Medicinal Chemistry and Pharmaceutics Commons^™

Unique Behavioral And Neurochemical Effects Induced By Repeated Adolescent Consumption Of Caffeine-Mixed Alcohol In C57bl/6 Mice., Meridith T. Robins, Julie Lu, Richard M. Van Rijn

Borch Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

The number of highly caffeinated products has increased dramatically in the past few years. Among these products, highly caffeinated energy drinks are the most heavily advertised and purchased, which has resulted in increased incidences of co-consumption of energy drinks with alcohol. Despite the growing number of adolescents and young adults reporting caffeine-mixed alcohol use, knowledge of the potential consequences associated with co-consumption has been limited to survey-based results and in-laboratory human behavioral testing. Here, we investigate the effect of repeated adolescent (post-natal days P35-61) exposure to caffeine-mixed alcohol in C57BL/6 mice on common drug-related behaviors such as locomotor sensitivity, drug …

High Affinity Block Of Icl,Swell By Thiol-Reactive Small Molecules, Sung H. Park

Theses and Dissertations

Ebselen (Ebs) is considered as a glutathione peroxidase (GPx) mimetic and primarily thought to function by scavenging intracellular reactive oxygen species (ROS). Previous to our work, Deng et al. (2010a) demonstrated complete block of I_Cl,swell with 15 microM Ebs following endothelin-1 (ET-1) induced activation of the current in cardiomyocytes. This block was presumed to take effect mainly via the quenching of ROS. Nonetheless, our work with DI TNC1 astrocytes strongly emphasizes that Ebs might function by an alternative mechanism based on its kinetic profile in blocking I_Cl,swell. Our experiments showed that 45 nM Ebs can fully block …

Exploration Of The Srx-Prx Axis As A Small-Molecule Target, Murli Mishra

Theses and Dissertations--Toxicology and Cancer Biology

Lung cancer is a leading cause of cancer-related mortality irrespective of gender. The Sulfiredoxin (Srx) and Peroxiredoxin (Prx) are a group of thiol-based antioxidant proteins that plays an essential role in non-small cell lung cancer. Understanding the molecular characteristics of the Srx-Prx interaction may help design the strategies for future development of therapeutic tools. Based on existing literature and preliminary data from our lab, we hypothesized that the Srx plays a critical role in lung carcinogenesis and targeting the Srx-Prx axis or Srx alone may facilitate future development of targeted therapeutics for prevention and treatment of lung cancer. First, …

Medical Interns', Residents' And Attending Physicians' Attitudes Towards Integrative Medicine And Recommended Treatments For Patients With Psoriasis, Jennifer L. Pacyon

PCOM Psychology Dissertations

Background: Psoriasis is a multifactorial disease that effect approximately 7.5 million Americans. There are a variety of traditional treatments for psoriasis (e.g. topical medications, biologics) that for many, are effective in combating the disease. However, traditional treatments often have aversive side effects and may not be appropriate for every patient (e.g. pregnant women). Additionally, the efficacy of these medications are variable leaving some looking for adjunctive treatment options. There is increasing evidence to support the use of adjunctive treatments for psoriatic patients (e.g. psychotherapy, mindfulness). However, research is variable in regards to medical professionals’ attitudes towards integrative medicine (IM) as …

Piperlongumine (Piplartine) And Analogues: Antiproliferative Microtubule-Destabilising Agents, Mary J. Meegan, Seema M. Nathwani, Brendan Twamley, Daniela M. Zisterer, Niamh O'Boyle

Articles

Piperlongumine (piplartine, 1) is a small molecule alkaloid that is receiving intense interest due to its antiproliferative and anticancer activities. We investigated the effects of 1 on tubulin and microtubules. Using both an isolated tubulin assay, and a combination of sedimentation and Western blotting, we demonstrated that 1 is a tubulin-destabilising agent. This result was confirmed by immunofluorescence and confocal microscopy, which showed that microtubules in MCF-7 breast cancer cells were depolymerised when treated with 1. We synthesised a number of analogues of 1 to explore structure-activity relationships. Compound 13 had the best cytotoxic profile of this series, …

