Medical Pharmacology Commons^™

Serum Metabolomics Reveals Distinct Profiles During Ischemia And Reperfusion In A Porcine Model Of Myocardial Ischemia–Reperfusion, Eric Goetzman, Zhenwei Gong, Dhivyaa Rajasundaram, Ishan Muzumdar, Traci Goodchild, David Lefer, Radhika Muzumdar

School of Medicine Faculty Publications

Acute myocardial infarction (MI) is one of the leading causes of death worldwide. Early identification of ischemia and establishing reperfusion remain cornerstones in the treatment of MI, as mortality and morbidity can be significantly reduced by establishing reperfusion to the affected areas. The aim of the current study was to investigate the metabolomic changes in the serum in a swine model of MI induced by ischemia and reperfusion (I/R) injury, and to identify circulating metabolomic biomarkers for myocardial injury at different phases. Female Yucatan minipigs were subjected to 60 min of ischemia followed by reperfusion, and serum samples were collected …

Genomic Features Underlie The Co-Option Of Sva Transposons As Cis-Regulatory Elements In Human Pluripotent Stem Cells, Samantha M Barnada, Andrew Isopi, Daniela Tejada-Martinez, Clément Goubert, Sruti Patoori, Luca Pagliaroli, Mason Tracewell, Marco Trizzino

Department of Biochemistry and Molecular Biology Faculty Papers

Domestication of transposable elements (TEs) into functional cis-regulatory elements is a widespread phenomenon. However, the mechanisms behind why some TEs are co-opted as functional enhancers while others are not are underappreciated. SINE-VNTR-Alus (SVAs) are the youngest group of transposons in the human genome, where ~3,700 copies are annotated, nearly half of which are human-specific. Many studies indicate that SVAs are among the most frequently co-opted TEs in human gene regulation, but the mechanisms underlying such processes have not yet been thoroughly investigated. Here, we leveraged CRISPR-interference (CRISPRi), computational and functional genomics to elucidate the genomic features that underlie SVA domestication …

Genetically Encoded Atp Biosensors For Direct Monitoring Of Cellular Atp Dynamics, Donnell White, Qinglin Yang

School of Medicine Faculty Publications

Adenosine 5′-triphosphate, or ATP, is the primary molecule for storing and transferring energy in cells. ATP is mainly produced via oxidative phosphorylation in mitochondria, and to a lesser extent, via glycolysis in the cytosol. In general, cytosolic glycolysis is the primary ATP producer in proliferative cells or cells subjected to hypoxia. On the other hand, mitochondria produce over 90% of cellular ATP in differentiated cells under normoxic conditions. Under pathological conditions, ATP demand rises to meet the needs of biosynthesis for cellular repair, signaling transduction for stress responses, and biochemical processes. These changes affect how mitochondria and cytosolic glycolysis function …

Lysosomal Zn 2+ Release Triggers Rapid, Mitochondria-Mediated, Non-Apoptotic Cell Death In Metastatic Melanoma, Wanlu Du, Mingxue Gu, Meiqin Hu, Timothy Nold, Prateeksunder Pinchi, Wei Chen, Michael Ryan, Ahmed Bannaga, Haoxing Xu

Medical Student Research Symposium

During tumor progression, lysosome function is often maladaptively upregulated to match the high energy demand required for cancer cell hyper-proliferation and invasion. Here, we report that mucolipin TRP channel 1 (TRPML1), a lysosomal Ca2+ and Zn2+ release channel that regulates multiple aspects of lysosome function, is dramatically upregulated in metastatic melanoma cells compared with normal cells. TRPML-specific synthetic agonists (ML-SAs) are sufficient to induce rapid (within hours) lysosomal Zn2+-dependent necrotic cell death in metastatic melanoma cells while completely sparing normal cells. ML-SA-caused mitochondria swelling and dysfunction lead to cellular ATP depletion. While pharmacological inhibition or genetic silencing of TRPML1 in …

Ethanol Exposure Up-Regulates Pd-L1/Pd-1 Immune Checkpoint Pathway And Promotes Mammary Tumor Development, Wenhua Xu, Linqing Wu, Mei Xu, Jia Luo, Gang Chen

