Medicinal Chemistry and Pharmaceutics Commons^™

The Effects Of Alcohol On Crash Avoidance Reaction Time In A Driving Simulator Task In Humans, Aishwarya Vasudevan

Wayne State University Theses

AIM 1: Alcohol-impaired driving continues to be a significant cause of car crash injuries and deaths. The blood alcohol concentration (BAC) cut-off level for drunk driving is 0.08% in Michigan, and is estimated that lowering this cut-off to 0.05%would save 500–800 lives every year in the US alone. We used a portable virtual reality (VR)-based driving simulator to demonstrate the effects of alcohol at BAC concentrations 0.02-0.08%, grouped into 0.01% increments, on driving performance, specifically Crash Avoidance Reaction Time (CART), i.e., the time (in msec) required to initiate a steering avoidance response. We found that BAC concentrations as low as …

Small G- Protein Regulators Of Islet Beta Cell Function, Suhadinie Sameera Gamage

Wayne State University Dissertations

Defects in insulin secretion from pancreatic islet beta- cells leads to long term complications such as type 2 diabetes mellitus. The mechanism and regulation of glucose stimulated insulin secretion (GSIS) as well as factors contributing to pancreatic islet beta-cell demise are yet poorly understood. Previous work from our laboratory demonstrated that Ras-related C3 botulinum toxin substrate 1 (Rac1), a small G- protein is involved in GSIS as well as in culminating dysfunction under metabolic stress. Cycling of Rac1 between its inactive and active form is considered a vital event in glucose stimulated insulin secretion. This conversion is made possible by …

The Arsenic Induced Endoplasmic Reticulum Stress Response Via The Activating Transcription Factor 6 In Human Bronchial Epithelial Beas-2b Cells, Priya Wadgaonkar

Wayne State University Dissertations

Arsenic is a well-known human carcinogen associated with a number of cancers, including lung cancers. We have previously shown that long-term exposure to an environmentally relevantconcentration of inorganic arsenic (As3+) leads to the malignant transformation of the BEAS-2B cells, and some of the transformed cells show cancer stem-like features (CSCs) with a significant upregulation of glycolysis and downregulation of mitochondrial oxidative phosphorylation. In the present report, we investigate the short-term effect of As3+ on the endoplasmic reticulum (ER) stress response—the “unfolded protein response (UPR)” and metabolism in human bronchial epithelial cell line BEAS-2B cells. Treatment of the cells with inorganic …

The Effect Of Pioglitazone On Phosphoproteome And Interactome Of Protein Phosphatase 2a In Primary Human Skeletal Muscle Cells, Lana Alghanem

Wayne State University Dissertations

Skeletal muscle insulin resistance is one of the main contributors to Type 2 Diabetes (T2D), which is a chronic disease affecting 37.3 million people in United States (US), with an estimated annual cost exceeding $300 billion in the US. T2D is being treated with a variety of medications, including Pioglitazone (PIO), a potent insulin sensitizer for skeletal muscle. PIO is a synthetic ligand for the peroxisome proliferator-activated receptor (PPAR-γ), nuclear receptors regulating the expression of many genes involved in lipid and glucose metabolism. To date, the molecular action of PIO that sensitizes muscle to insulin is incompletely understood. Protein phosphorylation …

Protein Phosphatase 2a In Metformin’S Action In Primary Human Skeletal Muscle Cells, Aktham H. Mestareehi

Wayne State University Dissertations

Diabetes is a group of metabolic diseases characterized by hyperglycemia caused by defects in insulin secretion, insulin action, or both. Diabetes is associated with damage, dysfunction, and failure of various organs, such as the eyes, heart, kid-neys, and brain. Diabetes is mainly classified into type 1 (T1DM) and type 2 diabetes (T2D). Diabetes affects more than 34 million people in the USA (about 1 in 10) and more than 90% of diabetic patients have type 2 diabetes (T2D). Insulin resistance is a main characteristic feature of type 2 diabetes. Skeletal muscle insulin resistance is con-sidered to be the primary defect …