Mechanisms Of Pancreatic Beta Cell Dysfunction In Diabetes, Vaibhav Sidarala

Wayne State University Dissertations

Diabetes is a serious medical condition characterized by decreased insulin secretion from pancreatic β-cells and decreased insulin sensitivity in the peripheral tissues, resulting in elevated levels of blood glucose. According to the International Diabetes Federation, about 387 million cases have been reported worldwide in the year 2013 and it is estimated that about 500 million people would be affected by 2050. Type 2 diabetes, which accounts for about 90% of the total number of cases, is caused by decreased insulin sensitivity in the peripheral tissues and decreased glucose-stimulated insulin secretion from the pancreatic β-cells. The underlying mechanisms involved in β-cell …

Exploration Of Cancer Proliferative Signaling In Chemotherapy Drug Resistance And Mdig-Induced Tumorigenesis, Kai Wu

Wayne State University Dissertations

ABSTRACT

EXPLORATION OF CANCER PROLIFERATIVE SIGNALING IN CHEMOTHERAPY DRUG RESISTANCE AND MDIG-INDUCED TUMORIGENESIS

by

KAI WU

August 2016

Advisor: Dr. Fei Chen

Major: Pharmaceutical Sciences

Degree: Doctor of Philosophy

Aberrant intracellular signaling pathway is one of the major driving forces of malignancy through multiple stages of human cancers. Our study demonstrates that in cancer cells, the signaling pathways are profoundly and actively intertwined with each other so they can synergistically affect cell biology, including promoting development of malignancy and compensating the loss of proliferation or survival signals in responses to anti-tumor drug. Moreover, cancer cells can also adopt “non-canonical” mechanisms …

The Effectiveness Of A Preoperative Multimodal Antiemetic Regimen On Reducing Early Postoperative Nausea And Vomiting In Total Joint Arthroplasty Patients, Jerry Mosley

Doctoral Projects

Postoperative nausea and vomiting (PONV) occurs frequently in all types of surgeries including after total joint orthopedic procedures. The resulting PONV can lead to many unwanted occurrences including immobilization, distress, and many serious adverse health complications. These unwanted occurrences may then lead to increased cost to the patient and healthcare facility. Administration of a preoperative multimodal regimen known to reduce PONV has the potential to reduce such unwanted anesthetic side effects influencing a reduction in overall healthcare cost. The purpose of this study is to determine the effectiveness of the preoperative kit which includes the administration of metoclopramide, famotidine, ondansetron, …

Street Drug Markets Beyond Favelas In Belo Horizonte, Brazil, Elenice De Souza Oliveira, Braulio Figueiredo Alves Silva, Marcos Oliveira Prates

Department of Justice Studies Faculty Scholarship and Creative Works

This study examines whether social disorganization mechanisms that explain clusters of street drug markets in socially disorganized neighborhoods in developed countries can also help explain geographical patterns of drug dealing across neighborhoods in Belo Horizonte, Brazil. Data for this study includes drug arrests from 2007 to 2011 and socio demographic data from the 2010 Census. To examine the influence of exploratory variables on drug market locations, the Negative Binominal regression model was used at two levels of analysis—the Belo Horizonte city center and other neighborhoods including favelas. The findings show that a high hot spot of street drug markets located …

Normal Glycolytic Enzyme Activity Is Critical For Hypoxia Inducible Factor-1a Activity And Provides Novel Targets For Inhibiting Tumor Growth, Geoffrey Grandjean Phd

Dissertations and Theses (Open Access)

Normal Glycolytic Enzyme Activity is Critical for Hypoxia Inducible Factor-1α Activity and Provides Novel Targets for Inhibiting Tumor Growth

By Geoffrey Grandjean

Advisory Professor: Garth Powis, D. Phil

Unique to proliferating cancer cells is the observation that their increased need for energy is provided by a high rate of glycolysis followed by lactic acid fermentation in a process known as the Warburg Effect, a process many times less efficient than oxidative phosphorylation employed by normal cells to satisfy a similar energy demand ^[1]. This high rate of glycolysis occurs regardless of the concentration of oxygen in the cell and …

Anticancer Activity Of Some Boronic Acid Arylidene Heterocycles, Joy Kim

Honors Theses

This research was done in order to investigate the anticancer activity of boronic acid arylidene heterocycles. Boronic acid, heterocycles, and aryl compounds have all independently exhibited various anti-microbial properties and have shown potential to be used in pharmaceuticals for the treatment of viruses and cancers. Using a one-step protocol developed by Dr. Murray, several different arylheterocyclic compounds were combined with an arylboronic acid to synthesize novel compounds. These were then tested for their anti-cancer activity on glioblastoma brain cancer cells. Although varied in potency, all had some amount of anti-cellular effect on the cancer cells. This is only the start …

