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Description
This project details the synthesis and analysis of five analogs of model compound NEt-4IB (6-[ethyl(4-isobutoxy-3-isopropylphenyl)amino]nicotinic acid), that target the retinoid-X-receptor (RXR). These molecules were synthesized by substituting, adding, or removing substituents in the nitrogen-containing ring of NEt-4IB. The parent compound is a RXR partial agonist and has proven to be

This project details the synthesis and analysis of five analogs of model compound NEt-4IB (6-[ethyl(4-isobutoxy-3-isopropylphenyl)amino]nicotinic acid), that target the retinoid-X-receptor (RXR). These molecules were synthesized by substituting, adding, or removing substituents in the nitrogen-containing ring of NEt-4IB. The parent compound is a RXR partial agonist and has proven to be effective in the treatment of type II diabetes without the unwanted side effects seen with full agonists. Many of the current drugs used to treat type II diabetes are accompanied by adverse effects including increased triglyceride levels, weight gain, and hypoglycemia. Biological evaluation with KK-Ay (obese diabetic) model mice indicates that NEt-4IB may even be more effective than current drugs on the market, like pioglitazone. As a result, it is predicted that due to such structural similarity, the analogs synthesized for this work will perform equally, if not better than, NEt-4IB.
ContributorsMaiorella, Emma Lauren (Author) / Wagner, Carl (Thesis director) / Marshall, Pamela (Committee member) / School of Mathematical and Natural Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
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Description
Bexarotene is a commercially produced drug commonly known as Targetin presecribed to treat cutaneous T-cell lymphoma (CTCL). Bex mimics the actions of natural 9-cis retinoic acid in the body, which are derived from Vitamin A in the diet and boost the immune system. Bex has been shown to be effective

Bexarotene is a commercially produced drug commonly known as Targetin presecribed to treat cutaneous T-cell lymphoma (CTCL). Bex mimics the actions of natural 9-cis retinoic acid in the body, which are derived from Vitamin A in the diet and boost the immune system. Bex has been shown to be effective in the treatment of multiple types of cancer, including lung cancer. However, the disadvantages of using Bex include increased instances of hypothyroidism and excessive concentrations of blood triglycerides. If an analog of Bex can be developed which retains high affinity RXR binding similar to the 9-cis retinoic acid while exhibiting less interference for heterodimerization pathways, it would be of great clinical significance in improving the quality of life for patients with CTCL. This thesis will detail the biological profiling of additional novel (Generation Two) analogs, which are currently in submission for publication, as well as that of Generation Three analogs. The results from these studies reveal that specific alterations in the core structure of the Bex "parent" compound structure can have dramatic effects in modifying the biological activity of RXR agonists.
ContributorsYang, Joanna (Author) / Jurutka, Peter (Thesis director) / Wagner, Carl (Committee member) / Hibler, Elizabeth (Committee member) / Barrett, The Honors College (Contributor)
Created2012-05
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Description
Bexarotene (Targretin®) is an FDA approved drug used to treat cutaneous T-cell lymphoma (CTCL), as well as off-label treatments for various cancers and neurodegenerative diseases. Previous research has indicated that bexarotene has a specific affinity for retinoid X receptors (RXR), which allows bexarotene to act as a ligand-activated-transcription factor

Bexarotene (Targretin®) is an FDA approved drug used to treat cutaneous T-cell lymphoma (CTCL), as well as off-label treatments for various cancers and neurodegenerative diseases. Previous research has indicated that bexarotene has a specific affinity for retinoid X receptors (RXR), which allows bexarotene to act as a ligand-activated-transcription factor and in return control cell differentiation and proliferation. Bexarotene targets RXR homodimerization to drive transcription of tumor suppressing genes; however, adverse reactions occur simultaneously when bound to other nuclear receptors. In this study, we used novel bexarotene analogs throughout 5 iterations synthesized in the laboratory of Dr. Wagner to test for their potency and ability to bind RXR. The aim of our study is to quantitatively measure RXR homodimerization driven by bexarotene analogs using a yeast two-hybrid system. Our results suggests there to be several compounds with higher protein activity than bexarotene, particularly in generations 3.0 and 5.0. This higher affinity for RXR homodimers may help scientists identify a compound that will minimize adverse effects and toxicity of bexarotene and serve as a better cancer treatment alternative.
ContributorsSeto, David Hua (Author) / Marshall, Pamela (Thesis director) / Wagner, Carl (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Natural Sciences (Contributor) / School of Social and Behavioral Sciences (Contributor)
Created2015-05
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Description
Diabetes mellitus is a disease characterized by many chronic and acute conditions. With the prevalence and cost quickly increasing, we seek to improve on the current standard of care and create a rapid, label free sensor for glycated albumin (GA) index using electrochemical impedance spectroscopy (EIS). The antibody, anti-HA, was

