Pharmacology Commons^™

Enteroendocrine Cell Regulation Of The Gut-Brain Axis, Joshua Barton, Annie Londregan, Tyler Alexander, Ariana Entezari, Manuel Covarrubias, Scott Waldman

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Enteroendocrine cells (EECs) are an essential interface between the gut and brain that communicate signals about nutrients, pain, and even information from our microbiome. EECs are hormone-producing cells expressed throughout the gastrointestinal epithelium and have been leveraged by pharmaceuticals like semaglutide (Ozempic, Wegovy), terzepatide (Mounjaro), and retatrutide (Phase 2) for diabetes and weight control, and linaclotide (Linzess) to treat irritable bowel syndrome (IBS) and visceral pain. This review focuses on role of intestinal EECs to communicate signals from the gut lumen to the brain. Canonically, EECs communicate information about the intestinal environment through a variety of hormones, dividing EECs into …

Gpr75 Deficiency Attenuates High Fat Diet-Driven Obesity And Glucose Intolerance, Sakib Hossain

NYMC Student Theses and Dissertations

Recently, a collaboration between Regeneron Pharmaceuticals and the Schwartzman-Garcia labs at New York Medical College published an exome sequencing study of individuals across the United Kingdom, United States, and Mexico which concluded that individuals possessing non-functioning, truncated mutations to the orphan g protein coupled receptor (GPCR), GPR75, had lower BMI and 54% reduced likelihood of obesity. The present study was undertaken to fully characterize the metabolic phenotype of Gpr75 deficient mice when fed a high fat diet (HFD) and explore potential mechanisms by which GPR75 activation links to increased adiposity and decreased glucose tolerance. After 14 weeks of HFD-feeding we …

Prevention Of Doxorubicin-Induced Cardiotoxicity By A Coumestan Analogue, Psoralidin, Mujtaba H. Shah, Myia Aiges, Kota V. Ramana

Annual Research Symposium

Natural phenolic compound Psoralidin limits cardiotoxicity associated with Doxorubicin

Dataset For Manuscript: Comparing Performance Of Spectral Image Analysis Approaches For Detection Of Cellular Signals In Time-Lapse Hyperspectral Imaging Fluorescence Excitation-Scanning Microscopy, Silas J. Leavesley

BioImaging and BioSystems Research

The dataset contains raw and processed hyperspectral timelapse image data that are described in the manuscript:

Parker, M., Annamdevula, N. S., Pleshinger, D., Ijaz, Z., Jalkh, J., Penn, R., Deshpande, D., Rich, T. C. & Leavesley, S. J. Comparing Performance of Spectral Image Analysis Approaches for Detection of Cellular Signals in Time-Lapse Hyperspectral Imaging Fluorescence Excitation-Scanning Microscopy. Bioengineering 10, 642 (2023).

The Effect Of Oatp2b1-Mediated Statin Transport On Beta Cell Dysfunction, Jihoon Kwon

Electronic Thesis and Dissertation Repository

Statins are a class of cholesterol-lowering drugs which work by inhibiting the mevalonate pathway. Statin treatment has been linked to an increase in the risk of new-onset diabetes mellitus, and previous studies have suggested impairment in insulin secretion following statin treatment. Recent work from our laboratory confirmed the expression of organic anion transporting polypeptide 2B1 (OATP2B1), an important statin uptake transporter, in human pancreatic beta cells. Our study examined the role of OATP2B1 in statin-associated beta cell toxicity using INS-1 cells as a beta cell model. We showed that OATP2B1 augments cellular accumulation of rosuvastatin and atorvastatin, but not pravastatin. …

Prefrontal Coding Of Naturalistic Working Memory: Mechanisms During Normal Maintenance And Modelled Disease, Megan P. Roussy

