Medical Pharmacology Commons^™

Thrombospondin 1 Deficiency Ameliorates The Development Of Adriamycin-Induced Proteinuric Kidney Disease, Hasiyeti Maimaitiyiming, Qi Zhou, Shuxia Wang

Pharmacology and Nutritional Sciences Faculty Publications

Accumulating evidence suggests that thrombospondin 1 (TSP1) is an important player in diabetic nephropathy. However, the role of TSP1 in podocyte injury and the development of non-diabetic proteinuric kidney disease is largely unknown. In the current study, by using a well-established podocyte injury model (adriamycin-induced nephropathy mouse model), we examined the contribution of TSP1 to the development of proteinuric kidney disease. We found that TSP1 was up-regulated in the glomeruli, notably in podocytes, in adriamycin injected mice before the onset of proteinuria. ADR treatment also stimulated TSP1 expression in cultured human podocytes in vitro. Moreover, increased TSP1 mediated ADR-induced …

Development Of A Course-Based Undergraduate Research Experience To Introduce Drug-Receptor Concepts, Hollie I. Swanson, Ok-Kyong Park-Sarge, Thushani Rodrigo-Peiris, Lin Xiang, Vincent M. Cassone

Pharmacology and Nutritional Sciences Faculty Publications

Course-based research experiences (CUREs) are currently of high interest due to their potential for engaging undergraduate students in authentic research and maintaining their interest in science, technology, engineering, and mathematics (STEM) majors. As part of a campuswide initiative called STEMCats, which is a living learning program offered to freshman STEM majors at the University of Kentucky funded by a grant from Howard Hughes Medical Institute, we have developed a CURE for freshmen interested in pursuing health care careers. Our course, entitled “Drug–Drug Interactions in Breast Cancer,” utilized a semester-long, in-class authentic research project and instructor-led discussions to engage students in …

Metabolic Drift In The Aging Brain., Julijana Ivanisevic, Kelly L. Stauch, Michael Petrascheck, H. Paul Benton, Adrian A. Epstein, Mingliang Fang, Santhi Gorantla, Minerva Tran, Linh Hoang, Michael E. Kurczy, Michael D. Boska, Howard Gendelman, Howard S. Fox, Gary Siuzdak

Journal Articles: Pharmacology & Experimental Neuroscience

Brain function is highly dependent upon controlled energy metabolism whose loss heralds cognitive impairments. This is particularly notable in the aged individuals and in age-related neurodegenerative diseases. However, how metabolic homeostasis is disrupted in the aging brain is still poorly understood. Here we performed global, metabolomic and proteomic analyses across different anatomical regions of mouse brain at different stages of its adult lifespan. Interestingly, while severe proteomic imbalance was absent, global-untargeted metabolomics revealed an energymetabolic drift or significant imbalance in core metabolite levels in aged mouse brains. Metabolic imbalance was characterized by compromised cellular energy status (NAD decline, increased AMP/ATP, …

Comparing Direct Factor Xa Inhibitors And Warfarin In The Prevention Of Stroke In Patients With Atrial Fibrillation, Alessandra Lof, Stephanie Pillai

Physician Assistant Capstones, 2016 to 2019

Objective: To evaluate the overall efficacy, advantages, and disadvantages of treatment with direct factor Xa inhibitors as compared to warfarin in the prevention of stroke in patients with atrial fibrillation. Methods: A quantitative meta-analysis was performed on three separate studies, each of which evaluated the efficacy and safety outcomes of a direct factor Xa inhibitor versus warfarin in preventing stroke in patients with atrial fibrillation. The direct factor Xa inhibitors that were evaluated included apixaban, edoxaban, and rivaroxaban. Results: The direct factor Xa inhibitors were found to be as effective, and in some cases more effective, than …

Fecal Transplant Vs Vancomycin For Recurrent Clostridium Diffile, Lauren M. Taylor, Todd E. Edwards