Diabetes mellitus is a disease characterized by many chronic and acute conditions. With the prevalence and cost quickly increasing, we seek to improve on the current standard of care and create a rapid, label free sensor for glycated albumin (GA) index using electrochemical impedance spectroscopy (EIS). The antibody, anti-HA, was fixed to gold electrodes and a sine wave of sweeping frequencies was induced with a range of HA, GA, and GA with HA concentrations. Each frequency in the impedance sweep was analyzed for highest response and R-squared value. The frequency with both factors optimized is specific for both the antibody-antigen binding interactions with HA and GA and was determined to be 1476 Hz and 1.18 Hz respectively in purified solutions. The correlation slope between the impedance response and concentration for albumin (0 \u2014 5400 mg/dL of albumin) was determined to be 72.28 ohm/ln(mg/dL) with an R-square value of 0.89 with a 2.27 lower limit of detection. The correlation slope between the impedance response and concentration for glycated albumin (0 \u2014 108 mg/dL) was determined to be -876.96 ohm/ln(mg/dL) with an R-squared value of 0.70 with a 0.92 mg/dL lower limit of detection (LLD). The above data confirms that EIS offers a new method of GA detection by providing unique correlation with albumin as well as glycated albumin. The unique frequency response of GA and HA allows for modulation of alternating current signals so that several other markers important in the management of diabetes could be measured with a single sensor. Future work will be necessary to establish multimarker sensing on one electrode.
ContributorsEusebio, Francis Ang (Author) / LaBelle, Jeffrey (Thesis director) / Pizziconi, Vincent (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2014-05
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Description
Currently, the management of diabetes mellitus (DM) involves the monitoring of only blood glucose using self-monitoring blood glucose devices (SMBGs) followed by taking interventional steps, if needed. To increase the amount of information that diabetics can have to base DM care decisions off of, the development of an insulin biosensor

Currently, the management of diabetes mellitus (DM) involves the monitoring of only blood glucose using self-monitoring blood glucose devices (SMBGs) followed by taking interventional steps, if needed. To increase the amount of information that diabetics can have to base DM care decisions off of, the development of an insulin biosensor is explored. Such a biosensor incorporates electrochemical impedance spectroscopy (EIS) to ensure an extremely sensitive platform. Additionally, anti-insulin antibody was immobilized onto the surface of a gold disk working electrode to ensure a highly specific sensing platform as well. EIS measurements were completed with a 5mV sine wave that was swept through the frequency spectrum of 100 kHz to 1 Hz on concentrations of insulin ranging from 0 pM to 100 μM. The frequency at which the interaction between insulin and its antibody was optimized was determined by finding out at which frequency the R2 and slope of the impedance-concentration plot were best. This frequency, otherwise known as the optimal binding frequency, was determined to be 459 Hz. Three separate electrodes were developed and the impedance data for each concentration measured at 459 Hz was averaged and plotted against the LOG (pM insulin) to construct the calibration curve. The response was calculated to be 263.64 ohms/LOG(pM insulin) with an R2 value of 0.89. Additionally, the average RSD was determined to be 19.24% and the LLD was calculated to be 8.47 pM, which is well below the physiological normal range. These results highlight the potential success of developing commercial point-of-care insulin biosensors or multi-marker devices operating with integrated insulin detection.
ContributorsDecke, Zachary William (Author) / LaBelle, Jeffrey (Thesis director) / Pizziconi, Vincent (Committee member) / Cook, Curtiss (Committee member) / Barrett, The Honors College (Contributor) / Harrington Bioengineering Program (Contributor)
Created2013-05
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Description
A point of care glucose sensor using electrochemical impedance spectroscopy (EIS) with a glutaraldehyde-linked enzyme shows promise as an effective biosensor platform. This report details the characterization of various factors on optimal binding frequency (OBF) and sensor performance to better prepare the sensor for future experimentation. Utilizing a screen printed

