Chemicals and Drugs Commons^™

Transplantation Of Thioredoxin-1 Exosomes In A Murine Model Of Hind-Limb Ischemia: A Novel Therapeutic Approach, Shubham Kanake

Honors Scholar Theses

Peripheral artery disease is one of the most prevalent cardiovascular diseases in the United States and worldwide. It is estimated that over 8 million people in the United States are affected with peripheral artery disease, and up to 40% of people over 80 years old may have some degree of the disease. Peripheral artery disease can increase one’s chances for having other cardiovascular co-morbidities such as coronary artery disease, among others. Current interventional strategies are endovascular treatments such as transluminal angioplasty and stenting, or in more advanced cases peripheral artery bypass grafting. Medical interventions focus on managing symptoms and treating …

A Cytotoxic Evaluation Of A Chalcone Derivative Library On A549 Cells, Mary Elaine Kuo

Undergraduate Theses

Chalcones, a precursor to flavonoids, are chemical compounds found naturally in plants. The chalcones’ structure consists of a ketone bridge attached to two aromatic rings. Varying substituents on the aromatic rings allow for different affects, including anti-cancer properties. As a Michael acceptor, chalcones interact with pathways that cause inhibition of the initiation, promotion, and progression of cancer tumors. We have screened 32 compounds for growth inhibition in lung cells that vary the flexibility and confirmation of the 3 carbon bridge between the two aromatic rings as well as the effects of electronic modifications to the aromatic ring. We have found …

Paclitaxel Enhances Oncolytic Potential Of Herpes Simplex Virus Type-1 In Cancer Cells, Misagh Naderi

LSU Master's Theses

Taxanes are spindle poisons that bind to and stabilize microtubules resulting in mitotic arrest. Herpes simplex Typ-1 (HSV-1) virions utilize the microtubular network for intracellular transport during both virus entry and virus egress from infected cells. It has been reported previously that taxanes may synergize with oncolytic herpes simplex viruses in the treatment of experimental prostate and breast tumors in mice. Other reports have indicated that taxanes may inhibit viral replication in infected cells. In this study the previously characterized Oncolytic Herpes Simplex Virus type 1 (OSVP), which was constructed in Kousoulas lab was used in conjugation with paclitaxel (taxol) …

Antibody-Drug Conjugates For Cancer Therapy: Chemistry To Clinical Implications, Nirnoy Dan, Saini Setua, Vivek K. Kashyap, Sheema Khan, Meena Jaggi, Murali M. Yallapu, Subhash C. Chauhan

School of Medicine Publications

Chemotherapy is one of themajor therapeutic options for cancer treatment. Chemotherapy is often associated with a low therapeutic window due to its poor specificity towards tumor cells/tissues. Antibody-drug conjugate (ADC) technology may provide a potentially new therapeutic solution for cancer treatment. ADC technology uses an antibody-mediated delivery of cytotoxic drugs to the tumors in a targeted manner, while sparing normal cells. Such a targeted approach can improve the tumor-to-normal tissue selectivity and specificity in chemotherapy. Considering its importance in cancer treatment, we aim to review recent efforts for the design and development of ADCs. ADCs are mainly composed of an …

Cost-Effectiveness Of Alternative Anticoagulation Strategies For Postoperative Management Of Total Knee Arthroplasty Patients, Savannah R. Smith, Jeffrey Katz, Elena Losina

GW Research Days 2016 - 2020

Background: Anticoagulation is essential for deep vein thrombosis (DVT) and pulmonary embolism (PE) prevention following total knee arthroplasty (TKA). Some research has suggested that longer duration anticoagulation can substantially reduce the risks of DVT and PE; however, in the absence of definitive recommendations, physicians are left weighing the risks of DVT and PE against those of anticoagulation, including gastrointestinal (GI) and central nervous system (CNS) hemorrhage and increased likelihood of prosthetic joint infection (PJI). We conducted a cost-effectiveness analysis to evaluate the benefits and risks of 14- and 35-day therapy with the most commonly prescribed anticoagulants post-TKA.

