Medical Pharmacology Commons^™

Paradoxes Of Cellular Sumoylation Regulation: A Role Of Biomolecular Condensates?, Xiaodong Cheng, Wenli Yang, Wei Lin, Fang Mei

Faculty, Staff and Student Publications

Protein SUMOylation is a major post-translational modification essential for maintaining cellular homeostasis. SUMOylation has long been associated with stress responses as a diverse array of cellular stress signals are known to trigger rapid alternations in global protein SUMOylation. In addition, while there are large families of ubiquitination enzymes, all small ubiquitin-like modifiers (SUMOs) are conjugated by a set of enzymatic machinery comprising one heterodimeric SUMO-activating enzyme, a single SUMO-conjugating enzyme, and a small number of SUMO protein ligases and SUMO-specific proteases. How a few SUMOylation enzymes specifically modify thousands of functional targets in response to diverse cellular stresses remains an …

Topiramate (Topamax): Evolving Role In Weight Reduction Management: A Narrative Review, Irza Wajid, Alexis Vega, Katherine Thornhill, Jack Jenkins, Chandler Merriman, Debbie Chandler, Sahar Shekoohi, Elyse M. Cornett, Alan D. Kaye

School of Medicine Faculty Publications

Obesity has emerged as a widespread disease with epidemic proportions, necessitating effective management to enhance the overall health outcomes of patients. Medical intervention for weight loss becomes necessary when diet and exercise prove ineffective, and topiramate emerges as a potential treatment option for this global problem. Currently approved as an anti-epileptic and migraine prophylaxis medication, topiramate is frequently utilized as adjunctive therapy for patients with mood and eating disorders, as well as for alcohol use disorders. Its multifaceted mechanisms of action contribute to reducing neuronal excitation and enhancing neuronal inhibition. Given its variety of mechanisms, topiramate shows several off-label outcomes, …

The Role Of Pharmacogenetics On Breast Cancer Treatment Efficacy And Toxicity, Noor Alani, Nicholas Barber, Britt Benn, Justin M. Gambini

Doctor of Medical Science (DMSc)

Purpose: This research article aims to shed light on the pivotal role of pharmacogenetics in breast cancer treatment by examining genetic variations that influence the efficacy and toxicity of commonly used drugs. Furthermore, this study highlights the significance of personalized treatment approaches in optimizing patient outcomes.

Method: A comprehensive literature search was conducted using databases such as PubMed. Search terms included "pharmacogenetics," "breast cancer treatment," "genetic markers," and "adverse effects." This review critically analyzes relevant studies that focus on the impact of genetic variations on the response to drugs used in breast cancer treatment.

Results: The review …

Severe Covid-19 Following Rituximab And Nirmatrelvir/Ritonavir Treatment In A Patient With Mctd, Case Report, Rohail A. Baig, Faieja Chowdhury, Omar Siddiqui, Adnaan Sheikh, Varun Mehta, Pranjali Dakwale

Advances in Clinical Medical Research and Healthcare Delivery

This is an article about how the use of medications such as nirmatrelvir/ritonavir can cause rebound COVID-19 and how the use of Rituximab, a biologic agent, can prolong the duration and increase severity of symptoms of COVID-19 in patients with pre-disposed autoimmune diseases that are on chronic pharmacotherapy.

Identification Of A Β-Arrestin-Biased Negative Allosteric Modulator For The Β2-Adrenergic Receptor, Michael Ippolito, Francesco De Pascali, Nathan Hopfinger, Konstantin E. Komolov, Daniela Laurinavichyute, Poli Adi Narayana Reddy, Leon A. Sakkal, Kyle Z. Rajkowski, Ajay P. Nayak, Justin Lee, Jordan Lee, Gaoyuan Cao, Preston S. Donover, Melvin Reichman, Stevens. An, Joseph M. Salvino, Raymond B. Penn, Roger S S. Armen, Charles P. Scott, Jeffrey L. Benovic

Department of Biochemistry and Molecular Biology Faculty Papers

Catecholamine-stimulated β2-adrenergic receptor (β2AR) signaling via the canonical Gs–adenylyl cyclase–cAMP–PKA pathway regulates numerous physiological functions, including the therapeutic effects of exogenous β-agonists in the treatment of airway disease. β2AR signaling is tightly regulated by GRKs and β-arrestins, which together promote β2AR desensitization and internalization as well as downstream signaling, often antithetical to the canonical pathway. Thus, the ability to bias β2AR signaling toward the Gs pathway while avoiding β-arrestin-mediated effects may provide a strategy to improve the functional consequences of β2AR activation. Since attempts to develop Gs-biased agonists and allosteric modulators for the β2AR have been largely unsuccessful, here we …