Physician Assistant Capstones, 2016 to 2019

Objective: To compare fecal transplant and vancomycin in the treatment of recurrent clostridium difficile to determine which has the higher cure rate. Design: Systematic literature review. Methods: Pubmed, Google Scholar, and TRIP database using the search terms “recurrent clostridium difficile.” Filters were implemented in the Pubmed database including: randomized control trials, English, and published in the past 5 years. Records were screened for RCT with fecal transplant and full-text. Results: van Nood et al. revealed an initial cure rate of 81% for the infusion group, and a re-treated cure rate of 94%, compared to the vancomycin alone group of 31% …

Novel Reversal Agents For Non-Vitamin K Oral Anticoagulants, Kimberly Hoilman, Melanie Reyer

Physician Assistant Capstones, 2016 to 2019

Background Non-vitamin K oral anticoagulants have become an appealing alternative treatment for the prevention of stroke in non-valvular atrial fibrillation and in treatment of venous thromboembolism. The major limitation to the use of these drugs is the lack of reversal agents. The purpose of this review is to investigate the development and efficacy of novel agents for reversal of NOACs. Methods Two separate literature searches were conducted in the PubMed database using the terms “prothrombin complex concentrate” and “idarucizumab”, respectively. Only in vivo clinical trials involving human subjects within the last five years were included for possible analysis. Studies with …

Role Of Chemokine Rantes In The Regulation Of Perivascular Inflammation, T-Cell Accumulation, And Vascular Dysfunction In Hypertension., Tomasz P Mikolajczyk, Ryszard Nosalski, Piotr Szczepaniak, Klaudia Budzyn, Grzegorz Osmenda, Paul J. Marvar, +10 Additional Authors

Pharmacology and Physiology Faculty Publications

Recent studies have emphasized the role of perivascular inflammation in cardiovascular disease. We studied mechanisms of perivascular leukocyte infiltration in angiotensin II (Ang II)-induced hypertension and their links to vascular dysfunction. Chronic Ang II infusion in mice increased immune cell content of T cells (255 ± 130 to 1664 ± 349 cells/mg; P < 0.01), M1 and M2 macrophages, and dendritic cells in perivascular adipose tissue. In particular, the content of T lymphocytes bearing CC chemokine receptor (CCR) 1, CCR3, and CCR5 receptors for RANTES chemokine was increased by Ang II (CCR1, 15.6 ± 1.5% vs. 31 ± 5%; P < 0.01). Hypertension was associated with an increase in perivascular adipose tissue expression of the chemokine RANTES (relative quantification, 1.2 ± 0.2 vs. 3.5 ± 1.1; P < 0.05), which induced T-cell chemotaxis and vascular accumulation of T cells expressing the chemokine receptors CCR1, CCR3, and CCR5. Mechanistically, RANTES(-/-) knockout protected against vascular leukocyte, and in particular T lymphocyte infiltration (26 ± 5% in wild type Ang II vs. 15 ± 4% in RANTES(-/-)), which was associated with protection from endothelial dysfunction induced by Ang II. This effect was linked with diminished infiltration of IFN-γ-producing CD8(+) and double-negative CD3(+)CD4(-)CD8(-) T cells in perivascular space and reduced vascular oxidative stress while FoxP3(+) T-regulatory cells were unaltered. IFN-γ ex vivo caused significant endothelial dysfunction, which was reduced by superoxide anion scavenging. In a human cohort, a significant inverse correlation was observed between circulating RANTES levels as a biomarker and vascular function measured as flow-mediated dilatation (R = -0.3, P < 0.01) or endothelial injury marker von Willebrand factor (R = +0.3; P < 0.01). Thus, chemokine RANTES is important in the regulation of vascular dysfunction through modulation of perivascular inflammation.-Mikolajczyk, T. P., Nosalski, R., Szczepaniak, P., Budzyn, K., Osmenda, G., Skiba, D., Sagan, A., Wu, J., Vinh, A., Marvar, P. J., Guzik, B., Podolec, J., Drummond, G., Lob, H. E., Harrison, D. G., Guzik, T. J. Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension.