Background: Anticoagulation is …

Acute Hepatic Failure And Oral Amiodarone, Hani Alhamoud, Sivateja Mandava, Talal Alzahrani

GW Research Days 2016 - 2020

Introduction:

Amiodarone is associated with serious complications such as lung toxicity, thyroid dysfunction, and QT-prolongation. Further, hepatic failure from the intravenous (IV) formulation of amiodarone is described in numerous case reports and case series. Although there are reports of elevated liver enzymes from the oral formulation of amiodarone, to our knowledge, none have definitively identified a case of acute hepatic failure from the oral formulation alone. In this case, we report an instance of acute hepatic failure after increasing the oral amiodarone dosage as well as rapid recovery following cessation of the medication.

Case report:

A 61-year-old male with a …

Cross Talk Between Serum Kisspeptin-Leptin During Assisted Reproduction Techniques, Rehana Rehman, Zehra Jamil, Aqsa Khalid, Syeda Sadia Fatima

Department of Biological & Biomedical Sciences

Background & Objective: Leptin facilitates onset of puberty by impact on hypothalamic Kisspeptin, gonadotropin releasing hormone, follicle stimulating and luteinizing hormone. The link of peripheral Leptin-Kisspeptin in regulating the ovarian and endometrial tissue in relation to adiposity is unknown. Therefore, we wanted to identify Kisspeptin-Leptin association with body mass index (BMI) and success of assisted reproductive treatments (ART) in infertile females.
Methods: A cross sectional study was carried from August 2014 till May 2016 after receiving ethical approval at Australian Concept Infertility Medical Centre, and Aga Khan University. The study group comprised of females with an age range …

Chemiluminescent Agents For In Vivo Imaging, Jian Cao

Chemistry Theses and Dissertations

Chemiluminescence is the light production directly from a highly exothermic chemical reaction by generating electronically excited species, and the light will be generated upon relaxation to the ground state. We utilize this light as the readout to construct imaging agents for reactive species. Chemiluminescence as an imaging modality has many advantages compared with current widely used imaging modalities, such as fluorescence and bioluminescence. The main advantages are the elimination of extraneous light excitation or genetic modification, which are required for fluorescence and bioluminescence imaging. Therefore, chemiluminescence as a imaging modality holds great potential for in vivo imaging.

In this dissertation, …

Aging Exacerbates Development Of Cerebral Microbleeds In A Mouse Model, Rachita K. Sumbria, Mher Mahoney Grigoryan, Vitaly Vasilevko, Annlia Paganini-Hill, Kelley Kilday, Ronald Kim, David H. Cribbs, Mark J. Fisher

Pharmacy Faculty Articles and Research

Background: Cerebral microhemorrhages (CMH) are commonly found in the aging brain. CMH are also the neuropathological substrate of cerebral microbleeds (CMB), demonstrated on brain MRI. Recent studies demonstrate the importance of systemic inflammation in CMH development, but the relationships among inflammation, aging, and CMH development are not well-defined. In the current study, we hypothesized that the pathogenesis of inflammation-induced CMH in mice differs by age.

Methods: We studied young (3 months, n = 20) and old (18 months, n = 25) C57BL/6 mice injected with low-dose lipopolysaccharide (LPS; 1 mg/kg, i.p.) or saline at 0, 6, and 24 …

Studies Of Amino Acid Mutations In Drug Resistance Of The Smo Protein, Eunice Wintona

UNO Student Research and Creative Activity Fair

Smoothened receptor (SMO) is a protein that in humans, is encoded by the SMO gene. A systemic mutation in its binding pocket helps predict the sensitivity of mutant proteins to different drugs. Known as a GPCR-like receptor, it is a component of the hedgehog signaling pathway; a pathway involved in body patterning and the regulation of adult stem cells. An uncontrolled or inappropriate activation of the Hedgehog pathway drives tumor progression in cancers and a number of birth defects. To achieve these goals, the molecular modeling software MOE was used to build small molecules and drug molecules like Vismodegib and …