Electronic Thesis and Dissertation Repository

Neural activity in the primate lateral prefrontal cortex (LPFC) has been causally linked to working memory (WM) ⁠— the brief maintenance and mental manipulation of information. Primates use WM to perform tasks in complex contexts; however, neural mechanisms of WM and the pathophysiology related to WM deficits have traditionally been studied using simple tasks that deviate from naturalistic conditions. This raises the question, how is WM processed in naturalistic conditions? To explore this, I trained two macaque monkeys on a spatial WM task set in a naturalistic virtual environment. During the task, a target was presented in 1 of 9 …

Identifying A Glucocorticoid-Activated Gpcr That Rapidly And Non-Genomically Increases Camp Levels In Mammalian Cells, Francisco Nunez

Pharmaceutical Sciences (PhD) Dissertations

Glucocorticoids (GCs) are steroid hormones that regulate diverse physiological processes. Synthetic versions of GCs are commonly used to treat inflammatory diseases such as asthma by modulating gene expression to suppressing several inflammatory activities. However, it is estimated that 5-10% of asthmatics are unresponsive to GCs, which may be explained by receptor desensitization and/or the presence of a neutrophilic endotype. One understudied phenomenon of GCs is their ability to induce rapid, non-genomic actions. For example, GCs can acutely modulate calcium concentrations levels, induce smooth muscle relaxation and modulate nitric oxide synthase activity, within minutes and sometimes seconds, which is too rapid …

Cortisol Receptor Sensitivity As A Risk Factor For Depression, Michela Michielli

Honors Theses

In 2020, the World Health Organization reported over 264 million people across the world were suffering from depression. Studies have demonstrated that one source of depression is a hormonal imbalance involved in the stress response. Cortisol is a stress hormone regulated by the Hypothalamic-Anterior-Pituitary (HPA) Axis. Its effects on the stress response and other metabolic activities in the body are exerted through the glucocorticoid and mineralocorticoid receptors (GR and MR respectively).

Our research has examined mutations known as single-nucleotide-polymorphisms (SNPs) relating to cortisol-receptor sensitivity and the behavior of cortisol in the body to investigate the link between cortisol activity and …

Building Tools For Improved Modulation Of The Human Gabaa Receptor, A Central Nervous System Target For The Treatment Of Anxiety, Garrett Edward Zinck

Theses and Dissertations--Pharmacy

In the U.S., anxiety is recognized as an increasing range of mentally and physically debilitating psychiatric health disorders with significant economic repercussions. Over the last 20 years, several novel anti-anxiety therapies have entered the drug development pipeline, but none have made it to market.

The work in this dissertation focused on structurally modifying valerenic acid (VA), a structurally unique carboxylated sesquiterpene acid found in Valeriana officinalis. VA is putatively reported to have allosteric modulatory activity of the human GABA_A receptor, a ligand-gated ion channel responsible for attenuating neurotransmissions. Structural modeling of VA’s GABA_A receptor interaction suggests that …

Effects Of Exogenous Ketone Therapy On Performance, Cardiorespiration, And Seizure Genesis During Exposure To Hbo2 In The Sprague Dawley Rat, Nicole M. Stavitzski

USF Tampa Graduate Theses and Dissertations

Hyperbaric oxygen (HBO2) is used for clinical HBO2 therapy and in undersea and aerospace medicine. HBO2 is a humanmade extreme environment and protracted exposures can cause several adverse physiological effects on the body. For example, HBO2 increases the partial pressure of oxygen (PO2) in the body leading to redox stress. Redox stress is, in part, a cause of oxygen toxicity that manifests as seizures in its most severe form (central nervous system oxygen toxicity, CNS-OT). This dissertation focuses on strategies to be employed specifically for the warfighter breathing HBO2. Currently, the only way to prevent CNS-OT is to lower the …

Race And Drug Toxicity: A Study Of Three Cardiovascular Drugs With Strong Pharmacogenetic Recommendations., Travis J. O'Brien, Kevin Fenton, Alfateh Sidahmed, April Barbour, Arthur F Harralson

Pharmacology and Physiology Faculty Publications

No abstract provided.