Acrolein Is A Critical Mediator Of Alcohol-Induced Liver And Intestinal Injury In Alcoholic Liver Disease., Wei-Yang (Jeremy) Chen

Electronic Theses and Dissertations

Alcohol consumption can cause alcoholic liver disease (ALD), which remains a major cause of morbidity and mortality in the United States. Chronic alcohol consumption causes a pro-oxidant environment in the liver and increases hepatic lipid peroxidation. Acrolein is the most reactive and toxic aldehyde generated through lipid peroxidation. Acrolein forms protein adducts and triggers endoplasmic reticulum (ER) stress and hepatocyte apoptosis, which are recognized etiologic factors in ALD. Several studies have established the critical role of the gut-liver axis in ALD pathogenesis, wherein alcohol-induced gut barrier dysfunction contributes to liver injury. This study investigates, in vitro and in vivo, the …

Role Of Phosphodiesterase-4 In Alcohol-Induced Organ Injury., Diana Veronica Avila

Electronic Theses and Dissertations

Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the U.S., and there is still no FDA-approved therapy. Alcohol metabolism leads to generation of free radicals and oxidative stress with a resultant formation of lipid peroxidation products, which, in turn, contribute to the development of ALD. Alcohol induced hepatic steatosis is the earliest and most frequent manifestation of ALD and a significant risk factor for progressive liver disease. Cyclic adenosine monophosphate (cAMP) signaling has been shown to significantly regulate lipid metabolism. Moreover, agents that increase cAMP have been shown to effectively mitigate oxidative stress both …

Network-Driven Plasma Proteomics Expose Molecular Changes In The Alzheimer's Brain, Philipp A. Jaeger, Kurt M. Lucin, Markus Britschgi, Badri Vardarajan, Ruo-Pan Huang, Elizabeth D. Kirby, Rachelle Abbey, Bradley F. Boeve, Adam L. Boxer, Lindsay A. Farrer, Nicole Finch, Neill R. Graff-Radford, Elizabeth Head, Matan Hofree, Ruochun Huang, Hudson Johns, Anna Karydas, David S. Knopman, Andrey Loboda, Eliezer Masliah, Ramya Narasimhan, Ronald C. Petersen, Alexei Podtelezhnikov, Suraj Pradhan, Rosa Rademakers, Chung-Huan Sun, Steven G. Younkin, Bruce L. Miller, Trey Ideker, Tony Wyss-Coray

Pharmacology and Nutritional Sciences Faculty Publications

Background: Biological pathways that significantly contribute to sporadic Alzheimer’s disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted to late-stage post-mortem studies of brain tissue. However, the disease process is expected to trigger numerous cellular signaling pathways and modulate the local and systemic environment, and resulting changes in secreted signaling molecules carry information about otherwise inaccessible pathological processes.

Results: To access this information we probed relative levels of close to 600 secreted signaling proteins from patients’ blood samples using …

Na/K-Atpase Amplification Of Oxidant Stress; A Universal But Unrecognized Clinical Target?, Zijian Xie, Phd, Joseph I. Shapiro, Md

Joseph I Shapiro MD

The Na/K-ATPase has a signaling function which appears to be separate from its ion pumping function. This signaling function refers to the transduction of conformational changes in the Na/K-ATPase alpha1 subunit into activating Src’s tyrosine kinase activity, triggering a cascade which generates reactive oxygen species (ROS), modulates other signaling pathways, and causes many physiological and pathophysiological effects. We have recently observed that ROS themselves as well as cardiotonic steroids can actually initiate the signal by directly inducing conformational changes in alpha1. It therefore appears that the Na/K-ATPase signal cascade can serve as a feed forward amplification for ROS with circulating …