Pharmacology and Nutritional Sciences Faculty Publications

Alcohol consumption in women enhances breast cancer incidence and ethanol is the main causal factor. Compromised host immunity through immunosuppression facilitates the development of many types of cancer, including breast cancer. Immune cells in breast tissues, particularly tumor-infiltrating CD8 cytotoxic T cells, play a critical role in the host anti-tumor immunity against breast tumorigenesis. These cytotoxic T cells are the major immune cells to carry out anti-tumor immunity through their cytotoxic effector function, which can be regulated by immune checkpoint pathways. The PD-1/PD-L1 pathway (the interaction between programmed death-1, PD-1, and its ligand, programmed deathligand 1, PD-L1) is the best …

Remifentanil Patient Controlled Analgesia Use In Laboring Women: A Feasibility And Acceptability Study, Joshua Carr

Dissertations

Background/Purpose: Interest in remifentanil patient controlled analgesia (RPCA) as a treatment for labor pain has increased due to its unique pharmacodynamics and effectiveness on pain control among parturients. Despite its promise, RPCA remains infrequently used in the US. The purpose of this study was to 1) examine the implementation and acceptability of a new RPCA protocol in the labor and delivery ward of a mid-sized hospital, and 2) identify the attitudes and beliefs of healthcare workers in a real-world clinical setting.

Theoretical/Conceptual Framework: The holistic nature of Comfort Theory can account for the proposed mechanisms contributing to the …

The Effects Of Thc On Hiv Tat Protein-Mediated Neuroinflammation, Camille Martin

Honors Theses

Although antiretroviral therapies have allowed people living with human immunodeficiency virus (HIV) to achieve normal life expectancies, they cannot cure HIV nor the neurological symptoms associated with infection, termed neuroHIV. NeuroHIV describes a myriad of neurological disorders including mood disorders (depression and anxiety), cognitive impairment, neuropathic pain, and motor disinhibition. The mechanisms by which HIV promotes neurological impairment are not known, but may involve actions of its neurotoxic proteins. One such protein that has been well-characterized is the HIV trans-activator of transcription (Tat). Tat exerts neurotoxic effects via various means, one of which is to activate microglia, the macrophages of …

Therapeutic Efficacy Of Zinc In The Treatment Of Covid-19 Patients: A Systematic Review, Olivia Schimmel, Varna Taranikanti

Posters

INTRODUCTION
Novel therapeutic interventions are of utmost importance to alleviate the clinical symptoms caused by inflammation in COVID-19 patients. The beneficial role of zinc has been suggested due to its ability to mitigate the effects of the inflammatory cascade. Hence it has been hypothesized that patients with zinc deficiency may benefit symptomatically from treatment with zinc. The primary goal of this systematic review of randomized controlled trials conducted between February and March 2021 is to determine the efficacy of zinc as a treatment for COVID-19 infection.

Decreasing Time To Antibiotic Administration In Febrile Neutropenic Adult Oncology Patients In The Emergency Department: An Evidence-Based Quality Improvement Project, Kristin Murray

DNP Projects

Introduction—Significance and Background: Febrile Neutropenia (FN) is the most common and serious complication of hematopoietic cancers and in patients receiving chemotherapy. Patients in this immunocompromised state have weakened immunity to fight off infection and a mortality rate of almost 10%. Thus, Infectious Diseases Society of America has identified the single most important determining factor of outcomes is the timing of antibiotic (TTA) administration and has identified the gold standard to be 60 minutes. Current practice does not follow guidelines and the current policy does not address the urgency of antibiotic administration.

Purpose: The purpose of this project is to improve …

An Investigation Of The Anti-Stemness Actions Of Two Mirnas After Their Induction By Aminoflavone In Luminal A Breast Cancer, Nicole Ursula Rumbidzai Mavingire

Loma Linda University Electronic Theses, Dissertations & Projects

Approximately 40% of estrogen receptor positive breast cancer (BC) patients develop resistance to endocrine therapy (ET) agents like tamoxifen (Tam). Resistance promotes metastasis, recurrence, and death since metastatic BC is often incurable. Breast cancer stem cells (CSCs) greatly contribute to disease progression and drug resistance. We previously showed that aryl hydrocarbon receptor (AhR) agonist aminoflavone (AF) inhibits the expression of CSC biomarker α6-integrin (ITGA6) to disrupt the formation of endocrine-sensitive and -resistant luminal A mammospheres. In this study, we performed miRNAsequencing analysis of luminal A MCF-7 and MCF-7TamR mammospheres before and after AF treatment to further develop the mechanism of …

Phytochemical And Synthetic Ahr Ligands As Novel Therapy For Refractory Breast Cancer, Jonathan V. Wooten