Management Of Asymptomatic Hypertension In The Inpatient Setting., Charles Meadows, Mehiar Elhamdani, Dial Larry, Murad Kheetan, Khaled Al-Baqain

Marshall Journal of Medicine

Hypertension is common in hospitalized patients and is most often asymptomatic. While there are no guidelines for management of such patients, aggressive blood pressure treatment, including the use of intravenous antihypertensives, is often undertaken. While evidence of benefit is lacking, emerging data suggest that treatment of asymptomatic hypertension in the inpatient setting is associated with adverse outcomes, including acute kidney injury and ischemic stroke. In addition, the intensification of a preexisting antihypertensive regimen at hospital discharge significantly increases the risk of readmission without significant improvement in outpatient hypertension control. Such a combination of a common problem with the demonstrable benefit …

Computational Modeling And Synthesis Of Pyridine Variants Of Benzoyl-Phenoxy-Acetamide With High Glioblastoma Cytotoxicity And Brain Tumor Penetration, Charles H. Ingraham, Joanna Stalinska, Sean C. Carson, Susan B. Colley, Monika Rak, Adam Lassak, Francesca Peruzzi, Krzysztof Reiss, Branko S. Jursic

School of Graduate Studies Faculty Publications

Glioblastomas are highly aggressive brain tumors for which therapeutic options are very limited. In a quest for new anti-glioblastoma drugs, we focused on specific structural modifications to the benzoyl-phenoxy-acetamide (BPA) structure present in a common lipid-lowering drug, fenofibrate, and in our first prototype glioblastoma drug, PP1. Here, we propose extensive computational analyses to improve the selection of the most effective glioblastoma drug candidates. Initially, over 100 structural BPA variations were analyzed and their physicochemical properties, such as water solubility (− logS), calculated partition coefficient (ClogP), probability for BBB crossing (BBB_SCORE), probability for CNS penetration (CNS-MPO) and calculated cardiotoxicity (hERG), were …

Sers Of Human Red Blood Cells In Non-Resonant Conditions: Benefits, Limitations, And Complementary Tools (Cytoviva And Gfaas), Kelsey L. Wells, Praveen K. Alla, Kyra G. Kaiser, Ioana T. Murgulet, Norma C. Adragna, Ioana E. Pavel

Pharmacology and Toxicology Faculty Publications

Herein, Raman and surface-enhanced Raman spectroscopies (SERS) were successfully employed to establish the chemical interactions of citrate-capped silver nanoparticles (AgNPs, 10–15 nm) with human red blood cells (RBCs). The Raman/SERS spectra offered spectral evidence for the cellular uptake of AgNPs and the subsequent change in the conformation of the most abundant component, hemoglobin (Hb), from oxyhemoglobin to deoxyhemoglobin. The spectral characterization of AgNPs’ interactions with other RBC biomarkers (membrane proteins and lipids) was impeded by the dominant Hb bands, even for non-resonant Hb conditions. CytoViva hyperspectral imaging and graphite furnace atomic absorption spectroscopy (GFAAS) served as complementary tools to effectively …

Equine Polyclonal Antibodies Prevent Acute Chikungunya Virus Infection In Mice, Douglas Barker, Xiaobing Han, Eryu Wang, Ashley Dagley, Deborah M. Anderson, Aruni Jha, Scott C. Weaver, Justin Julander, Cory Nykiforuk, Shantha Kodihalli

Office of Research Faculty and Staff Publications

Chikungunya virus (CHIKV) is a mosquito-transmitted pathogen that causes chikungunya disease (CHIK); the disease is characterized by fever, muscle ache, rash, and arthralgia. This arthralgia can be debilitating and long-lasting, seriously impacting quality of life for years. Currently, there is no specific therapy available for CHIKV infection. We have developed a despeciated equine polyclonal antibody (CHIKV-EIG) treatment against CHIKV and evaluated its protective efficacy in mouse models of CHIKV infection. In immunocompromised (IFNAR^−/−) mice infected with CHIKV, daily treatment for five consecutive days with CHIKV-EIG administered at 100 mg/kg starting on the day of infection prevented mortality, reduced …

Her3-Targeted Therapeutic Antibodies And Antibody–Drug Conjugates In Non-Small Cell Lung Cancer Refractory To Egfr-Tyrosine Kinase Inhibitors, Margaret E. Larsen, Hui Lyu, Bolin Liu

