Medical Pharmacology Commons^™

Opposing Regulation Of Endolysosomal Pathways By Long-Acting Nanoformulated Antiretroviral Therapy And Hiv-1 In Human Macrophages., Mariluz Araínga, Dongwei Guo, Jayme Wiederin, Pawel Ciborowski, Joellyn Mcmillan, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

BACKGROUND: Long-acting nanoformulated antiretroviral therapy (nanoART) is designed to improve patient regimen adherence, reduce systemic drug toxicities, and facilitate clearance of human immunodeficiency virus type one (HIV-1) infection. While nanoART establishes drug depots within recycling and late monocyte-macrophage endosomes, whether or not this provides a strategic advantage towards viral elimination has not been elucidated.

RESULTS: We applied quantitative SWATH-MS proteomics and cell profiling to nanoparticle atazanavir (nanoATV)-treated and HIV-1 infected human monocyte-derived macrophages (MDM). Native ATV and uninfected cells served as controls. Both HIV-1 and nanoATV engaged endolysosomal trafficking for assembly and depot formation, respectively. Notably, the pathways were deregulated …

Pact/Rax Regulates The Migration Of Cerebellar Granule Neurons In The Developing Cerebellum, Yue Yong, Ya Meng, Hanqing Ding, Zhiqin Fan, Yifen Tang, Chenghua Zhou, Jia Luo, Zun-Ji Ke

Pharmacology and Nutritional Sciences Faculty Publications

PACT and its murine ortholog RAX were originally identified as a protein activator for the dsRNA-dependent, interferon-inducible protein kinase PKR. Recent studies indicated that RAX played a role in embryogenesis and neuronal development. In this study, we investigated the expression of RAX during the postnatal development of the mouse cerebellum and its role in the migration of cerebellar granule neurons (CGNs). High expression of RAX was observed in the cerebellum from postnatal day (PD) 4 to PD9, a period when the CGNs migrate from the external granule layer (EGL) to the internal granule layer (IGL). The migration of the EGL …

Metabolic Interplay Between Astrocytes And Neurons Regulates Endocannabinoid Action, Andreu Viader, Jacqueline L. Blankman, Peng Zhong, Xiaojie Liu, Joel E. Scholsburg, Christopher M. Joslyn, Qing-Song Liu, Aaron J. Tomarchio, Aron H. Lichtman, Dana E. Selley, Laura J. Sim-Selley, Benjamin F. Cravatt

Pharmacology and Toxicology Publications

The endocannabinoid 2-arachidonoylglycerol (2-AG) is a retrograde lipid messenger that modulates synaptic function, neurophysiology, and behavior. 2-AG signaling is terminated by enzymatic hydrolysis—a reaction that is principally performed by monoacylglycerol lipase (MAGL). MAGL is broadly expressed throughout the nervous system, and the contributions of different brain cell types to the regulation of 2-AG activityin vivo remain poorly understood. Here, we genetically dissect the cellular anatomy of MAGL-mediated 2-AG metabolism in the brain and show that neurons and astrocytescoordinately regulate 2-AG content and endocannabinoid-dependent forms of synaptic plasticity and behavior. We also find that astrocytic MAGL is mainly responsible …

Differing Roles Of Autophagy In Hiv-Associated Neurocognitive Impairment And Encephalitis With Implications For Morphine Co-Exposure, Seth M. Dever, Myosotys Rodriguez, Jessica Lapierre, Blair N. Costin, Nazira El-Hage

Pharmacology and Toxicology Publications

We investigated the role of autophagy in HIV-infected subjects with neurocognitive impairment (NCI) ± HIV encephalitis (HIVE), many of which had a history of polysubstance abuse/dependence, using post-mortem brain tissues to determine whether differences in autophagy related factors may be more associated with NCI or NCI-encephalitis. Using qRT-PCR, we detected significant differences in gene expression levels with SQSTM1, LAMP1 higher in HIV-infected subjects without NCI while ATG5, SQSTM1 were then lower in HIV infection/NCI and ATG7, SQSTM1 being higher in NCI-HIVE. Immunohistochemical labeling of these autophagy associated proteins (also including Beclin 1 and LC3B) in Iba1-positive microglial cells showed generally …

Redox Regulation Of Nlrp3 Inflammasomes: Ros As Trigger Or Effector?, Justine M. Abais, Min Xia, Yang Zhang, Krishna M. Boini, Pin-Lan Li