Targeted Combination Therapy Of Triple-Negative Breast Cancer, Ketki Bhise

Wayne State University Dissertations

TARGETED COMBINATION THERAPY OF TRIPLE-NEGATIVE BREAST CANCERby KETKI BHISE May 2021 Advisor: Dr. Arun Iyer Major: Pharmaceutical Sciences Degree: Doctor of Philosophy Triple Negative Breast Cancer (TNBC) accounts for 10-20% of the total breast carcinoma cases. There is no FDA-approved targeted therapy for TNBC due to lack estrogen, progesterone and HER-2. We have identified the role of a hypoxia biomarker, carbonic anhydrase IX (CAIX) in proliferation and metastasis of TNBC. Based on this observation, we have developed CAIX-targeted Doxorubicin (Dox) prodrug, abbreviated as DoxAtz. To improve the delivery of DoxAtz to the tumor, we developed long circulating liposomes (LipoDoxAtz) and …

Gentamicin-Modified Nanocarriers For Placental Targeted Drug Delivery To Treat Pregnancy-Related Complications, Ali Alfaifi

Wayne State University Dissertations

Diseases of pregnancy are the leading cause of maternal and neonatal morbidity and mortality affecting more than 20% (26 million) of all pregnancies annually. Those diseases include preeclampsia, preterm labor, intrauterine growth restriction and gestational diabetes, many of which are caused by compromised functions of the placenta. Placenta is a specialized organ that is only present during pregnancy where it creates a maternal-fetal interface that is responsible for many functions that contribute to the development of the fetus. Unfortunately, there is currently no treatment for any of those diseases. Our work focuses on the development of a novel nanoplatform that …

Drug Delivery Strategies For The Treatment Of Advanced Lung Cancer And Various Lung Metastases, Elizabeth Bielski

Wayne State University Dissertations

Lung cancer remains the leading cause of cancer-related deaths in the United States. Secondary lung tumors metastasized from other cancer sites also remains highly prevalent, in which most metastatic tumors cannot be cured with existing therapies. Chemoresistance (multi drug resistance – MDR) that develops intrinsically or acquired is one of the key factors leading to fatality in these patients. MDR develops form a variety of resistance mechanisms that can occur consecutively or concurrently, therefore, making most current treatments unsuccessful. Current therapies have known to slow tumor growth, but rarely provide a cure. Immunotherapy has seen some promise, including the use …

Tumor Multicomponent Targeting Polymer-Lipid Hybrid Nanoparticles To Overcome Drug Resistance In Renal Cell Carcinoma, Hashem Obaid Alsaab

Wayne State University Dissertations

Renal Cell Carcinoma (RCC) contributes to more than 90% of the most common form of kidney tumor and remains one of the ten leading causes of cancer death in the United States. Although surgery remains an option for operable tumors, high metastatic index and resistance to radiation and chemotherapies prompted recent development of therapeutics that target the RCC angiogenesis and cell proliferation pathways. Tyrosine kinase inhibitors or TKIs (Cabozantinib, Axitinib, Sorafenib, and Sunitinib) and mammalian target of rapamycin (mTOR) inhibitors (Temsirolimus and Everolimus) have increased the therapeutic options for treating RCC. Although the impact towards decreasing disease progression is encouraging, …

Carbazole Based Multifunctional Dopamine Agonists And Related Molecules As Potential Symptomatic And Disease Modifying Therapeutic Agents For Parkinson’S Disease, Asma S.Mohamed Elmabruk

Wayne State University Dissertations

Parkinson’s disease (PD) is a progressive neurodegenerative disease that develops from gradual depletion of dopamine (DA) and dopaminergic neurons in the substantia nigra pars compacta (SNc) with the accumulation of intraneuronal proteinaceous matter named as Lewy bodies. The four cardinal symptoms associated with PD are tremor, rigidity, bradykinesia, and postural instability. Although the exact mechanism and etiology of PD are not fully understood, several factors have been implicated in the pathogenesis and progression of PD including protein aggregation, oxidative stress, mitochondrial dysfunction, environmental, and genetic factors.

