Digital Commons Network^™

Prolonged In Vivo Retention Of A Cathepsin D Targeted Optical Contrast Agent In A Mouse Model Of Alzheimer's Disease., Jonatan A Snir, Mojmir Suchy, Keith St Lawrence, Robert H E Hudson, Stephen H Pasternak, Robert Bartha

Brain and Mind Institute Researchers' Publications

BACKGROUND: Cathepsin D (CatD) is a lysosomal protease that is elevated early in Alzheimer's disease (AD). We have previously developed a Targeted contrast agent (CA) to detect CatD activity in vivo, consisting of a magnetic resonance imaging/fluorescent moiety linked to a cell penetrating peptide (CPP) by means of a CatD cleavage site and have demonstrated its uptake in the brain of an AD mouse model.

OBJECTIVE: The purpose of this study was to characterize the in vivo retention of a near infra-red fluorescent dye labeled version of this CA.

METHODS: Six adult C57Bl/6 wild-type mice and six adult 5XFAD transgenic …

High-Field Functional Imaging Of Pitch Processing In Auditory Cortex Of The Cat., Blake E. Butler, Amee J Hall, Stephen G Lomber

Brain and Mind Institute Researchers' Publications

The perception of pitch is a widely studied and hotly debated topic in human hearing. Many of these studies combine functional imaging techniques with stimuli designed to disambiguate the percept of pitch from frequency information present in the stimulus. While useful in identifying potential "pitch centres" in cortex, the existence of truly pitch-responsive neurons requires single neuron-level measures that can only be undertaken in animal models. While a number of animals have been shown to be sensitive to pitch, few studies have addressed the location of cortical generators of pitch percepts in non-human models. The current study uses high-field functional …

Early Initiation Of Antiretroviral Therapy Can Functionally Control Productive Hiv-1 Infection In Humanized-Blt Mice, Qingsheng Li, For Yue Tso, Guobin Kang, Wuxun Lu, Yue Li, Wenjin Fan, Zhe Yuan, Christopher J. Destache, Charles Wood

Nebraska Center for Virology: Faculty Publications

Background—Recent reports showed that functional control of HIV-1 infection for a prolonged time is possible by early anti-retroviral therapy (ART); however its underlying mechanism needs to be studied with a suitable animal model. Recently, humanized-BLT (bone marrow, liver and thymus) mouse (hu-BLT) was shown to be an excellent model for studying HIV-1 infection. We thus tested the feasibility of studying functional control of HIV-1 infection using hu-BLT mice.

Methods—Animals in three treatment groups (Rx-6h, Rx-24h, Rx-48h) and untreated group were infected with HIV-1, followed by ART initiation at 6, 24 or 48 hours post-infection and continued daily for two weeks. …

The Role Of Dendritic Cell Subsets And Innate Immunity In The Pathogenesis Of Type 1 Diabetes And Other Autoimmune Diseases, Jeffrey D. Price, Kristin V. Tarbell

Nebraska Center for Virology: Faculty Publications

Dendritic cells (DCs) are key antigen-presenting cells that have an important role in autoimmune pathogenesis. DCs control both steady-state T cell tolerance and activation of pathogenic responses. The balance between these two outcomes depends on several factors, including genetic susceptibility, environmental signals that stimulate varied innate responses, and which DC subset is presenting antigen. Although the specific DC phenotype can diverge depending on the tissue location and context, there are four main subsets identified in both mouse and human: conventional cDC1 and cDC2, plasmacytoid DCs, and monocyte-derived DCs. In this review, we will discuss the role of these subsets in …

Cerium Oxide Nanoparticles Attenuate Polymicrobial Sepsis Induced Splenic Damage In Male Sprague Dawley Rats, Venkata Vinay Kumar Bandarupalli

Theses, Dissertations and Capstones

Sepsis is a serious life threatening medical emergency which, if not treated properly, oftentimes results in organ failure and death. Current sepsis treatment protocols are largely centered on the use of antibiotics and supportive care. Recent studies have suggested that antibiotics fail to be effective for sepsis treatment when administered during hypo-dynamic phase of sepsis that is usually characterized by the presence of a cytokine storm. As such, there is an urgent need to develop novel therapeutic drugs that target the inflammatory cytokines that are secreted as a result of increased reactive oxygen species. Cerium oxide nanoparticles (CeO2) have been …

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 …

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 …

Genetic Modifiers Of Duchenne Muscular Dystrophy And Dilated Cardiomyopathy., Andrea Barp, Luca Bello, Luisa Politano, Paola Melacini, Chiara Calore, Eric P. Hoffman, +16 Additional Authors

Genomics and Precision Medicine Faculty Publications

OBJECTIVE: Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset.