Lack Of Resistance Of Plasmodium Falciparum To Dihydroartemisinin In Uganda Based On Parasitogolgical And Molecular Assays, Roland A. Cooper, Melissa D. Conrad, Quentin D. Watson, Stephanie J. Huezo, Harriet Ninsiima, Patrick Tumwebaze, Samuel L. Nsobya, Philip J. Rosenthal

Collected Faculty Scholarship

• Artemisinin-­‐based combination therapy is now standard treatment for falciparum malaria. However, this regimen is threatened by resistance to artemisinins, manifest as delayed clearance of parasitemia after therapy, in southeast Asia.

• Artemisinin resistance in southeast Asia is associated with increased parasitemias in culture, compared to those in sensi0ve parasites, 72 hours a=er a 6 hour pulse with 700 nM dihydroartemisinin (DHA), and with propeller domain polymorphisms in the Plasmodium falciparum kelch (K13; PF3D7_1343700) gene

• Given that artemether/lumefantrine has been adopted as standard therapy for malaria within the last decade in Uganda, we characterized artemisinin sensiBvity in fresh P. falciparum isolates from …

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Mutations In The Plasmodium Falciparum Chloroquine Resistance Transporter, Pfcrt, Enlarge The Parasite's Food Vacuole And Alter Drug Sensitivities, Serena Pulcini, Henry M. Staines, Andrew H. Lee, Sarah H. Shafik, Guillaume Bouyer, Catherine M. Moore, Daniel A. Daley, Matthew J. Hoke, Lindsey M. Altenhofen, Heather J. Painter, Jianbing Mu, David J. P. Ferguson, Manuel Llinas, Rowen E. Martin, David A. Fidock, Roland Cooper, Sanjeev Krishna

Collected Faculty Scholarship

Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, are the major determinant of chloroquine resistance in this lethal human malaria parasite. Here, we describe P. falciparum lines subjected to selection by amantadine or blasticidin that carry PfCRT mutations (C101F or L272F), causing the development of enlarged food vacuoles. These parasites also have increased sensitivity to chloroquine and some other quinoline antimalarials, but exhibit no or minimal change in sensitivity to artemisinins, when compared with parental strains. A transgenic parasite line expressing the L272F variant of PfCRT confirmed this increased chloroquine sensitivity and enlarged food vacuole phenotype. Furthermore, the introduction …

Development Of Polymer Peptide Conjugates For Enhanced Pancreatic Cancer Imaging, Wen Shi

Theses & Dissertations

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US with very poor prognosis. All clinically available biomarkers and diagnostic tools either fail to detect early stage PDAC or suffer from low specificity and sensitivity. There is an urgent need for diagnostic agents with greater efficacy for PDAC detection and staging. Nanomaterials such as N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymers can effectively target tumors, and offer novel opportunities for the development of effective diagnostic agents for cancer. However, a major problem of many nanomaterials-based diagnostics is their opsonization and sequestration by the mononuclear phagocyte system (MPS), leading …

Macrophage Uptake And Cytotoxicity Of Paclitaxel Nanocrystals, Deborah Lee, Emeri Zhang, Wei Gao, Tonglei Li

The Summer Undergraduate Research Fellowship (SURF) Symposium

Effective drug delivery remains one of the most challenging tasks in combatting cancer cells. Anti-cancer drugs such as Paclitaxel (PTX) often struggle in having a high drug effect because they are often phagocytized by macrophages in Reticuloendothelial System (RES) before reaching the cancer cells. To combat this problem, PTX was inserted in a nanocrystal, coated with non-ionic surfactant F68; it is speculated that this formulation will minimize the particle aggregation and decrease the cellular uptake in the RES, which will increase the overall efficacy of the drug in the target areas. The aim of this project was to compare the …

Lack Of Artemisinin Resistance In Plasmodium Falciparum In Uganda Based On Parasitological And Molecular Assays, Roland A. Cooper, Melissa D. Conrad, Quentin D. Watson, Stephanie J. Huezo, Harriet Ninsiima, Patrick Tumwebaze, Samuel L. Nsobya, Philip J. Rosenthal

Collected Faculty Scholarship

We evaluated markers of artemisinin resistance in Plasmodium falciparum isolated in Kampala in 2014. By standard in vitro assays, all isolates were highly sensitive to dihydroartemisinin (DHA). By the ring-stage survival assay, after a 6-h DHA pulse, parasitemia was undetectable in 40 of 43 cultures at 72 h. Two of 53 isolates had nonsynonymous K13-propeller gene polymorphisms but did not have the mutations associated with resistance in Asia. Thus, we did not see evidence for artemisinin resistance in Uganda.