Mitigation Strategies For Central Nervous System Oxygen Toxicity In Rodents: Ketone Metabolic Therapy And Mitochondrial Antioxidant Therapy, Christopher Manuel Hinojo

USF Tampa Graduate Theses and Dissertations

Hyperbaric oxygen (HBO2) is a frequently encountered condition in undersea medicine and hyperbaric oxygen therapy (HBOT). The risk of CNS oxygen toxicity (CNS-OT) seizures limits its use in hyperbaric medicine and limits bottom time for diving operations. In this study, we sought to understand the role of reactive oxygen species (ROS) in two mitigation strategies for CNS-OT; ketone metabolic therapy (KMT), which is known to delay onset of CNS-OT seizures, and mitochondria targeted antioxidant therapy (MitoTAT), which has never been tested under HBO2 conditions. We specifically focused on superoxide anions, one of the early reduction products of molecular oxygen, and …

Characterizing The Structural, Biophysical And Functional Effects Of S-Glutathionylation On Stim1 Ca2+ Sensing, Christian Michael Sirko

Electronic Thesis and Dissertation Repository

Stromal interaction molecule 1 (STIM1) is an endo/sarcoplasmic reticulum (ER/SR) calcium (Ca²⁺) sensing protein that initiates cytoplasmic Ca²⁺ influx via store-operated calcium entry (SOCE). STIM1, in conjunction with Orai, a plasma membrane (PM) protein, function as mediators of SOCE through the formation of calcium-release activated calcium (CRAC) channels. S-Glutathionylation of STIM1 at Cys56 has been shown to evoke constitutive Ca²⁺ entry in DT40 cells, however no studies have carefully investigated the biophysical and structural effects of this covalent modification to the luminal domain, which are critical for understanding the molecular mechanism underlying the regulation of …

A Study Of Trpa1 Activation Via Covalent Electrophilic Modification Of Cysteines, Thomas A. Parks

USF Tampa Graduate Theses and Dissertations

A subset of sensory nerves called nociceptors are stimulated by noxious stimuli and evoke nocifensive responses in different organ systems. Transient Receptor Potential Ankyrin 1 (TRPA1) is a tetrameric, nonselective, cation channel that initiates the generator potential that evokes afferent signaling in nociceptive nerves. TRPA1 is activated many harmful irritants, such as food chemicals, environmental pollutants, reactive oxygen species and other endogenous mediators. Most TRPA1 agonists have electrophilic properties, which covalently modify cysteine residues on the cytosolic side of the channel. Biochemical studies in our lab have identified four cysteines (C273, C621, C665, C1085) that rapidly bound iodoacetamide (irreversible electrophile); …

Morphological Changes In Dorsal Root Ganglia Macrophages Associated With Neuropathic Pain Mechanisms Suggest A Novel Target For Chronic Pain Therapy, Emily Kussick

CMC Senior Theses

The present study examined morphological changes in the dorsal root ganglia (DRG) following an innate immune stimulus. The importance of the DRG has increasingly become recognized in pain processing as more than just the home of primary afferent cell bodies. All sensory information passes through the DRG via the primary afferents, and on to the spinal cord. The primary afferents synapse with second-order neurons in the spinal cord that ascend towards the brain, where they transmit the pain signal to the limbic forebrain and/or the somatosensory cortex for processing. The DRG is an interesting niche to study at as it …

Opioid Use Disorder: The Timeline For Medication Assisted Therapy, Alexander Cristofori

Capstone Showcase

Opioid Use Disorder is patterns of opioid use leading to withdrawal, giving up important life events in order to use opioids, and excessive time spent using opioids, to name a few diagnostic criteria. The clinical progression of the disorder involves periods of acute exacerbation and remission that are cyclic in nature. Treatment is most effective when it includes both pharmacological and psychosocial modalities, referred to as medication assisted therapy (MAT). Three drugs used commonly in MAT-based treatment for OUD from oldest to newest include Methadone, Buprenorphine-naloxone, and Naltrexone. Treatment program models that prioritize total abstinence from the addictive substance attached …