Na/K-Atpase Amplification Of Oxidant Stress; A Universal But Unrecognized Clinical Target?, Zijian Xie, Phd, Joseph I. Shapiro, Md

Marshall Journal of Medicine

The Na/K-ATPase has a signaling function which appears to be separate from its ion pumping function. This signaling function refers to the transduction of conformational changes in the Na/K-ATPase alpha1 subunit into activating Src’s tyrosine kinase activity, triggering a cascade which generates reactive oxygen species (ROS), modulates other signaling pathways, and causes many physiological and pathophysiological effects. We have recently observed that ROS themselves as well as cardiotonic steroids can actually initiate the signal by directly inducing conformational changes in alpha1. It therefore appears that the Na/K-ATPase signal cascade can serve as a feed forward amplification for ROS with circulating …

Resveratrol Supplementation Confers Neuroprotection In Cortical Brain Tissue Of Nonhuman Primates Fed A High-Fat/Sucrose Diet, Michel Bernier, Devin Wahl, Ahmed Ali, Joanne Allard, Shakeela Faulkner, Artur Wnorowski, Mitesh Sanghvi, Ruin Moaddel, Irene Alfaras, Julie A. Mattison, Stefano Tarantini, Zsuzsanna Tucsek, Zoltan Ungvari, Anna Csiszar, Kevin J. Pearson, Rafael De Cabo

Pharmacology and Nutritional Sciences Faculty Publications

Previous studies have shown positive effects of long-term resveratrol (RSV) supplementation in preventing pancreatic beta cell dysfunction, arterial stiffening and metabolic decline induced by high-fat/high-sugar (HFS) diet in nonhuman primates. Here, the analysis was extended to examine whether RSV may reduce dietary stress toxicity in the cerebral cortex of the same cohort of treated animals. Middle-aged male rhesus monkeys were fed for 2 years with HFS alone or combined with RSV, after which whole-genome microarray analysis of cerebral cortex tissue was carried out along with ELISA, immunofluorescence, and biochemical analyses to examine markers of vascular health and inflammation in the …

Neonatal Abstinence Syndrome: Pharmacologic Strategies For The Mother And Infant., Walter K. Kraft, Megan W. Stover, Jonathan M. Davis

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Opioid use in pregnancy has increased dramatically over the past decade. Since prenatal opioid use is associated with numerous obstetrical and neonatal complications, this now has become a major public health problem. In particular, in utero opioid exposure can result in neonatal abstinence syndrome (NAS) which is a serious condition characterized by central nervous system hyperirritability and autonomic nervous system dysfunction. The present review seeks to define current practices regarding the approach to the pregnant mother and neonate with prenatal opiate exposure. Although the cornerstone of prenatal management of opioid dependence is opioid maintenance therapy, the ideal agent has yet …

Differential Involvement Of Hippocampal Angiotensin 1 Receptors In Learning And Memory Processes In Bulbectomized Rats, Roman Tashev, Margarita Ivanova, Stiliana Belcheva, Iren Belcheva

Journal of Mind and Medical Sciences

There is conflicting evidence regarding the effect of AT1 receptor antagonists on learning and memory processes. The effects of angiotensin II and losartan administration into CA1 hippocampal area on the avoidance performance in olfactory bulbectomized (OBX) rats using active avoidance (shuttle box) test and passive avoidance (step through) test were investigated. Rats were microinjected unilaterally through implanted guide cannulas into the CA1 area of the dorsal hippocampus and the drugs were administered separately, 5 minutes before each training session. The microinjections of losartan into the left, but not the right CA1 hippocampal area improved the acquisition and retention of active …

Hiv-1 Cellular And Tissue Replication Patterns In Infected Humanized Mice., Mariluz Araínga, Hang Su, Larisa Y Poluektova, Santhi Gorantla, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