METHODS: A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m2 as …

Transcriptional Pathways Associated With Skeletal Muscle Changes After Spinal Cord Injury And Treadmill Locomotor Training., Celine Baligand, Yi-Wen Chen, Fan Ye, Sachchida Nand Pandey, San-Huei Lai, Min Liu, Krista Vandenborne

Genomics and Precision Medicine Faculty Publications

The genetic and molecular events associated with changes in muscle mass and function after SCI and after the implementation of candidate therapeutic approaches are still not completely known. The overall objective of this study was to identify key molecular pathways activated with muscle remodeling after SCI and locomotor training. We implemented treadmill training in a well-characterized rat model of moderate SCI and performed genome wide expression profiling on soleus muscles at multiple time points: 3, 8, and 14 days after SCI. We found that the activity of the protein ubiquitination and mitochondrial function related pathways was altered with SCI and …

Using A Novel Optogenetic Approach To Directly Assess 5-Ht1a Somatodendritic Autoreceptor Function In Response To Chronic Selective Serotonin Reuptake Inhibitor Treatment, Kelly Marie Mcgregor

Wayne State University Dissertations

Antidepressant drugs are widely used but their mechanism of action remains only partially understood. One leading hypothesis holds that a key effect of chronic treatment with a Selective Serotonin Reuptake Inhibitor (SSRI) is loss of somatodendritic 5-HT1A receptor-mediated autoinhibition in serotonergic neurons of the dorsal raphe nucleus (DRN). However, technical limitations have prevented direct testing of this hypothesis. In the current study we took advantage of optogenetic strategies to assess the effects of the classic SSRI fluoxetine on 5-HT1A receptor-mediated autoinhibition. We conducted these experiments in mice expressing the light-sensitive ion channel Channelrhodopsin (ChR) in 5-HT neurons to facilitate their …

Neuroscience, Mindreading, And The Courts: The Example Of Pain, Henry T. Greely

Journal of Health Care Law and Policy

No abstract provided.

Neuronal Migration: How Do You Build A Brain?, Sravya Uppalapati

AUCTUS: The Journal of Undergraduate Research and Creative Scholarship

Senior biology major Alex Burkard is working in the Walsh Neurodevelopment Laboratory at VCU to help answer the question, ‘How do you build a brain?’ Burkard is researching neuronal migration in Zebrafish and how cellular polarity affects hindbrain development.

Immortal Mortals, Sterling Giles

AUCTUS: The Journal of Undergraduate Research and Creative Scholarship

Junior Information Systems and Bioinformatics major Michael Kiflezghi focuses his research interests on an organism’s lifespan and gut microbial communities.

Antidiarrheal And Antispasmodic Activities Of Polygonum Bistorta Rhizomes Are Mediated Predominantly Through K+ Channels Activation, Muhammad Zeeshan Ali, Khalid Hussain Janbaz, Hassan Mehmood, Anwar Hassan Gilani

Department of Biological & Biomedical Sciences

Polygonum bistorta is a popular medicinal herb used to treat diarrhea. This study provides pharmacological basis to its folk use in diarrhea using in vivo and in vitro assays. Administration of P. bistorta rhizomes extract to mice offered protection against castor oil-induced diarrhea at 300-1,000 mg/kg and was found safe up to the dose of 5 g/kg. In isolated rabbit jejunum, the extract caused a dose-dependent relaxation of spontaneous and low K⁺ (25 mM)-induced contractions with weak effect against high K⁺ (80 mM). In tissues pretreated with glibenclamide or tetraethylammonium chloride (TEA), the relaxant effect of the extract …

Antidiarrheal And Antispasmodic Activities Of Adiantum Capillus-Veneris Are Predominantly Mediated Through Atp-Dependent K+ Channels Activation, Khalid Hussain Janbaz, Waseem Hassan, Hassan Mehmood, Anwar Hassan Gilani

Department of Biological & Biomedical Sciences

The study was tempted to explore the scientific basis for the medicinal use of Adiantum capillus-veneris L. in diarrhea using the in vivo and in vitro assays. The crude extract of dried leaves of A. capillus-veneris exhibited antidiarrheal effect against castor oil-induced diarrhea in mice at 300 and 500 mg/kg, similar to the effect loperamide. It was also found safe up to administered dose of 7 g/kg in mice. In isolated rabbit jejunum, extract of A. capillus-veneris showed a concentration-dependent relaxation of spontaneous and low K⁺ (25 mM)-induced contractions and had weak inhibitory effect on high K⁺ (80 …