A Lin28b Tumor-Specific Transcript In Cancer, Weijie Guo, Zhixiang Hu, Yichao Bao, Yuchen Li, Shengli Li, Qiupeng Zheng, Dongbin Lyu, Di Chen, Tao Yu, Yan Li, Xiaodong Zhu, Jie Ding, Yingjun Zhao, Xianghuo He, Shenglin Huang

Markey Cancer Center Faculty Publications

The diversity and complexity of the cancer transcriptome may contain transcripts unique to the tumor environment. Here, we report a LIN28B variant, LIN28B-TST, which is specifically expressed in hepatocellular carcinoma (HCC) and many other cancer types. Expression of LIN28B-TST is associated with significantly poor prognosis in HCC patients. LIN28B-TST initiates from a de novo alternative transcription initiation site that harbors a strong promoter regulated by NFYA but not c-Myc. Demethylation of the LIN28B-TST promoter might be a prerequisite for its transcription and transcriptional regulation. LIN28B-TST encodes a protein isoform with additional N-terminal amino acids and is critical for cancer …

Relationship Between The Dimerization Of Thyroglobulin And Its Ability To Form Triiodothyronine, Cintia E. Citterio, Yoshiaki Morishita, Nada Dakka, Balaji Veluswamy, Peter Arvan

Pharmacy Faculty Articles and Research

Thyroglobulin (TG) is the most abundant thyroid gland protein, a dimeric iodoglycoprotein (660 kDa). TG serves as the protein precursor in the synthesis of thyroid hormones tetraiodothyronine (T₄) and triiodothyronine (T₃). The primary site for T₃ synthesis in TG involves an iodotyrosine acceptor at the antepenultimate Tyr residue (at the extreme carboxyl terminus of the protein). The carboxyl-terminal region of TG comprises a cholinesterase-like (ChEL) domain followed by a short unique tail sequence. Despite many studies, the monoiodotyrosine donor residue needed for the coupling reaction to create T₃ at this evolutionarily conserved …

Microrna 1207-3p In Prostate Cancer, Dibash Das

Dissertations, Theses, and Capstone Projects

Prostate cancer (PCa) is the most commonly diagnosed male cancer and the second leading cause of cancer-related death for men in the United States. Understanding the molecular mechanisms involved in progression from the asymptomatic androgen-dependent PCa to the lethal castration resistant prostate cancer (CRPC) is a major challenge. MicroRNAs (miRNAs), are known to be dysregulated in PCa. MicroRNA-1207-3p (miR-1207-3p) is encoded by the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, the role of miR-1207-3p in PCa is unclear. We have discovered that miR-1207-3p is significantly underexpressed in PCa cell lines …

Sustainability And Outcomes Of A Standardized Aminoglycoside Induced Ototoxicity Monitoring Algorithm, Claire Elson, Christopher M. Oermann, Michelle Weltman, Ellen Meier

Posters

No abstract provided.

The Role Of Ceramide In Neutrophil Elastase Induced Inflammation In The Lungs, Sophia Karandashova

Theses and Dissertations

Alterations to sphingolipid metabolism are associated with increased pulmonary inflammation, but the impact of inflammatory mediators, such as neutrophil elastase (NE), on airway sphingolipid homeostasis remains unknown. NE is a protease associated CF lung disease progression, and can be found in up to micromolar concentrations in patient airways. While sphingolipids have been investigated in the context of CF, the focus has been on loss of cystic fibrosis transmembrane conductance regulator (CFTR) function. Here, we present a novel observation: oropharyngeal aspiration of NE increases airway ceramides in mice. Using a previously characterized mouse model of NE-induced inflammation, we demonstrate that NE …

