent the most common animal models for studying lung cancer biology and for evaluating potential anticancer agents. However, orthotopic lung cancer models based on intrapulmonary injection of suspended cancer cells feature premature leakage of the cancer cells to both sides of the lung within five days, which generates a quick artifact of metastasis and thus belies the development and progression of lung cancer as seen ...


The Development Of Novel Proteasome Inhibitors For The Treatment Of Multiple Myeloma And Alzheimer’S Disease, Min Jae Lee 2019 University of Kentucky

The Development Of Novel Proteasome Inhibitors For The Treatment Of Multiple Myeloma And Alzheimer’S Disease, Min Jae Lee

Theses and Dissertations--Pharmacy

Over a decade, proteasome inhibitors (PIs), bortezomib, carfilzomib (Cfz) and ixazomib, have contributed to a significant improvement in the overall survival for multiple myeloma (MM) patients. However, the response rate of PI was fairly low, leaving a huge gap in MM patient care. Given this, mechanistic understanding of PI resistance is crucial towards developing new therapeutic strategies for refractory/relapsed MM patients.

In this dissertation work, we found H727 human bronchial carcinoid cells are inherently resistant to Cfz, yet susceptible to other PIs and inhibitors targeting upstream components of the ubiquitin-proteasome system (UPS). It indicated H727 cells may serve as ...


Development Of A New Class Of Ligand-Targeted Chemotherapeutics With Enhanced Safety And Efficacy Profile, Arindom Pal 2019 University of the Pacific

Development Of A New Class Of Ligand-Targeted Chemotherapeutics With Enhanced Safety And Efficacy Profile, Arindom Pal

University of the Pacific Theses and Dissertations

The hydrophobicity of many chemotherapeutic agents usually results in their nonselective passive distribution into healthy cells and organs causing collateral toxicity. Ligand-targeted drugs (LTDs) are a promising class of targeted anticancer agents. The hydrophilicity of the targeting ligands in LTDs limits its nonselective passive tissue distribution and toxicity to healthy cells. In addition, the small size of LTDs allows for better tumor penetration, especially in the case of solid tumors. However, the short circulation half-life of LTDs, due to their hydrophilicity and small size, remains a significant challenge for achieving their full therapeutic potential. Therefore, extending the circulation half-life of ...


Use Of Clofibrate To Bypass Nuclear Targeting In The Development Of Non-Viral Gene Delivery Systems, Kelsey Blocklinger 2019 University of Iowa

Use Of Clofibrate To Bypass Nuclear Targeting In The Development Of Non-Viral Gene Delivery Systems, Kelsey Blocklinger

Honors Theses at the University of Iowa

Clofibrate is a commercially available chemical that has been found to induce increased cell division in the hepatocytes of rodents. Previous experiments in our lab have investigated the use of clofibrate to bypass the need for nuclear targeting in non-viral gene delivery systems, since the large size of the gene delivery vector limits its ability to enter the nucleus of hepatocytes. We decided to replicate these experiments, with the intention of seeing higher levels of gene expression by using targeted DNA nanoparticles that contained additional targeting for mice hepatocytes. Mice were dosed with corn oil, clofibrate, clofibrate and non-targeted DNA ...


Toward An Enzyme-Coupled, Bioorthogonal Platform For Methyltransferases: Probing The Specificity Of Methionine Adenosyltransferases, Tyler D. Huber 2019 University of Kentucky

Toward An Enzyme-Coupled, Bioorthogonal Platform For Methyltransferases: Probing The Specificity Of Methionine Adenosyltransferases, Tyler D. Huber

Theses and Dissertations--Pharmacy

Methyl group transfer from S-adenosyl-l-methionine (AdoMet) to various substrates including DNA, proteins, and natural products (NPs), is accomplished by methyltransferases (MTs). Analogs of AdoMet, bearing an alternative S-alkyl group can be exploited, in the context of an array of wild-type MT-catalyzed reactions, to differentially alkylate DNA, proteins, and NPs. This technology provides a means to elucidate MT targets by the MT-mediated installation of chemoselective handles from AdoMet analogs to biologically relevant molecules and affords researchers a fresh route to diversify NP scaffolds by permitting the differential alkylation of chemical sites vulnerable to NP MTs that are unreactive to ...


Xflow: An Algorithm For Extracting Ion Chromatograms, Mathew M. Gutierrez, Rob Smith 2019 University of Montana, Missoula

Xflow: An Algorithm For Extracting Ion Chromatograms, Mathew M. Gutierrez, Rob Smith

Graduate Student Theses, Dissertations, & Professional Papers

Abstract: Mass spectrometry is a fundamental tool for modern proteomics. The increasing availability of mass spectrometry data paired with the increasing sensitivity and fidelity of the instruments necessitates new and more potent analytical methods. To that end, we have created and present XFlow, a feature detection algorithm for extracting ion chromatograms from MS1 LC-MS data. XFlow is a parameter-free procedurally agnostic feature detection algorithm that utilizes the latent properties of ion chromatograms to resolve them from the surrounding noise present in MS1 data. XFlow is designed to function on either profile or centroided data across different resolutions and instruments. This ...


Development And Ex Vivo Characterization Of Enteric Coated Chitosan Beads For Crohn’S Disease Management, Craig Mendonca 2018 University of Connecticut

Development And Ex Vivo Characterization Of Enteric Coated Chitosan Beads For Crohn’S Disease Management, Craig Mendonca

University Scholar Projects

Drug delivery is the process of transporting a drug to its site of action. It includes controlled delivery, where the drug is released at the tissue in a regulated manner. Additionally, it includes targeted delivery, where the drug is aimed at a specific tissue or region to avoid unwanted side effects (that would occur if the drug were distributed throughout the body). A cellulose acetate phthalate coated chitosan bead was developed as a formulation for controlled and targeted release of dexamethasone to the ilium and colon. This formulation was determined to be effective in delaying dexamethasone release until the formulation ...


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