A point of care glucose sensor using electrochemical impedance spectroscopy (EIS) with a glutaraldehyde-linked enzyme shows promise as an effective biosensor platform. This report details the characterization of various factors on optimal binding frequency (OBF) and sensor performance to better prepare the sensor for future experimentation. Utilizing a screen printed carbon electrode, the necessary amount of glucose oxidase was determined to be 10 mg/mL. Binding time trials ranging from 1-3 minutes demonstrated that 1.5 minutes was the optimal binding time. This timeframe produced the strongest impedance response at each glucose concentration. Using this enzyme concentration and binding time, the native OBF of the biosensor was found to be 1.18 Hz using vector analysis. Temperature testing showed little change in OBF in sensors exposed to 4 \u00B0C through 43.3 \u00B0C. Only exposure to 60 \u00B0C resulted in rapid OBF change which was likely due to glucose oxidase becoming denatured. Humidity tests showed little change in OBF and sensor performance between sensors prepared at the humidities of 7.5%, 10.625% and 16.5% humidity. Alternatively, solutions containing common interference molecules such as uric acid, acetaminophen, and ascorbic acid resulted in a highly shifted OBF and drastically reduced signal.
ContributorsMatloff, Daniel (Co-author) / Khanwalker, Mukund (Co-author) / Johns, Jared (Co-author) / LaBelle, Jeffrey (Thesis director) / Pizziconi, Vincent (Committee member) / Lin, Chi (Committee member) / Dean, W.P. Carey School of Business (Contributor) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-12
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Description
The American Diabetes Association reports that diabetes costs $322 billion annually and affects 29.1 million Americans. The high out-of-pocket cost of managing diabetes can lead to noncompliance causing serious and expensive complications. There is a large market potential for a more cost-effective alternative to the current market standard of screen-printed

The American Diabetes Association reports that diabetes costs $322 billion annually and affects 29.1 million Americans. The high out-of-pocket cost of managing diabetes can lead to noncompliance causing serious and expensive complications. There is a large market potential for a more cost-effective alternative to the current market standard of screen-printed self-monitoring blood glucose (SMBG) strips. Additive manufacturing, specifically 3D printing, is a developing field that is growing in popularity and functionality. 3D printers are now being used in a variety of applications from consumer goods to medical devices. Healthcare delivery will change as the availability of 3D printers expands into patient homes, which will create alternative and more cost-effective methods of monitoring and managing diseases, such as diabetes. 3D printing technology could transform this expensive industry. A 3D printed sensor was designed to have similar dimensions and features to the SMBG strips to comply with current manufacturing standards. To make the sensor electrically active, various conductive filaments were tested and the conductive graphene filament was determined to be the best material for the sensor. Experiments were conducted to determine the optimal print settings for printing this filament onto a mylar substrate, the industry standard. The reagents used include a mixture of a ferricyanide redox mediator and flavin adenine dinucleotide dependent glucose dehydrogenase. With these materials, each sensor only costs $0.40 to print and use. Before testing the 3D printed sensor, a suitable design, voltage range, and redox probe concentration were determined. Experiments demonstrated that this novel 3D printed sensor can accurately correlate current output to glucose concentration. It was verified that the sensor can accurately detect glucose levels from 25 mg/dL to 400 mg/dL, with an R2 correlation value as high as 0.97, which was critical as it covered hypoglycemic to hyperglycemic levels. This demonstrated that a 3D-printed sensor was created that had characteristics that are suitable for clinical use. This will allow diabetics to print their own test strips at home at a much lower cost compared to SMBG strips, which will reduce noncompliance due to the high cost of testing. In the future, this technology could be applied to additional biomarkers to measure and monitor other diseases.
ContributorsAdams, Anngela (Author) / LaBelle, Jeffrey (Thesis advisor) / Pizziconi, Vincent (Committee member) / Abbas, James (Committee member) / Arizona State University (Publisher)
Created2017
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Description

Carbohydrate counting has been shown to improve HbA1c levels for people with diabetes. However, the learning curve and inconvenience of carbohydrate counting make it difficult for patients to adhere to it. A deep learning model is proposed to identify food from an image, where it can help the user manage

Carbohydrate counting has been shown to improve HbA1c levels for people with diabetes. However, the learning curve and inconvenience of carbohydrate counting make it difficult for patients to adhere to it. A deep learning model is proposed to identify food from an image, where it can help the user manage their carbohydrate counting. This early model has a 68.3% accuracy of identifying 101 different food classes. A more refined model in future work could be deployed into a mobile application to identify food the user is about to consume and log it for easier carbohydrate counting.