5-Ht2b Receptor-Mediated Cardiac Valvulopathy, Pallavi Nistala

Theses and Dissertations

5-HT_2B receptor agonism causes cardiac valvulopathy, a condition characterized by thickening of the heart valves and as a result, regurgitation of blood within the heart. The anti-obesity drug fenfluramine, which was originally prescribed as an anorectic, was withdrawn from the market due to causing cardiac valvulopathy. Fenfluramine, after metabolism by N-dealkylation, produces the metabolite norfenfluramine, which acts as a more potent valvulopathogen. The same was seen with MDMA (ecstasy), a popular drug of abuse, which is metabolized by N-dealkylation to produce MDA, a more potent valvulopathogen. Glennon and co-workers. studied a series of 2,5-dimethoxy-4- substituted phenylisopropylamines (DOX type) hallucinogens …

Gene Regulation In The Hypothalamic-Pituitary-Gonadal Axis Of The Green Anole Lizard (Anolis Carolinensis)., Joshua N. Peters

All Graduate Theses, Dissertations, and Other Capstone Projects

Studies examining the hypothalamic-pituitary-gonad axis (HPG) in Anolis carolinensis provide insight into the regulation of this axis under extremely different reproductive conditions. Molecular studies indicate that kisspeptin proteins, transcribed from kiss1 and kiss2 genes, are produced in the hypothalamus where they bind G protein-coupled receptor 54 (GPR54), activating the HPG axis. Gonadotropin inhibitory hormone (GnIH) and its receptors, G protein-coupled receptor 147 and 74 (GPR147 and GPR74), down regulate HPG axis function. In this experiment we examined HPG axis gene expression in the green anole lizard (Anolis carolinensis), a seasonally breeding species with higher steroid hormone levels in the breeding …

Medication Education In The Pediatric Rheumatology Clinic, Ashley M. Cooper, Julia G. Harris

Posters

No abstract provided.

Elevated L-Lactate Drives Major Cellular Pathologies Associated With Neurodegeneration, Jessica Behnke

Dissertations, Master's Theses and Master's Reports

Within the past few decades, lactate research has expanded from initial findings deeming lactate as a dead-end metabolic product to recognition of lactate’s role as a potential energy substrate in the CNS. Due to the tight relationship between lactate and energy metabolism, interest in the scientific community has been mounting around associations among metabolic dysregulation, elevated lactate and neurodegenerative states such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, ischemia/reperfusion (AD, PD, ALS, I/R injuries), and physiological aging, however underlying cellular mechanisms and/or facilitators for neuronal degeneration pathologies still remain unknown. Here, we tested several hypotheses that implicate L-lactate to various neurodegenerative …

Medication Timeliness In Emergency Department In Pediatric Sickle Cell Disease Population Presenting With Vaso-Occlusive Episode, Derrick Goubeaux, Kaitlyn Hoch, Gerald Woods, Julie Routhieaux, Maureen Guignon, Valerie Mcdougall Kestner

Posters

No abstract provided.

The Evaluation Of Mefloquine Drug Repurposing On Acute Myeloid Leukemia, Jessica L. Phan, Bhavuk Garg, Hrishikesh Mehta, Seth Corey

UROP Posters

The aim of this study is to observe cell proliferation, cell viability, apoptosis, and autophagy on acute myeloid leukemia (AML) cell lines, NB4 and U937, with the drug repurposing of mefloquine (MQ). Methods such as the 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay and trypan blue staining have shown a decrease in live cells with high concentrations of mefloquine. Using their average perspective IC50 values of MQ concentration, Western blotting was applied by means of apoptosis and autophagy markers to determine if the induction of apoptosis and inhibition of autophagy was present in MQ-treated AML cells. The experiment will be continued with more …

Bromodomain And Extraterminal Domain (Bet) Inhibitor Rvx-208 Ameliorates Periodontal Bone Loss, Nicholas J. Clayton