The Effects Of Maternal Delta-9-Tetrahydrocannabinol And Cannabidiol Exposure On Fetal Heart Development In Mice, Gregory Robinson

Electronic Thesis and Dissertation Repository

Up to 22.6% of pregnant women consume cannabis during pregnancy despite the uncertainty of teratogenicity of the main ingredients in cannabis, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). This study tested the hypothesis that gestational THC and CBD exposure leads to heart abnormalities. Daily, oral THC exposure induced heart abnormalities in 68% of offspring with three main phenotypes including thickened semilunar valves, ventricular myocardial hypertrophy and hypoplastic coronary arteries in fetuses, and postnatal cardiac dysfunction. Altered gene expression of key cardiogenic regulators, increased proliferation, and reduced epicardial epithelial-to-mesenchymal-transition were demonstrated implicating potential mechanisms responsible for these abnormalities. Also, maternal CBD exposure resulted …

Rats Genetically Selected For High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin By Upregulation Of Hepatic Biliverdin Reductase-A (Bvra) And Suppression Of Ugt1a1, Terry D. Hinds Jr., Justin F. Creeden, Darren M. Gordon, Adam C. Spegele, Steven L. Britton, Lauren G. Koch, David E. Stec

Pharmacology and Nutritional Sciences Faculty Publications

Exercise in humans and animals increases plasma bilirubin levels, but the mechanism by which this occurs is unknown. In the present study, we utilized rats genetically selected for high capacity running (HCR) and low capacity running (LCR) to determine pathways in the liver that aerobic exercise modifies to control plasma bilirubin. The HCR rats, compared to the LCR, exhibited significantly higher levels of plasma bilirubin and the hepatic enzyme that produces it, biliverdin reductase-A (BVRA). The HCR also had reduced expression of the glucuronyl hepatic enzyme UGT1A1, which lowers plasma bilirubin. Recently, bilirubin has been shown to activate the peroxisome …

The Impact Of Age/Rage Signaling On Oxidative Stress Under Diabetic Conditions In Cardiac Fibroblasts, Christopher Dorroh

Honors Theses

Diabetes is a major health concern in the United States, with 1.5 million new cases diagnosed each year. Patients who suffer from diabetes have an increased risk of developing heart failure, a form of cardiovascular disease. Heart failure has been shown to result from increased left ventricular stiffness, which in turn is caused by increased remodeling of the extracellular matrix (ECM). This increase in ECM remodeling is a result of AGE/RAGE signaling, which occurs at a heightened level in the cardiac fibroblast cells of diabetics. Studies have shown that diabetics have elevated levels of AGEs (Advanced Glycation End-Products), which bind …

Functional Significance Of Endothelial Sigma-1 Receptors In Vascular Reactivity And Barrier Function, Zeinab Y. Motawe

USF Tampa Graduate Theses and Dissertations

The sigma-1 receptor (σ1) is a single 25 kD polypeptide that acts as a chaperone protein residing primarily in the endoplasmic reticulum Its interaction with mitochondria at the mitochondria-associated ER membrane domain is well-documented. Following activation, σ1 binds to the inositol trisphosphate receptor (Hayashi & Su), and modulates intracellular calcium homeostasis. Also, the activated σ1 modulates plasma membrane receptors and ion channel functions, and may regulate cellular excitability. Further, σ1 affects trafficking of lipids and proteins essential for neurotransmission, cell growth and motility. Activation of σ1 provides neuroprotection and cardio-protection in various models. Examples of neuroprotection include but not limited …

Excess No Stabilizes The Luminal Domain Of Stim2 In A Cys-Specific Manner Thereby Regulating Basal Calcium Homeostasis And Store-Operated Calcium Entry, Matthew Novello