School of Medicine Faculty Publications

Human epidermal growth factor receptor 3 (HER3) is a unique member of the human epidermal growth factor receptor (HER/EGFR) family, since it has negligible kinase activity. Therefore, HER3 must interact with a kinase-proficient receptor to form a heterodimer, leading to the activation of signaling cascades. Overexpression of HER3 is observed in various human cancers, including non-small cell lung cancer (NSCLC), and correlates with poor clinical outcomes in patients. Studies on the underlying mechanism demonstrate that HER3-initiated signaling promotes tumor metastasis and causes treatment failure in human cancers. Upregulation of HER3 is frequently observed in EGFR-mutant NSCLC treated with EGFR-tyrosine kinase …

Effects Of Interleukin-22 (Il-22) On Necroptosis, Inflammatory Responses, And Metabolism Of Mycobacterium Tuberculosis Stimulated Type 2 Diabetes Mellitus Mouse Macrophages, Bismark Owusu-Afriyie

Biotechnology Theses

Mycobacterium tuberculosis (Mtb) infects one-third of the world’s population and causes nearly 1.3 million deaths per year. Limited information is available about the immune responses during Mtb infection in type 2 diabetic hosts. Our laboratory developed an experimentally induced type 2 diabetes (T2DM) model in wild-type C57BL/6 mice and found that IL-22 and type 3 innate lymphoid cells (ILC3s) reduce inflammation and mortality of Mtb-infected T2DM mice. Our laboratory also found that Mtb-infected alveolar macrophages (AMs) from T2DM mice undergo necroptosis compared to Mtb-infected AMs of non-T2DM mice. In the current study, we determined whether …

Development Of Novel, Brain Permeable, Mpges-1 Inhibitors For Inflammatory Conditions, Madison Sluter

Theses and Dissertations (ETD)

Prostaglandin E2 (PGE2) is a potent proinflammatory lipid signaling molecule produced downstream of the cyclooxygenase (COX) cascade. The COX pathway has long been implicated for its role in inflammation, with drugs like aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) non-selectively targeting the upstream COX enzymes to suppress inflammation. However, despite displaying potent anti-inflammatory effects it has been demonstrated that when taken chronically, NSAIDs can cause gastrointestinal bleeding. COX-2 selective inhibitors (COXIBs) were then developed to combat the gastrointestinal bleeding induced by nonselective NSAIDs by specifically inhibiting the COX enzyme most infamous for its role in inflammation. Yet, soon after entering …

Pediatric Serum-Like Sickness: A Multicenter Analysis, Maya Gibson, Sarah Suppes, Jared Lovins, Emma Monique, Keith Feldman, Jennifer Goldman

Research Days

Background: Serum sickness-like reaction (SSLR) is a type III immune hypersensitivity reaction that presents 5-21 days following exposure to a medication. SSLR has nonspecific symptoms including fever, rash, and joint involvement. There are no standardized diagnostic criteria or treatment for SSLR, making this a challenging diagnosis.

Objectives/Goal: Our objective was to describe pediatric SSLR clinical manifestations, medical encounter types, and treatment strategies.

Methods/Design: A retrospective chart review across 2 freestanding children’s hospitals was used to identify patients 0-21 years of age diagnosed with SSLR by ICD-9/10 codes [T80.69XA, 999.59], SNOMED codes [1782626019, 3293325014], or pharmacovigilance review in the emergency department …

Study Of The Potential Toxicity Of Adrenaline To Neurons, Using The Sh-Sy5y Human Cellular Model, Vera Marisa Costa, João Paulo Capela, Maria Lourdes Bastos, Fernando Remião, Kurt James Varner, José Alberto Duarte, Félix Carvalho

School of Graduate Studies Faculty Publications

Prolonged overexposure to catecholamines causes toxicity, usually credited to continuous adrenoceptor stimulation, autoxidation, and the formation of reactive pro-oxidant species. Non-differentiated SH-SY5Y cells were used to study the possible contribution of oxidative stress in adrenaline (ADR)-induced neurotoxicity, as a model to predict the toxicity of this catecholamine to peripheral nerves. Cells were exposed to several concentrations of ADR (0.1, 0.25, 0.5 and 1mM) and two cytotoxicity assays [lactate dehydrogenase (LDH) release and 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction] were performed at several time-points (24, 48, and 96h). The cytotoxicity of ADR was concentration-and time-dependent in both assays, since the lowest concentration …

Comparison Of The Inhibition Of An Oct3 Transporter Inhibitor, Nilotinib, On Doxorubicin’S Effects On Cardiac And Cancer Cell Lines, Zachary G. Tan, Juliet Melnik, Aakash Belsare, James Huang, Meagan Lyons, Kimberly Dowes, Gurpreet Kaur, Lindon H. Young, Robert J. Barsotti, Qian Chen

Research Day

Introduction

Doxorubicin (DOX)-induced cardiotoxicity remains a significant barrier limiting its clinical application due to a lack of effective resolution. Targeting how DOX enters cardiac and cancer cells is a promising new strategy. Research suggests that an OCT3 transporter significantly contributes to DOX entry into the heart tissue. By contrast, it expresses much lower on breast cancer cell lines. Moreover, Nilotinib (NIB) can suppress OCT3 transporter function by 80%. Therefore, exploring the impact of NIB on the DOX’s effects on cardiac and cancer cell lines by altering DOX intracellular accumulation is intriguing.