Theses and Dissertations

Periodontal disease affects 47% of Americans over 30 and is a growing global concern. Current treatments for periodontal disease focus on the mechanical elimination of periodontal biofilms. Very few treatments are available that target the rampant, unregulated host immune response that is ultimately responsible for tissue degradation. BET proteins have been shown to play critical roles in inflammatory gene regulation and are therefore potentially ideal therapeutic targets for treating periodontal disease. RVX-208 is a selective BET-inhibitor with a high affinity for Bromodomain 2 (BD2) as compared to BD1 in BET proteins. Our previous studies have shown that RVX-208 inhibits inflammatory …

Development Of Polyvinylpyrrolidone/Paclitaxel Self-Assemblies For Breast Cancer, Pallabita Chowdhury, Prashanth K.B. Nagesh, Sheema Khan, Bilal B. Hafeez, Subhash C. Chauhan, Meena Jaggi, Murali M. Yallapu

School of Medicine Publications

The goal of this investigation was to develop and demonstrate a polymer/paclitaxel self-assembly (PTX-SA) formulation. Polymer/PTX-SAs were screened based on smaller size of formulation using dynamic light scattering analysis. Additionally, fluorescence microscopy and flow cytometry studies exhibited that polyvinylpyrrolidone (PVP)-based PTX-SAs (PVP/PTX-SAs) had superior cellular internalization capability in MCF7 and MDA-MB-231 breast cancer cells. The optimized PVP/PTX-SAs exhibited less toxicity to human red blood cells indicating a suitable formulation for reducing systemic toxicity. The formation of PVP and PTX self-assemblies was confirmed using fluorescence quenching and transmission electron microscopy which indicated that the PVP/PTX-SAs were spherical in shape with an …

9-Aminoacridine Inhibits Ribosome Biogenesis And Synergizes With Cytotoxic Drugs To Induce Selective Killing Of P53-Deficient Cells, Leonid Anikin, Dimitri G Pestov

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Common cancer treatments target rapidly dividing cells and do not discriminate between cancer and normal host cells. One approach to mitigating negative side‐effects of cancer treatment is to temporarily arrest cell cycle progression and thus protect normal cells during cytotoxic treatments, a concept called cyclotherapy. We recently proposed that transient inhibition of post‐transcriptional steps of ribosome biogenesis (RBG) can be used to selectively arrest p53‐positive host cells and not p53‐null cancer cells. In this study, we investigated whether cytoprotective RBG inhibition can be achieved through small molecule treatment.

Targeting Ribosome Assembly Factors Selectively Protects P53 Positive Cells From Chemotherapeutic Agents, Russell T. Sapio, Anastasiya Nezdyur, Matthew Krevetski, Leonid Anikin, Vincent J. Manna, N. Minkovsky, Dimitri G Pestov

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Many chemotherapeutic agents act in a nondiscriminatory fashion, targeting both cancerous and noncancerous cells in Sphase and Mphase. One approach to reduce the toxic side effects in normal tissue is to exploit the differences in p53 functionality between cancerous and noncancerous cells. For example, activating p53 signaling by nongenotoxic means can transiently arrest noncancerous p53 positive cells in G1 phase and protect them from the cytotoxic effects of chemotherapeutic drugs. However, since most cancerous cells have faulty p53 signaling, they will proceed to cycle, and continue to be affected by the drug. In this study we asked if this G1‐phase …

Serum Amyloid A3 Is A High Density Lipoprotein-Associated Acute-Phase Protein, Lisa R. Tannock, Maria C. De Beer, Ailing Ji, Preetha Shridas, Victoria P. Noffsinger, Laura Den Hartigh, Alan Chait, Frederick C. De Beer, Nancy R. Webb