ContributorsCarreto, Cesar (Author) / Pizziconi, Vincent (Thesis director) / Vernon, Brent (Committee member) / Harrington Bioengineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description

The ever-increasing importance of cancer and neurodegenerative diseases continues to grow as populations across the world are affected by death and aging. The vitamin A (RXR) and vitamin D (VDR) receptor pathways offer promising potential to aid in treatment of cancer and Alzheimer’s disease. This thesis discusses the potential application

The ever-increasing importance of cancer and neurodegenerative diseases continues to grow as populations across the world are affected by death and aging. The vitamin A (RXR) and vitamin D (VDR) receptor pathways offer promising potential to aid in treatment of cancer and Alzheimer’s disease. This thesis discusses the potential application of novel analogs of Bexarotene (RXR agonist), MeTC7 (a new potent VDR antagonist), and vitamin D as possible therapeutics for cancer and Alzheimer’s disease.

ContributorsHong, Jennifer (Author) / Jurutka, Peter (Thesis director) / Wagner, Carl (Committee member) / Marshall, Pamela (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Natural Sciences (Contributor)
Created2023-05
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Description
Bexarotene is a Food and Drug administration (FDA)-approved therapeutic used in the treatment of cutaneous T-cell lymphoma (CTCL). However, bexarotene therapy causes significant side effects like hyperlipidemia and hypothyroidism due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. More

Bexarotene is a Food and Drug administration (FDA)-approved therapeutic used in the treatment of cutaneous T-cell lymphoma (CTCL). However, bexarotene therapy causes significant side effects like hyperlipidemia and hypothyroidism due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. More recently bexarotene has shown promise to reverse neurodegeneration, improve cognition and decrease levels of amyloid- β in transgenic mice expressing familial Alzheimer’s disease (AD) mutations. Bexarotene is a high affinity ligand for the retinoid X receptor (RXR) that heterodimerizes with the liver- X- receptors (LXR) and with peroxisome proliferator-activated receptor-gamma (PPARϒ) to control cholesterol efflux, inflammation, and transcriptionally upregulates the production of apolipoprotein (ApoE) in the brain. Enhanced ApoE expression may promote clearance of soluble Aβ peptides from the brain and reduce Aβ plaques, thus resolving both amyloid pathology and cognitive deficits. The present study assessed the potential of bexarotene and a group of 62 novel rexinoids to bind and activate RXR using a series of biological assays and screening methods, including: 1) a mammalian two-hybrid system (M2H) and an 2) Retinoid X Receptor response element (RXRE)-mediated reporter assays in cultured human cells. Moreover, Liver X Receptor response element (LXRE)-mediated luciferase assays were performed to analyze the ability of the novel analogs to activate LXRE - directed transcription, and to induce ApoE messenger ribonucleic acid (mRNA) in U87 glial cells. Furthermore, the most potent analogs were analyzed via quantitative polymerase chain reaction (qPCR) to determine efficacy in modulating expression of two critical tumor suppressor genes, activating transcription factor 3 (ATF3) and early growth response 3 (EGR3). Results from these multiple assays indicate that the panel of RXR ligands contains compounds with a range of activities, with some analogs capable of binding to RXR with higher affinity than others, and in some cases upregulating ApoE expression to a greater extent than bexarotene. The data suggests that minor modifications to the bexarotene core chemical structure may yield novel analogs possessing an equal or greater capacity to activate RXR and may be useful as therapeutic agents against CTCL and Alzheimer’s disease.
ContributorsReshi, Sabeeha Mushtaq (Author) / Jurutka, Peter (Thesis advisor) / Wagner, Carl (Committee member) / Marshall, Pamela (Committee member) / Arizona State University (Publisher)
Created2023