Loma Linda University Electronic Theses, Dissertations & Projects

Patients with triple-negative breast cancer (TNBC) possess tumors that lack estrogen receptor, progesterone receptor, and human growth factor receptor 2 expression. Such patients have lower survival rates than those diagnosed with other breast cancer subtypes in part, due to the scarcity of targeted therapy for TNBC. In addition to chemotherapy, patients with TNBC often consume natural remedies, which has led us and others to evaluate the ability of plant isolates to confer anticancer and chemopreventive actions. Poly-ADP ribose polymerase (PARP) is an enzyme that promotes DNA single-strand break repair. PARP inhibitor olaparib exploits DNA repair enzyme deficiency in tumors to …

Targeting Neuronal Nitric Oxide Synthase (Nnos) For Melanoma Treatment, Shirley Tong

Pharmaceutical Sciences (PhD) Dissertations

Human cutaneous melanoma is the most aggressive form of skin cancer and the incidence rates have continued to increase over the years. Neuronal nitric oxide synthase (nNOS) produces nitric oxide (NO) has been found to be overexpressed in human melanoma and the expression of nNOS is induced by interferon-gamma (IFN-γ). In our studies, nNOS has been implicated in IFN-γ-stimulated melanoma progression and the inhibition of nNOS using novel inhibitors effectively inhibited IFN-γ-stimulated tumor growth in a xenograft mouse model. Programmed death-ligand 1 (PD-L1) is overexpressed in melanoma and plays an important role in suppressing the immune system ^12-14. Our …

Non-Opioid Pharmacologic Agents In The Treatment Of Non-Cancer Chronic Pain In The Outpatient Setting, Diane Eannotti

DNP Projects

Opioid prescription related overdose deaths have increased substantially with evidence demonstrating only modest short-term benefits in chronic pain and thus represents the need to identify alternative treatments to opioids. A needs assessment performed for a federally qualified community health center revealed patients presently taking non-opioid pharmacologic agents in the treatment of chronic non-cancer pain (CNCP) needed additional education in managing multiple non-opioid medications. A targeted approach at improving patient experience and population health supporting the quadruple aim was undertaken with this project.

Purpose: The purpose of this quality improvement project consisted of performing medication management visits for 28 referred patients …

Targeting Squalene Epoxidase Interrupts Homologous Recombination Via The Er Stress Response And Promotes Radiotherapy Efficacy, Zhipeng Hong, Tao Liu, Lingfeng Wan, Pengyan Fa, Pankaj Kumar, Yanan Cao, Chandra Bhushan Prasad, Zhaojun Qiu, Joseph Liu, Hongbing Wang, Zaibo Li, Qi-En Wang, Peixuan Guo, Deliang Guo, Ayse S. Yilmaz, Lanchun Lu, Ioanna Papandreou, Naduparambil K. Jacob, Chunhong Yan, Qing-Bai She

Pharmacology and Nutritional Sciences Faculty Publications

Over 50% of all patients with cancer are treated with radiotherapy. However, radiotherapy is often insufficient as a monotherapy and requires a nontoxic radiosensitizer. Squalene epoxidase (SQLE) controls cholesterol biosynthesis by converting squalene to 2,3-oxidosqualene. Given that SQLE is frequently overexpressed in human cancer, this study investigated the importance of SQLE in breast cancer and non–small cell lung cancer (NSCLC), two cancers often treated with radiotherapy. SQLE-positive IHC staining was observed in 68% of breast cancer and 56% of NSCLC specimens versus 15% and 25% in normal breast and lung tissue, respectively. Importantly, SQLE expression was an independent predictor of …

Efforts To Increase The Ketamine-Like Activity Of The Rapid-Acting Antidepressant Ro-25-6981 (Mi-4) By Increasing Ampa Potentiation, Nathan Heger

Annual Research Symposium

The small molecule ketamine has generated much interest due to its rapid antidepressant effects. Despite having a rapid onset, ketamine has poor bioavailability, short duration of action, toxicities with long-term use, and a high potential for abuse. The molecule MI-4 (RO 25-6981) has also been shown to have both a rapid and sustained antidepressant effect. Most of the research into the mechanism of the rapid onset of MI-4 and ketamine has focused on their interaction with the NMDA receptor in addition to some monoamine transporters. Some recent publications have shown a significant role of AMPA receptors in the ketamine antidepressant …