Electronic Thesis and Dissertation Repository

Stromal-interaction molecule 2 (STIM2) is an endoplasmic reticulum (ER) membrane-inserted Ca²⁺-sensing protein which, together with the plasma membrane Ca²⁺ channel Orai1, regulates basal Ca²⁺ homeostasis and store-operated Ca²⁺ entry (SOCE). Recent evidence suggests that S-nitrosylation, which is the covalent attachment of a nitric oxide (NO) moiety to a cysteine thiol, can attenuate the function of the paralog STIM1 protein. Compared to STIM1, STIM2 also functions as a basal Ca²⁺ homeostatic feedback regulator. Therefore, the objective of my study was to evaluate the susceptibility of STIM2 to S-nitrosylation and the effects that this …

Pregestational Diabetes Induced Congenital Heart Defects And Coronary Artery Malformations; Mechanisms And Preventative Therapies, Anish Engineer

Electronic Thesis and Dissertation Repository

Congenital heart defects (CHDs) arise from perturbations in complex molecular and cellular processes underlying normal embryonic heart development. CHDs are the most common congenital malformation, occurring in 1 to 5% of live births, and are the leading cause of pediatric mortality. Adverse genetic and environmental factors can impede normal cardiogenesis and increase the likelihood of CHDs. Pregestational maternal diabetes increases the risk of CHDs in children by more than four-fold. As the prevalence of diabetes rapidly rises among women of childbearing age, there is a need to investigate the mechanisms and potential preventative strategies for these defects. The aim of …

Maternal Nicotine Exposure Induces Congenital Heart Defects In The Offspring Of Mice, Elizabeth Greco

Electronic Thesis and Dissertation Repository

Congenital heart defects are the most prevalent birth defect, and maternal cigarette smoking is a known risk factor. Nicotine replacement therapies are recommended to pregnant women who smoke to aid in smoking cessation, as this alternative is thought to be much safer compared to cigarette smoking. However, these products contain nicotine, and the safety of nicotine on the developing heart is not well known. In this thesis, a mouse model was used to test the hypothesis that maternal nicotine exposure (MNE) during pregnancy leads to congenital heart defects and coronary artery defects in the offspring of mice. MNE resulted in …

Molecular Targets Of Psychedelics And Their Role In Behavioral Models Of Hallucinogenic Action, Hiba Z. Vohra

Theses and Dissertations

Psychedelics are a subset of hallucinogenic drugs that exert their characteristic effects through agonist activity at the serotonin receptor 2A (5-HT_2A). In this study, I aimed to characterize the modulatory role of the metabotropic glutamate subtype 2 receptor (mGluR2) in the 5-HT_2A-specific rodent model of hallucinogenic action, head-twitch response (HTR). Secondly, I aimed to explore if 5-HT_2A agonist-induced deficits in prepulse inhibition (PPI) of the startle response, an additional model of hallucinogenic action, could be produced in mice. Though 5-HT_2A agonist-induced PPI deficits, which represent interruptions in normal sensorimotor gating, have been described in …

The Use Of Current Steering During Subthalamic Deep Brain Stimulation To Alleviate Upper Limb Symptoms Of Parkinson's Disease, Shabna Iftikar Mohideen

Electronic Thesis and Dissertation Repository

Subthalamic (STN) deep brain stimulation (DBS) is an established treatment to alleviate the appendicular motor symptoms of Parkinson's Disease (PD). Current steering during DBS allows the unequal fractionation of current between two electrodes on the lead, resulting in a non-spherical electrical field. It is hypothesized that the way the electrical field is shaped will affect a patient’s upper limb symptom alleviation. Seven PD patients who underwent bilateral STN-DBS were tested over four weeks post-operation. 16 current fractionation settings were tested each week at an amplitude that increased weekly. Optimal setting was defined as the setting that provided the best …

The Role Of Perivascular Fibrosis In Post-Stroke Glymphatic Impairment And Cerebral Amyloid Angiopathy, Matthew D. Howe

Dissertations & Theses (Open Access)