The current therapy of Parkinson’s disease is categorized into four classes: levodopa, DA agonists, …

Discovery Of Piperlongumine Derivatives As Anti-Leukemic And Anti-Prostate Cancer Agents, Yi Liao

Wayne State University Dissertations

Piperlongumine (PL) is an electrophilic anti-cancer natural product. Through non-covalent or covalent interactions with cellular targets, PL inactivates multiple oncogenic pathways and suppresses key components of cellular anti-oxidant/anti-electrophile defense systems. These actions result in pleiotropic anticancer effects and are expected to be effective to heterogeneous acute myeloid leukemia (AML) and prostate cancer (PCa). We applied two approaches to enhance the anticancer potency of PL: 1) To design PL-histone deacetylase inhibitor hybrid drugs (PL-HDACis; e.g., 1-58), and 2) To dimerize PL pharmacophore to generate a dimeric PL (DiPL) warhead that is suitable for further conjugation (e.g., 5-17). Both 1-58 and 5-17 …

Design, Synthesis And Biological Evaluation Of Pyrido[2,3-D]Pyrimidines As Inhibitors Of N5-Cair Synthetase, Qian Lin

Wayne State University Dissertations

The spread of drug-resistant bacterial infections has increased the need for novel antimicrobial agents. One potential but unexplored target is the de novo purine biosynthetic pathway. PurK, found only in bacteria, yeast, and fungi, catalyzes the sixth step in purine biosynthesis and has no human homolog. Herein we disclose the discovery of the first PurK inhibitor with submicromolar potency.

PurK is a member of the ATP-grasp superfamily of enzymes and recently, nanomolar inhibitors of biotin carboxylase, a related enzyme, were published. We hypothesized that those inhibitors, which target the ATP-binding site, could also inhibit PurK. To explore this hypothesis, four …

Approach Towards The Development Of Novel Disease Modifying Therapeutics For Parkinson's Disease, Dan Luo

Wayne State University Dissertations

Parkinson’s disease (PD) is an age-related neurodegenerative disease, which is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of intraneuronal proteinaceous deposits named Lewy bodies (LBs) or Lewy neurites (LNs). A broad spectrum of motor and non-motor symptoms has been observed in PD, with bradykinesia, resting tremor, rigidity, and postural instability as its key clinical features. Although the etiology of PD is still not well-understood, multiple pathological factors including oxidative stress, mitochondrial dysfunction, α-synuclein (αSN) protein aggregation, as well as genetic and environmental aspects are strongly implicated in the disease …

Protein Phosphatase 2a Function And Regulation In Insulin Resistant Human Skeletal Muscle Cells, Shukurat Sulaiman

Wayne State University Theses

Protein Phosphatase 2A (PP2A), a major serine/threonine phosphatase involved in insulin signaling pathway, plays a critical role in the development of insulin resistance and type 2 diabetes (T2D), which is characterized with hyperinsulinemic hyperglycemic condition. Moreover, majority of the glucose disposal takes place in the skeletal muscle which is also the main tissue responsible for insulin resistance. The catalytic subunit of PP2A (PP2Ac) can interact with multiple regulatory subunits and other regulatory proteins as well as substrates. These interactions are important for maintain normal PP2A function and subsequent cell signaling. We hypothesized that hyperinsulinemic hyperglycemic condition and insulin stimulation would …

An Evaluation Of Endocrine Disrupting Effects Of Emerging Contaminants Using Daphnia Pulex And Danio Rerio, Lakshmi Neha Reddy Alla