Internal Medicine Faculty Publications

Serum amyloid A (SAA) is a family of acute-phase reactants. Plasma levels of human SAA1/SAA2 (mouse SAA1.1/2.1) can increase ≥ 1,000-fold during an acute-phase response. Mice, but not humans, express a third relatively understudied SAA isoform, SAA3. We investigated whether mouse SAA3 is an HDL-associated acute-phase SAA. Quantitative RT-PCR with isoform-specific primers indicated that SAA3 and SAA1.1/2.1 are induced similarly in livers (∼2,500-fold vs. ∼6,000-fold, respectively) and fat (∼400-fold vs. ∼100-fold, respectively) of lipopolysaccharide (LPS)-injected mice. In situ hybridization demonstrated that all three SAAs are produced by hepatocytes. All three SAA isoforms were detected in plasma of LPS-injected mice, although …

Novel Therapeutic Approaches For Juvenile Neuronal Ceroid Lipofuscinosis (Cln3), Megan Elizabeth Bosch

Theses & Dissertations

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by autosomal recessive mutations in CLN3. Neuronal loss is thought to occur via glutamate excitotoxicity; however, little is known about neuron-astrocyte glutamate regulation in JNCL. We discovered that Cln3^Δex7/8 astrocytes have significantly lower basal spontaneous Ca²⁺ oscillations and decreased responses to glutamate, indicating a disrupted signaling network. Cln3^Δex7/8 astrocytes also displayed significantly lower basal mitochondrial respiration and ATP production, suggesting impaired metabolic functions. Concurrent with diminished astrocyte metabolism and Ca²⁺ signaling, Cln3^Δex7/8 neurons were hyper-responsive to glutamate stimulation. These studies suggest that CLN3 …

Novel Therapeutic Strategies For Treatment Of Castration-Resistant Prostate Cancer, Matthew A. Ingersoll

Theses & Dissertations

Prostate cancer (PCa) remains the most commonly diagnosed solid tumor and is the third leading cause of cancer-related death in United States men. While androgen deprivation therapy is the current standard-of-care treatment for metastatic PCa, most patients eventually relapse and develop castration-resistant (CR) tumors, for which there is currently no effective treatment. Therefore, synthesis of novel therapeutic agents and identification of alternative target proteins are necessary to improve treatment. Herein, I investigate the efficacy of novel imidazopyridine and statin derivatives as alternative therapeutic compounds. These molecules not only inhibit androgen receptor signaling, but also block activation of the AKT axis, …

Structural Insights Into The Potency Of Sk Channel Positive Modulators, Young-Woo Nam, Razan Orfali, Tingting Liu, Kunqian Yu, Meng Cui, Heike Wulff, Miao Zhang

Pharmacy Faculty Articles and Research

Small-conductance Ca2+-activated K+ (SK) channels play essential roles in the regulation of cellular excitability and have been implicated in neurological and cardiovascular diseases through both animal model studies and human genetic association studies. Over the past two decades, positive modulators of SK channels such as NS309 and 1-EBIO have been developed. Our previous structural studies have identified the binding pocket of 1-EBIO and NS309 that is located at the interface between the channel and calmodulin. In this study, we took advantage of four compounds with potencies varying over three orders of magnitude, including 1-EBIO, NS309, SKS-11 (6-bromo-5-methyl-1H-indole-2,3-dione-3-oxime) and …

Successful Reversal Of Furosemide-Induced Secondary Hyperparathyroidism With Cinacalcet., Tarak Srivastava, Shahryar Jafri, William E. Truog, Judith Sebestyen Vansickle, Winston M. Manimtim, Uri S. Alon

Manuscripts, Articles, Book Chapters and Other Papers

Secondary hyperparathyroidism (SHPT) is a rare complication of furosemide therapy that can occur in patients treated with the loop diuretic for a long period of time. We report a 6-month-old 28-weeks premature infant treated chronically with furosemide for his bronchopulmonary dysplasia, who developed hypocalcemia and severe SHPT, adversely affecting his bones. Discontinuation of the loop diuretic and the addition of supplemental calcium and calcitriol only partially reversed the SHPT, bringing serum parathyroid hormone level down from 553 to 238 pg/mL. After introduction of the calcimimetic Cinacalcet, we observed a sustained normalization of parathyroid hormone concentration at 27 to 63 pg/mL …