In healthy brain tissue, toxic amyloid-β (Aβ) proteins are transported by the pulsatile flow of cerebrospinal fluid (CSF) along perivascular drainage pathways. Ischemic stroke may disrupt this process, leading to a perivascular build-up of Aβ, termed cerebral amyloid angiopathy (CAA). I hypothesize that an abnormal pattern of extracellular matrix deposition within the vascular basement membrane, termed fibrosis, impairs Aβ drainage from the aged brain after stroke. I further hypothesize that inhibition of astrocytic transforming growth factor-β (TGF-β) signaling can reverse these phenotypes. Finally, I also hypothesize that serum biomarkers of perivascular fibrosis can be used to diagnose CAA following intracerebral …

Radical Social Ecology As Deep Pragmatism: A Call To The Abolition Of Systemic Dissonance And The Minimization Of Entropic Chaos, Arielle Brender

Student Theses 2015-Present

This paper aims to shed light on the dissonance caused by the superimposition of Dominant Human Systems on Natural Systems. I highlight the synthetic nature of Dominant Human Systems as egoic and linguistic phenomenon manufactured by a mere portion of the human population, which renders them inherently oppressive unto peoples and landscapes whose wisdom were barred from the design process. In pursuing a radical pragmatic approach to mending the simultaneous oppression and destruction of the human being and the earth, I highlight the necessity of minimizing entropic chaos caused by excess energy expenditure, an essential feature of systems that aim …

Systematic Pan-Cancer Analysis Of Somatic Allele Frequency., Liam Spurr, Muzi Li, Nawaf Alomran, Qianqian Zhang, Paula Restrepo, Mercedeh Movassagh, Chris Trenkov, Nerissa Tunnessen, Tatiyana Apanasovich, Keith A Crandall, Nathan Edwards, Anelia Horvath

Pharmacology and Physiology Faculty Publications

Imbalanced expression of somatic alleles in cancer can suggest functional and selective features, and can therefore indicate possible driving potential of the underlying genetic variants. To explore the correlation between allele frequency of somatic variants and total gene expression of their harboring gene, we used the unique data set of matched tumor and normal RNA and DNA sequencing data of 5523 distinct single nucleotide variants in 381 individuals across 10 cancer types obtained from The Cancer Genome Atlas (TCGA). We analyzed the allele frequency in the context of the variant and gene functional features and linked it with changes in …

Disruption Of Neonatal Cardiomyocyte Physiology Following Exposure To Bisphenol-A., Manelle Ramadan, Meredith Sherman, Rafael Jaimes, Ashika Chaluvadi, Luther Swift, Nikki Gillum Posnack

Pharmacology and Physiology Faculty Publications

Bisphenol chemicals are commonly used in the manufacturing of polycarbonate plastics, polyvinyl chloride plastics, resins, and thermal printing applications. Humans are inadvertently exposed to bisphenols through contact with consumer products and/or medical devices. Recent reports have shown a link between bisphenol-a (BPA) exposure and adverse cardiovascular outcomes; although these studies have been limited to adult subjects and models. Since cardiac physiology differs significantly between the developing and adult heart, we aimed to assess the impact of BPA exposure on cardiac function, using a neonatal cardiomyocyte model. Neonatal rat ventricular myocytes were monitored to assess cell viability, spontaneous beating rate, beat …

The Effects Of Heart Medication On The Heart Rates Of Drosophila Melanogaster, Felicia A. Baer

Honors Program Projects

Background

Current animal models of human cardiac disease may be similar in anatomy and physiology but are often expensive and tedious to work with. The current need is for a model organism that is more efficient to work with in the lab but that still provides an accurate model of human cardiac disease. Drosophila melanogaster (D. mel) is such a candidate. While 74% of the genes coding for protein are conserved between D. mel and human hearts, it is unknown if cardiac medication used in humans, such as atropine and propranolol hydrochloride, similarly affect heart rate. I hypothesized that …