Objective

First, we would establish a dose-response curve of …

In Vitro Characterization Of A Novel Murine Model Of Cancerous Progression, Steven D. Scahill, Kelly Jean Sherman, Jessie J. Guidry, Whitney Walkowski, Theresa Nguyen, Durwood B. Ray, David H. Jones, Harry J. Gould, Dennis Paul

School of Graduate Studies Faculty Publications

To evaluate a potentially valuable tool to study cancer progression and metastasis, we characterized a novel murine model composed of a parental oncogene-transformed embryonic fibroblast line and five cell lines isolated from progressively advanced tumors. Lines derived from distant metastases displayed significantly greater rates of motility, invasiveness, and extracellular acidification than lines derived from a primary tumor or local metastases. A comprehensive proteomic analysis of these cells showed numerous oncogenes to be upregulated and tumor suppressors to be downregulated in the advanced lines, and provided novel targets for future examination. The first cell line capable of extravasation displayed particularly high …

Cytochrome P450 1b1 And 12/15 Lipoxygenase Interaction In Paraventricular Nucleus In Angiotensin Ii-Induced Hypertension In Females, Shubha Ranjan Dutta

Theses and Dissertations (ETD)

Background: Angiotensin (Ang) II releases arachidonic acid (AA) from tissue phospholipids that is metabolized by 12/15-lipoxygenase (ALOX15) generating 12(S)- and 15(S)-hydroxyeicosatetraenoic acid (HETE) which have been implicated in cardiovascular and renal diseases. This study was conducted to investigate a) the contribution of ALOX15 to Ang II-induced hypertension and associated pathogenesis in female mice, and b) the interaction between the cytochrome P450 (CYP)1B1-generated metabolite of 17β-estradiol (E2) (2-methoxyestradiol, 2-ME) and ALOX15 in the paraventricular nucleus (PVN) as a mechanism that protects against Ang II-induced hypertension and its associated pathogenesis in female mice. Methods: Experiments were conducted in intact and ovariectomized (OVX) …

Antioxidant Activity And Phytochemical Profile Of Traditional Chinese Medicinal Plant Extracts, Ashley Tai

Senior Honors Projects

Traditional Chinese medicine (TCM), specifically the extracts of Chinese medicinal plants, has been studied for thousands of years to prevent, diagnose, and treat diseases. Our research group has initiated a program to systemically investigate the phytochemical composition and biological activities of a library of TCM medicinal plants. Herein, extracts of four commonly used TCM plants including broccoli (Brassica oleracea) seeds, horny goat weed (Epimedium brevicomu), houpu magnolia (Magnolia officinalis) bark, and golden root (Rhodiola rosea) were selected for this study. The antioxidant effects of these extracts were evaluated in a biochemical assay …

Accidental Extravasation Of Mitomycin C Into The Subcutaneous Tissue, Johnathon Chung, Brooke Walterscheid, Jose Lopez-Vera, Hytham Rashid, Mike K. Liang

HCA Healthcare Journal of Medicine

Introduction

Mitomycin C (MMC) is a common chemotherapeutic agent used to treat a variety of solid tumors. Cutaneous adverse events are rare, but MMC is a known vesicant reported to cause tissue necrosis and sloughing, erythema, and ulceration if incorrectly infused into the subcutaneous tissue. Definitive treatment of extravasation injuries due to MMC depends on the severity of the cutaneous manifestation, which includes stopping the infusion, removing the catheter, or possible debridement.

Case Presentation

We present the case of a 70-year-old female with extensive soft-tissue injury secondary to extravasation of MMC that required hospital admission and surgical intervention to remove …

Beneficial Actions Of Sglt2 Inhibition And H2s Therapy In Heart Failure With Preserved Ejection Fraction, Jake Doiron, Zhen Li, Huijing Xia, Kyle B. Lapenna, Timothy D. Allerton, Daniel R. Kapusta, David J. Lefer

School of Graduate Studies Faculty Publications

Association for Clinical and Translational Science, ACTS 2023, April 18 - 20, 2023, Washington DC