Pharmacology and Toxicology Publications

Significance: Inflammasomes are multiprotein complexes localized within the cytoplasm of the cell that are responsible for the maturation of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, and the activation of a highly inflammatory form of cell death, pyroptosis. In response to infection or cellular stress, inflammasomes are assembled, activated, and involved in host defense and pathophysiology of diseases. Clarification of the molecular mechanisms leading to the activation of this intracellular inflammatory machinery may provide new insights into the concept of inflammation as the root of and route to human diseases. Recent Advances: The activation of inflammasomes, specifically the most …

Adipose-Derived Mesenchymal Stem Cells Improve Glucose Homeostasis In High-Fat Diet-Induced Obese Mice, Mingjun Cao, Qingjie Pan, Huanshen Dong, Xinxu Yuan, Yang Li, Zhen Sun, Xiao Dong, Hongjun Wang

Pharmacology and Toxicology Publications

Introduction

Effective therapies for obesity and diabetes are still lacking. The aim of this study was to evaluate whether a single intravenous infusion of syngeneic adipose-derived mesenchymal stem cells (ASCs) can reduce obesity, lower insulin resistance, and improve glucose homeostasis in a high-fat diet-induced obese (DIO) mouse model.

Methods

Seven-week-old C57BL/6 mice were fed a high-fat diet for 20 weeks to generate the DIO mouse model. Mice were given a single intravenous infusion of ex vivo expanded syngeneic ASCs at 2 × 10 ⁶ cells per mouse. DIO or CHOW mice injected with saline were used as controls. Body weights, …

Effects Of Menthol On Nicotine Pharmacokinetic, Pharmacology And Dependence In Mice, Sharki D. Alsharari, Justin R. King, Jacob C. Nordman, Pretal P. Muldoon, Asti Jackson, Andy Z. X. Zhu, Rachel F. Tyndale, Nadine Kabbani, M. Imad Damaj

Pharmacology and Toxicology Publications

Although menthol, a common flavoring additive to cigarettes, has been found to impact the addictive properties of nicotine cigarettes in smokers little is known about its pharmacological and molecular actions in the brain. Studies were undertaken to examine whether the systemic administration of menthol would modulate nicotine pharmacokinetics, acute pharmacological effects (antinociception and hypothermia) and withdrawal in male ICR mice. In addition, we examined changes in the brain levels of nicotinic receptors of rodents exposed to nicotine and menthol. Administration of i.p. menthol significantly decreased nicotine’s clearance (2-fold decrease) and increased its AUC compared to i.p. vehicle treatment. In addition, …

Contribution Of Nrf2 To Atherogenic Phenotype Switching Of Coronary Arterial Smooth Muscle Cells Lacking Cd38 Gene, Ming Xu, Xiao-Xue Li, Lei Wang, Mi Wang, Yang Zhang, Pin-Lan Li

Pharmacology and Toxicology Publications

Background/Aims: Recent studies have indicated that CD38 gene deficiency results in dedifferentiation or transdifferentiation of arterial smooth muscle cells upon atherogenic stimulations. However, the molecular mechanisms mediating this vascular smooth muscle (SMC) phenotypic switching remain unknown. Methods & Results: In the present study, we first characterized the phenotypic change in the primary cultures of coronary arterial myocytes (CAMs) from CD38-/- mice. It was shown that CD38 deficiency decreased the expression of contractile marker calponin, SM22α and α-SMA but increased the expression of SMC dedifferentiation marker, vimentin, which was accompanied by enhanced cell proliferation. This phenotypic change in CD38-/- CAMs was …

Stem Cell Conditioned Culture Media Attenuated Albumin-Induced Epithelial– Mesenchymal Transition In Renal Tubular Cells, Junping Hu, Qing Zhu, Pin-Lan Li, Weili Wang, Fan Yi, Ningjun Li

Pharmacology and Toxicology Publications

Background: Proteinuria-induced epithelial-mesenchymal transition (EMT) plays an important role in progressive renal tubulointerstitial fibrosis in chronic renal disease. Stem cell therapy has been used for different diseases. Stem cell conditioned culture media (SCM) exhibits similar beneficial effects as stem cell therapy. The present study tested the hypothesis that SCM inhibits albumin-induced EMT in cultured renal tubular cells. Methods: Rat renal tubular cells were treated with/without albumin (20 µmg/ml) plus SCM or control cell media (CCM). EMT markers and inflammatory factors were measured by Western blot and fluorescent images. Results: Albumin induced EMT as shown by significant decreases in levels of …