Humanized mice have emerged as a testing platform for HIV-1 pathobiology by reflecting natural human disease processes. Their use to study HIV-1 biology, virology, immunology, pathogenesis and therapeutic development has served as a robust alternative to more-well developed animal models for HIV/AIDS. A critical component in reflecting such human pathobiology rests in defining the tissue and cellular sites for HIV-1 infection. To this end, we examined the tissue sites for viral infection in bone marrow, blood, spleens, liver, gut, brain, kidney and lungs of human CD34+ hematopoietic stem cell engrafted virus-infected NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ mice. Cells were analyzed by flow cytometry …

Hiv-1 Cellular And Tissue Replication Patterns In Infected Humanized Mice., Mariluz Araínga, Hang Su, Larisa Y Poluektova, Santhi Gorantla, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

Humanized mice have emerged as a testing platform for HIV-1 pathobiology by reflecting natural human disease processes. Their use to study HIV-1 biology, virology, immunology, pathogenesis and therapeutic development has served as a robust alternative to more-well developed animal models for HIV/AIDS. A critical component in reflecting such human pathobiology rests in defining the tissue and cellular sites for HIV-1 infection. To this end, we examined the tissue sites for viral infection in bone marrow, blood, spleens, liver, gut, brain, kidney and lungs of human CD34+ hematopoietic stem cell engrafted virus-infected NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ mice. Cells were analyzed by flow cytometry …

Big Data Transforms Discovery-Utilization Therapeutics Continuum., Scott A. Waldman, Andre Terzic

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Enabling omic technologies adopt a holistic view to produce unprecedented insights into the molecular underpinnings of health and disease, in part, by generating massive high-dimensional biological data. Leveraging these systems-level insights as an engine driving the healthcare evolution is maximized through integration with medical, demographic, and environmental datasets from individuals to populations. Big data analytics has accordingly emerged to add value to the technical aspects of storage, transfer, and analysis required for merging vast arrays of omic-, clinical-, and eco-datasets. In turn, this new field at the interface of biology, medicine, and information science is systematically transforming modern therapeutics across …

Optimizing Guideline-Recommended Antibiotic Doses For Pediatric Infective Endocarditis, Chad A. Knoderer, Kristen R. Nichols, Emily N. Israel, Christopher A. Thomas

Scholarship and Professional Work – COPHS

The American Heart Association recently published an updated scientific statement on the management of infective endocarditis in childhood. The recommendations included for vancomycin, aminoglycoside, and β-lactam dosing and monitoring are based primarily on expert opinion and do not consider available evidence for dose optimization based on pharmacokinetic and pharmacodynamic principles in pediatric patients. This is concerning because even when clinically necessary, some practitioners may be hesitant to deviate from guideline-recommended doses. In this perspective, we highlight potential areas for improvement in the statement-recommended doses and summarize evidence supporting antibiotic dosing optimization. The addition of a pediatric clinical pharmacist with expertise …

Role Of Serum Biomarkers In Early Detection Of Diabetic Cardiomyopathy In The West Virginian Population, Adam Shaver, Alexandra Nichols, Ellen A. Thompson, Amrita Mallick, Nandini Manne, Shanmuga Sundaram, Joseph I. Shapiro Md, Komal Sodhi

Biochemistry and Microbiology

Objectives: Diabetic cardiomyopathy (DCM) is an established complication of diabetes mellitus. In West Virginia, the especially high incidence of diabetes and heart failure validate the necessity of developing new strategies for earlier detection of DCM. Since most DCM patients remain asymptomatic until the later stages of the disease when the fibrotic complications become irreversible, we aimed to explore biomarkers that can identify early-stage DCM.

Methods: The patients were grouped into 4 categories based on clinical diabetic and cardiac parameters: Control, Diabetes (DM), Diastolic dysfunction (DD), and Diabetes with diastolic dysfunction (DM+DD), the last group being the preclinical DCM group.

Results: …