Wayne State University Theses

The limit of the availability of water is based on two factors, scarcity and quality. Conserving and protecting our water resources one of the most critical issues facing humanity as we struggle to deal with contaminated lakes and rivers and climate change. The main aim of this study is to examine toxicity of known water contaminants on aquatic model organisms and be able to develop methodology that will enable the characterization of endocrine disrupting potential of water samples with unknown contaminants. Both the category of water contaminants known as pharmaceuticals, personal care products that are known as PPCPs and other …

Redox Responsive Cerium Oxide Nanoparticles And Cd44 Targeted Nanomicelles For Selective Cancer Therapy, Zhaoxian Wang

Wayne State University Theses

Redox-responsive cerium oxide nanoparticles (CNPs) can play a versatile role in cancer therapy due to their ability to induce oxidative stress under proper pH conditions. Hyaluronic acid micelles with a high affinity to CD44 receptor which achieved more cytotoxicity towards cancer cells. The polymer-coated CNPs and HA-SMA-TPGS-CDF nanomicelles were developed for cancer therapy. The results showed that the toxicity of CNPs in tumor cells was mediated by the pro-oxidant property of CNPs under relative low pH conditions (pH~6.5) of the tumor microenvironment whereas CNPs play a (cytoprotective) anti-oxidant role, scavenging reactive oxygen species and reducing oxidative stress under normal pH …

Endocrine-Disrupting Properties Of Pharmaceuticals And Personal Care Products (Ppcps): An Evaluation Using Aquatic Model Organisms, Manahil Monshi

Wayne State University Theses

Thousands of chemicals have introduced into the environment as a result of human activity since the industrial revolution, and the U.S. Government Accountability Office has estimated that as many as 1,500 new chemical entities are synthesized each year ("Key Issues: Toxic Chemicals - High Risk Issue," 2017). Many of these chemicals are now found in surface water and ground water and can have detrimental effects on environmental health and on human health. This anthropogenic contamination has resulted in the labeling of the diverse array of chemicals found in water, which are not routinely monitored or regulated, as contaminants of emerging …

The Role Of Line-1 Transposable Element In Methamphetamine Neurotoxicity In The Neurogenic Zones, Dongyue Yu

Wayne State University Theses

Methamphetamine (METH) is a widely abused psychostimulant, which can cause neurotoxicity in the striatum and hippocampus. Several epigenetic changes were identified after binge METH exposure, including histone modification, DNA methylation, and changes in miRNA levels. We have shown that binge METH increases expression and activity of Long INterspersed Element (LINE-1), a transposable element, in doublecortin-positive neurons within rat neurogenic zones [1]. The goal of the present study was to identify which type(s) of cells show increases in LINE-1 following binge METH exposure, and determine whether binge METH-induced increases in LINE-1 are associated with cell death. To achieve this goal, male …

Axonal Transport, Parkin, And Α-Synuclein; Novel Therapeutic Targets To Treat Methamphetamine Neurotoxicity, Bryan Andrew Killinger

Wayne State University Dissertations

Methamphetamine (METH) is a commonly abuse psychostimulant. Exposure to chronic high doses of METH can result in neurotoxicity primarily characterized by damage to striatal dopaminergic (DAergic) axons. There are currently no therapeutic interventions for METH neurotoxicity. To some extent damage to striatal DAergic axons is reversible and DAergic axon function may return following abstinence from METH. The reversible nature of METH neurotoxicity suggests that normal striatal function could be restored following exposure to METH. However, potential targets to treat METH neurotoxicity are needed. Axonal transport is required for restoration of DAergic axon components damaged or lost following METH. Here we …

Underlying Mechanisms Of Arsenic-Induced Tumorigenesis: From Epigenetics To Malignancy, Lingzhi Li

Wayne State University Dissertations

Arsenic is a well-recognized environmental health threat with the capability of inducing a number of human diseases, including cancer. The aim of this dissertation is to unveil the mechanisms underlying the carcinogenic activities of environmental arsenic. The biological functions of arsenic had been studied for decades. However, there are still many questions that remain to be fully answered, such as whether and how arsenic contributes to the epigenetic regulations and migration or metastasis control of the cancer cells. In this regard, we focused our attention on both histone modifications and miRNA regulations in the arsenic-induced malignant transformation of the cells, …