Concentration-Dependent Diversification Effects Of Free Cholesterol Loading On Macrophage Viability And Polarization, Xiaoyang Xu, Aolin Zhang, Ningjun Li, Pin-Lan Li, Fan Zhang

Pharmacology and Toxicology Publications

Background/Aims: The accumulation of free cholesterol in atherosclerotic lesions has been well documented in both animals and humans. In studying the relevance of free cholesterol buildup in atherosclerosis, contradictory results have been generated, indicating that free cholesterol produces both pro- and anti-atherosclerosis effects in macrophages. This inconsistency might stem from the examination of only select concentrations of free cholesterol. In the present study, we sought to investigate the implication of excess free cholesterol loading in the pathophysiology of atherosclerosis across a broad concentration range from (in µg/ml) 0 to 60. Methods:Macrophage viability was determined by measuring formazan formation and …

Voltage-Gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity And Invasion Via Persistent Mapk Signaling, Carrie D. House, Bi-Dar Wang, Kristin Ceniccola, Russell Williams, May Simaan, Norman H. Lee, +7 Additional Authors

Pharmacology and Physiology Faculty Publications

Functional expression of voltage-gated Na⁺ channels (VGSCs) has been demonstrated in multiple cancer cell types where channel activity induces invasive activity. The signaling mechanisms by which VGSCs promote oncogenesis remain poorly understood. We explored the signal transduction process critical to VGSC-mediated invasion on the basis of reports linking channel activity to gene expression changes in excitable cells. Coincidentally, many genes transcriptionally regulated by the SCN5A isoform in colon cancer have an over-representation of cis-acting sites for transcription factors phosphorylated by ERK1/2 MAPK. We hypothesized that VGSC activity promotes MAPK activation to induce transcriptional changes in invasion-related genes. Using …

Dual Pi3k/Mtor Inhibition With Bez235 Augments The Therapeutic Efficacy Of Doxorubicin In Cancer Without Influencing Cardiac Function, David E. Durrant

Theses and Dissertations

Cancer continues to be a leading cause death in the United States despite improved treatments. Cancerous lesions form after acquiring oncogenic driver mutations or losing tumor suppressor function in normal cells. Traditional therapies have included use of genotoxic substances that take advantage of the increased growth rate and loss of tumor suppressor function to cause cell death. One such drug is the anthracycline antibiotic doxorubicin (DOX). DOX interchelates into DNA and disrupts transcriptional machinery while also poisoning topoisomerase II. This results in single and double stranded DNA breaks, which if severe enough leads to either necrotic or apoptotic cell death. …

Mitochondrial And Neuroprotective Effects Of Phenelzine Related To Scavenging Of Neurotoxic Lipid Peroxidation Products, John Cebak

Theses and Dissertations--Neuroscience

Lipid peroxidation is a key contributor to the pathophysiology of traumatic brain injury (TBI). Traditional antioxidant therapies are intended to scavenge the free radicals responsible for either the initiation or propagation of lipid peroxidation (LP). However, targeting free radicals after TBI is difficult as they rapidly react with other cellular macromolecules, and thus has a limited post-injury time window in which they may be intercepted by a radical scavenging agent. In contrast, our laboratory has begun testing an antioxidant approach that scavenges the final stages of LP i.e. formation of carbonyl-containing breakdown products. By scavenging breakdown products such as the …

Cyp2d7 Sequence Variation Interferes With Taqman Cyp2d6 (*) 15 And (*) 35 Genotyping., Amanda K. Riffel, Mehdi Dehghani, Toinette Hartshorne, Kristen C. Floyd, J Steven Leeder, Kevin P. Rosenblatt, Andrea Gaedigk

Manuscripts, Articles, Book Chapters and Other Papers

TaqMan™ genotyping assays are widely used to genotype CYP2D6, which encodes a major drug metabolizing enzyme. Assay design for CYP2D6 can be challenging owing to the presence of two pseudogenes, CYP2D7 and CYP2D8, structural and copy number variation and numerous single nucleotide polymorphisms (SNPs) some of which reflect the wild-type sequence of the CYP2D7 pseudogene. The aim of this study was to identify the mechanism causing false-positive CYP2D6 (*) 15 calls and remediate those by redesigning and validating alternative TaqMan genotype assays. Among 13,866 DNA samples genotyped by the CompanionDx® lab on the OpenArray platform, 70 samples were identified as …

Drug Interactions With Glutaredoxin Orthologues, Kahlilah R. Napper, Thomas C. Leeper, Ram Khattri, Daniel Morris, Caroline Davis