In-Silico Determination Of Phytochemicals Against Spike Protein Of Covid-19, Muhammad Irfan, Muhammad Adil, Areej Fatima, Arooj Fatima, Ammara Khalid, Muhammad Bilal

Journal of Bioresource Management

Spike protein is present on the exterior of SARS-CoV-2 that mediates the binding of virus with human ACE2 receptor. S-protein has the ability to mutate in a short span of time. Using S-protein as a therapeutic target, Covid-19 infection can be prevented. Many plant-derived phytochemicals are found effective to treat viral infections. In this study, we selected top 10 phytochemicals following the Lipinski’s rule of five from total 82 candidate phytochemicals. The binding energies were determined through molecular docking of the phytochemical ligands. Top three compounds having maximal interactions and lowest binding energies were visualized. We suggested Dictamnine, Deoxypodophyllotoxin and …

Soy Formula Is Not Estrogenic And Does Not Result In Reproductive Toxicity In Male Piglets: Results From A Controlled Feeding Study, Martin J.J. Ronis, Horacio Gomez‐Acevedo, Kartik Shankar, Leah Hennings, Neha Sharma, Michael L. Blackburn, Isabelle Miousse, Harry Dawson, Celine Chen, Kelly E. Mercer, Thomas M. Badger

School of Graduate Studies Faculty Publications

Soy infant formula which is fed to over half a million infants per year contains isoflavones such as genistein, which have been shown to be estrogenic at high concentrations. The developing testis is sensitive to estrogens, raising concern that the use of soy formulas may result in male reproductive toxicity. In the current study, male White‐Dutch Landrace piglets received either sow milk (Sow), or were provided milk formula (Milk), soy formula (Soy), milk formula supplemented with 17‐beta‐estradiol (2 mg/kg/d) (M + E2) or supplemented with genistein (84 mg/L of diet; (M + G) from postnatal day 2 until day 21. …

Evaluation Of Hippocampal Allostatic Load-Associated Factors In Animal Models Of Post-Traumatic Stress Disorder: Relevance To Human Ptsd, Dennis Parker Kelley

LSU Doctoral Dissertations

Post-traumatic stress disorder (PTSD) is associated with elevated allostatic load, nearly double the risk for metabolic syndrome, reduced hippocampal volume, and contextual memory processing deficits. Emerging evidence suggests that these stress effects may predispose individuals to the development of PTSD, and there is a known relationship between chronic stress and metabolic dysfunction. In this work, we utilized two rat models of PTSD to explore these connections. We used an acute predator odor stressor to investigate the relationship between PTSD-like behaviors and mitochondrial dysfunction in the hippocampus of rats, and we observed that conditioned place avoidance was associated with reduced mitochondrial …

Effects Of St713 With Simultaneous Histamine H3 And Dopamine D2/D3 Receptor Antagonist Properties On Cognitive Impairments And Autism-Like Behaviors In Btbr T+Tf/J Mice, Mohammed Mustafa Alawad

Theses

Autism spectrum disorders (ASD) is a multifactorial neurodevelopmental disorder characterized by two core symptoms which are impairments in social interaction and communication, repetitive and restricted behaviors. Dopamine (DA) and histamine (HA) are two neurotransmitters that are proposed to be involved in several brain disorders including schizophrenia, depression, anxiety, and narcolepsy, all of those disorders are comorbid with ASD. Thus, the palliative effects of the novel multiple-active histamine H3 receptor (H3R) antagonist and dopamine D2/D3 receptor (D2/D3R) antagonist ST-713 with its high H3R antagonist affinity and balanced inhibitory effects on both dopaminergic receptor subtypes D2R and D3R on ASD-like behaviors in …

Targeting Gastrointestinal Cancers With Chimeric Antigen Receptor (Car)-T Cell Therapy, Ross E Staudt, Robert D Carlson, Adam E. Snook

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The immune system is capable of remarkably potent and specific efficacy against infectious diseases. For decades, investigators sought to leverage those characteristics to create immune-based therapies (immunotherapy) that might be far more effective and less toxic than conventional chemotherapy and radiation therapy for cancer. Those studies revealed many factors and mechanisms underlying the success or failure of cancer immunotherapy, leading to synthetic biology approaches, including CAR-T cell therapy. In this approach, patient T cells are genetically modified to express a chimeric antigen receptor (CAR) that converts T cells of any specificity into tumor-specific T cells that can be expanded to …