Human Kinome In Skeletal Muscle Insulin Resistance, Yue Qi

Wayne State University Dissertations

Protein kinases play fundamental roles in regulation of biological processes and functions, such as insulin signaling and glucose metabolism. Dysregulation of protein kinases may cause impaired cell signaling and human diseases, such as metabolic syndrome and type 2 diabetes (T2D). Skeletal muscle is the main site responsible for insulin-stimulated glucose disposal, and insulin resistance in skeletal muscle is one of the key features of the pathogenesis of T2D. Therefore, malfunction of protein kinases and their interaction proteins may contribute to the molecular mechanism of insulin resistance in human skeletal muscle. However, no large scale profiling study has been reported to …

Folate Receptor Alpha Targeted Delivery And Characterization Of Polyethyleneimine-Graft-Polycaprolactone-Block-Poly(Ethylene Glycol) Containing Sirna Micelleplexes, Steven Jones

Wayne State University Dissertations

This dissertation focuses on the ability of polyethyleneimine-graft-polycaprolactone-block-poly(ethylene glycol) (PEI-g-PCL-b-PEG-Fol) folate decorated tri-block copolymers ability to deliver a targeted dose of siRNA. The micelleplexes that are formed upon electrostatic interaction with siRNA are used to deliver siRNA in a targeted manner to ovarian cancer cells that over-express Folate Receptor-α (FRα). Each conjugate showed suitable sizes below 200 nm with full siRNA condensation ability. Furthermore, flow cytometry and western blot analysis demonstrated that the best FRα targeted polymer was able to effectively deliver siRNA which resulted in protein knockdown of Toll-like receptor 4 (TLR4). Consequently, TLR4 knock down within SKOV-3 cells …

Transferrin Receptor Targeted Delivery Of Sirna For Gene Therapy, Yuran Xie

Wayne State University Dissertations

Gene therapy is thought to be a solution for various difficult to treat diseases such as cancer. Small interfering RNA (siRNA) as a promising anti-sense molecule can specifically silence disease related gene have been exploit in different diseases. However, lack of safe and efficient siRNA delivery systems limits the application of siRNA therapy in clinic. Transferrin receptor (TfR) is an essential transmembrane receptor involved in iron uptake. TfR universally express in most cells/ tissues but upregulated in certain cells, for example, many cancer cells and activated T cells (ATCs). To overcome the biological barriers and increase siRNA delivery efficiency, in …

Protein Phosphatase 2a Interactions In Islet And Human Skeletal Muscle In Diabetes, Divyasri Damacharla

Wayne State University Dissertations

Type 2 Diabetes is a metabolic disorder associated with insulin resistance and consequent high blood glucose levels. Under normal conditions, in response to high blood glucose levels, pancreatic beta cells produce insulin. The secreted insulin is dis-tributed to tissues thereby stimulating insulin stimulated glucose uptake. However, maximum glucose disposal takes place in skeletal muscle. Thus, studying beta cells and skeletal muscle in respect to diabetes is crucial. Protein Phosphatase 2A (PP2A) is one of the major serine/threonine phosphatases belonging to PhosphoProteinPhospha-tase (PPP) family. It constitutes about 80% of all serine/threonine phosphatases. It is regulated by numerous regulatory subunits as well …

Novel Approaches For Assessment Of Copper Toxicity: Fast Scan Cyclic Voltammetry And Optical Bioassays, Annette R. Tremonti

Wayne State University Dissertations

Anthropogenic activities negatively impact fresh water ecosystems through toxic contaminants that are released into the environment. Copper (Cu) is a water contaminant that is fundamentally persistent once introduced into the environment that has the potential for bioaccumulation. Although Cu toxicity has been studied for decades, there is still a continuing problem with new sources and pathways. New approaches are needed to understand distribution and transport of Cu and its potential for complex biological impacts beyond the simple assessment of lethality. Several novel approaches were used in this research project to advance our understanding of Cu toxicity, including fast scan cyclic …