Williams Honors College, Honors Research Projects

Glutaredoxin, an enzymatic protein, is an important component of cell viability and function. It catalyzes reactions involved in DNA synthesis and innate immunity [1,4]. Glutaredoxin is also essential in antibiotic resistance in pathogenic bacterial species. Pseudomonas aeruginosa in particular is responsible for infecting the lung tissue of its human hosts, resulting in the development of pneumonia and cystic fibrosis [3]. Because glutaredoxin is pertinent in cell proliferation of eukaryotic and bacterial cells alike, medicinal fragments that take advantage of the subtle differences in protein structure of the orthologous proteins can be synthesized and enhanced to bind bacterial glutaredoxins, without inhibiting …

Predicting Aqueous Solubility Of Pharmaceutical Agents By Solid Dispersion Prepared By Solvent Evaporation Method, Karthik Reddy Patlolla

University of the Pacific Theses and Dissertations

Solubility of active pharmaceutical agents is a crucial process that determines drug absorption and ultimately its bioavailability. Many of the new therapeutically beneficial compounds discovered are lipophilic requiring various solubility enhancement strategies to improve their solubility. Among these strategies, solubility enhancement using solid dispersions is a leading method. To obtain a desirable increase in the solubility of a poorly-soluble compound, a good understanding of the molecular descriptors influencing the enhancement of solubility is essential. Therefore, the major research objective was to determine the descriptors which significantly influence the solubility enhancement by solid dispersions. After enhancing the solubility of selected poorly-soluble …

Use Of Oxytocin As A Preventative Treatment For Ptsd, Laurel V. Kovalchick

Undergraduate Research Posters

Posttraumatic stress disorder (PTSD) is a mental health disorder triggered by experiencing a traumatic event. PTSD causes recurrent flashbacks of traumatic memories that lead to over-consolidation. Memory over-consolidation prevents extinction of emotional and physiological responses to the memory. Because individuals can respond differently to stress and frightening experiences, no measures are currently practiced to prevent PTSD. By studying the changes in the brain during PTSD and after stress, it can be hypothesized that treatments that regulated HPA axis activity may prevent PTSD symptoms if applied soon after stress. Risk of developing PTSD is associated with abnormal cortisol and norepinephrine levels …

Feasibility Of Integrating Tripterygium Wilfordii Into Modern Cancer Therapy For Increased Efficacy And Minimal Toxicity, Ngoc T. Vo

Undergraduate Research Posters

Cancer is the second leading cause of death in the U.S. and millions of novel cancer cases are being diagnosed each year. While chemotherapy and ionizing radiation are effective treatments against these malignant tumors, the adverse effects that accompany such treatments are devastating. In order to find alternative treatment methods with less side effects, we turn to Eastern herbal medicine. Recent scientific research has found that Tripterygium wilfordii, an herbal medicine traditionally used to treat inflammation in China, contains compounds (triptolide and celastrol) that prevent the growth of solid tumors, induce apoptosis, and prevent metastasis of developed tumors. Investigations …

Functional Conservation Of An Ancestral Pellino Protein In Helminth Species, Christopher Cluxton, Brian Caffrey, Gemma Kinsella, Paul Moynagh, Mario Fares, Padraic Fallon

Articles

The immune system of H. sapiens has innate signaling pathways that arose in ancestral species. This is exemplified by the discovery of the Toll-like receptor (TLR) pathway using free-living model organisms such as Drosophila melanogaster. The TLR pathway is ubiquitous and controls sensitivity to pathogen-associated molecular patterns (PAMPs) in eukaryotes. There is, however, a marked absence of this pathway from the plathyhelminthes, with the exception of the Pellino protein family, which is present in a number of species from this phylum. Helminth Pellino proteins are conserved having high similarity, both at the sequence and predicted structural protein level, with that …

Efficacy Of Female Rat Models In Translational Cardiovascular Aging Research, Kevin M. Rice, J. C. Fannin, C. Gillette, Eric Blough

Pharmaceutical Science and Research

Cardiovascular disease is the leading cause of death in women in the United States. Aging is a primary risk factor for the development of cardiovascular disease as well as cardiovascular-related morbidity and mortality. Aging is a universal process that all humans undergo; however, research in aging is limited by cost and time constraints. Therefore, most research in aging has been done in primates and rodents; however it is unknown how well the effects of aging in rat models translate into humans. To compound the complication of aging gender has also been indicated as a risk factor for various cardiovascular diseases. …