Combating Infectious Diseases In Aquaculture With An Original Probiotic Product, Meagan Hamblin, Saebom Sohn, Christine Ahn Dao, Marta Gomez-Chiarri, David R. Nelson, David Worthen, David Rowley

Senior Honors Projects

Oyster production in Rhode Island accounts for over $2.5 million in annual revenue, making it the top aquaculture product in the state. However, larval tank infections significantly constrain production and create substantial economic losses for commercial hatcheries. In most cases antibiotics may not be used to prevent or treat larval tank infections. A probiotic, or beneficial microbe which competes with pathogens, is a safer and “green” approach to preventing infections. Vibriosis, a common cause of oyster larval mortality, is the result of Vibrio species infections. Previous studies have shown that a native Rhode Island microbe, Bacillus pumilus RI06-95, protects oyster …

Investigating The Bioactive Constituents Of The Edible Blue-Green Alga Spirulina Platensis, Georgette Appiah-Pippim

Honors Scholar Theses

More people die annually from cardiovascular disease than from any other cause. Two risk factors for cardiovascular disease are hyperlipidemia and inflammation. Current drugs that are prescribed to regulate lipid levels often have adverse effects such as liver dysfunction. Blue-green algae (BGA), also known as cyanobacteria, have been consumed for years for their health benefits because they are believed to increase energy and prevent disease. One genus of edible blue-green algae is Spirulina plantesis (SP, Spirulina). Various studies have shown that Spirulina may have anti-cancer and anti-inflammation and anti-bacterial properties. In a previous study, Spirulina platensis lowered triglyceride and cholesterol …

The Impact Of Stress History Of Deformable Dry Granules On The Mechanical Properties Of Tablets, Biplob K Mitra

Open Access Dissertations

A mechanistic understanding of the relationship among the granule composition, individual granule property, downstream robust processing, and the final tablet attributes is critical for rational development of a quality tablet. However, in the dry granulation literature, milled granules that are polydisperse in solid fraction, size, and shape are extensively used for compaction studies. Thus, the effect of an individual granule property or an individual component on the compaction properties of dry granules was not adequately separated. To advance the mechanistic understanding of the effect of dry granulation on tensile strength of tablets, individual granule properties such as size, solid fraction, …

Impact Of Antimalarial Treatment And Chemoprevention On The Drug Sensitivity Of Malaria Parasites Isolated From Ugandan Children, Patrick Tumwebaze, Melissa D. Conrad, Andrew Walakira, Norbert Leclair, Oswald Byaruhanga, Christine Nakazibwe, Benjamin Kozak, Jessica Bloome, Jaffer Okiring, Abel Kakuru, Victor Bigira, James Kapisi, Jennifer Legac, Jiri Gut, Roland A. Cooper, Moses R. Kamya, Diane V. Havlir, Grant Dorsey, Bryan Greenhouse, Samuel L. Nsobya, Philip J. Rosenthal

Collected Faculty Scholarship

Changing treatment practices may be selecting for changes in the drug sensitivity of malaria parasites. We characterized ex vivo drug sensitivity and parasite polymorphisms associated with sensitivity in 459 Plasmodium falciparum samples obtained from subjects enrolled in two clinical trials in Tororo, Uganda, from 2010 to 2013. Sensitivities to chloroquine and monodesethylamodiaquine varied widely; sensitivities to quinine, dihydroartemisinin, lumefantrine, and piperaquine were generally good. Associations between ex vivo drug sensitivity and parasite polymorphisms included decreased chloroquine and monodesethylamodiaquine sensitivity and increased lumefantrine and piperaquine sensitivity with pfcrt 76T, as well as increased lumefantrine sensitivity with pfmdr1 86Y, Y184, and 1246Y. …