Design And Synthesis Of Enzalutamide-Isothiocyanate Hybrid Drug As Anti-Prostate Cancer Agent, Siyu Ou

Wayne State University Theses

Isothiocyanate (ITC), such as sulforaphane (SFN), is an active metabolite of dietary glucosinolate from cruciferous vegetables. SFN-rich extracts have been recently tested in recurrent prostate cancer (PCa) patients and notably prolonged PSA doubling time without Grade 3 adverse events. One of the anti-PCa mechanisms of SFN is to inhibit HDAC6, which further triggering androgen receptor (AR) degradation. We have incorporated ITC to the chemical scaffold of enzalutamide (Enz) to create Enz-ITC hybrid molecules with an intention to intracellularly deliver ITC to AR-Hsp90-HDAC6 complex and therefore improving anti-PCa efficacy of both parental drugs. Two Enz-ITCs and one Enz-ITC N-acetyl cysteine (NAC) …

Impact Of Cefazolin Co-Administration With Vancomycin To Reduce Development Of Vancomycin Intermediate Staphylococcus Aureus, Nivedita Birbahadur Singh

Wayne State University Theses

IMPACT OF CEFAZOLIN CO-ADMINISTRATION WITH VANCOMYCIN TO REDUCE DEVELOPMENT OF VANCOMYCIN INTERMEDIATE STAPHYLOCOCCUS AUREUS

by

NIVEDITA B SINGH

August 2106

Advisor: Dr. Michael J. Rybak

Major: Pharmaceutical sciences

Degree: Masters of Science

Objective: Development of resistance in S. aureus has been a big concern in the treatment of infections caused by the organism. The line of therapy used today has a disadvantage of slowly developing cross-resistance for antibiotics such as DAP secondary to prior VAN exposure. Therefore, alternative therapy is needed to prevent the emergence of VAN resistance and cross-resistance to other antibiotics. The primary aim of this experiment is …

Targeted Delivery Of Nrf2 Sirna Using Modular Polymeric Micellar Nanodelivery System For Efficient Target Gene Knockdown In Hepatocellular Carcinoma, Shaimaa Mohamed Ibrahim Yousef

Wayne State University Theses

Tumor selective drug delivery as well as chemotherapy associated multi drug resistance (MDR) pose tremendous hurdles for effective cancer therapy. In this regard, designing multifunctional nanocarriers loaded with drug/gene payloads and engineered with tumor targeting ligands can serve as a modular platform for targeted drug/gene delivery. In this study we undertook the synthesis of a self-assembling block copolymer constructed using poly(styrene-co-maleic anhydride, partial iso-octyl ester) (SMAPIE) and branched polyethylenimine (PEI) as building blocks and evaluated its micelle forming ability, siRNA complexation and siRNA delivery potentials. In addition, we engineered galactosamine decorated nanomicelles using modular “click” chemistry based approaches for evaluating …

Dendrimer-Coated Iron Oxide Theranostic Nanoparticles For Cancer Imaging And Therapy, Duy Khanh Luong

Wayne State University Theses

The bleak prognosis for patients diagnosed with metastatic cancer along with the low therapeutic efficacy and the recurrence of cancer in conventional chemotherapy are prompting clinical medicine to adopt a new strategy to detect cancer in early stage and to deliver the anticancer drugs specifically to tumor site to enhance therapeutic efficiency and minimize side effects. The aim of this study is to design a theranostic nanocarrier consisting of iron oxide nanoparticles (SPIONs) for magnetic resonance imaging (MRI) and Polyamidoamine dendrimers conjugated with folic acid (FA-PAMAM) for active targeted delivery of a highly potent but extremely lipophilic anticancer compound 3,4-difluorobenzylidene …

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 …