Preparing The Periphery For A Subsequent Behavior: Motor Neuronal Activity During Biting Generates Little Force But Prepares A Retractor Muscle To Generate Larger Forces During Swallowing In Aplysia, Hui Lu, Jeffrey M. Mcmanus, Miranda J. Cullins, Hillel J. Chiel

Faculty Scholarship

Some behaviors occur in obligatory sequence, such as reaching before grasping an object. Can the earlier behavior serve to prepare the musculature for the later behavior? If it does, what is the underlying neural mechanism of the preparation? To address this question, we examined two feeding behaviors in the marine mollusk Aplysia californica, one of which must precede the second: biting and swallowing. Biting is an attempt to grasp food. When that attempt is successful, the animal immediately switches to swallowing to ingest food. The main muscle responsible for pulling food into the buccal cavity during swallowing is the I3 …

Liver Perilipin 5 Expression Worsens Hepatosteatosis But Not Insulin Resistance In High Fat-Fed Mice, Michelle B. Trevino, David Mazur-Hart, Yui Machida, Timothy King, Joseph Nadler, Elena V. Galkina, Arjun Poddar, Sucharita Dutta, Yumi Imai

Mathematics & Statistics Faculty Publications

Perilipin 5 (PLIN5) is a lipid droplet (LD) protein highly expressed in oxidative tissues, including the fasted liver. However, its expression also increases in nonalcoholic fatty liver. To determine whether PLIN5 regulates metabolic phenotypes of hepatosteatosis under nutritional excess, liver targeted overexpression of PLIN5 was achieved using adenoviral vector (Ad-PLIN5) in male C57BL/6J mice fed high-fat diet. Mice treated with adenovirus expressing green fluorescent protein (GFP) (Ad-GFP) served as control. Ad-PLIN5 livers increased LD in the liver section, and liquid chromatography with tandem mass spectrometry revealed increases in lipid classes associated with LD, including triacylglycerol, cholesterol ester, and phospholipid classes, …

Targeting Methylglyoxal And Ppar Gamma To Alleviate Neuropathic Pain Associated With Type 2 Diabetes, Ryan B. Griggs

Theses and Dissertations--Physiology

Neuropathic pain affects up to 50% of the 29 million diabetic patients in the United States. Neuropathic pain in diabetes manifests as a disease of the peripheral and central nervous systems. The prevalence of type 2 diabetes is far greater than type 1 (90%), yet the overwhelming focus on type 1 models this has left the mechanisms of pain in type 2 diabetes largely unknown. Therefore I aimed to improve the current mechanistic understanding of pain associated with type 2 diabetes using two preclinical rodent models: Zucker Diabetic Fatty rats and db/db mice. In addition, I highlight the translational importance …

Determining The Role Of Tlr Agonists In T Cell-Based Cancer Therapy, Marshall Andrew Diven

MUSC Theses and Dissertations

One of the main mechanisms by which total body irradiation (TBI) enhances adoptive cell transfer (ACT) immunotherapy is by inducing systemic innate immune activation, triggered by microbial LPS released from the radiation-injured gut. Although microbial LPS is a critical mediator of TBI enhancement, it is unknown whether exogenous administration of LPS can augment therapeutic outcome. We report here that administration of LPS to non-irradiated animals did not replicate the ACT effectiveness seen in irradiated animals. In contrast, however, we found that LPS dramatically augmented ACT treatment in irradiated mice. Moreover, bacterial derived TLR agonists other than LPS (such as CpG …

Panel 3: Chronic Pain, “Psychogenic” Pain, And Emotion, David Seminowicz, Amanda Pustilnik, M. Kaylie Gioioso, Jennifer Chandler, Robert Dinerstein, Jennifer A. Haythornthwaite, Tor D. Wager

Journal of Health Care Law and Policy

No abstract provided.

The Ct20 Peptide As An Agent For Cancer Treatment, Rania Bassiouni

Electronic Theses and Dissertations

Due to cancer recurrence and the development of drug resistance, metastatic breast cancer is a leading cause of death in women. In the search for a new therapeutic to treat metastatic disease, we discovered CT20p, an amphipathic peptide based on the C-terminus of Bax. Due to inherent properties of its sequence and similarity to antimicrobial peptides, CT20p is a promising cytotoxic agent whose activity is distinct from the parent protein (e.g. does not cause apoptosis). CT20p is not membrane permeable but can be introduced to cells using polymeric nanoparticles, a method that promotes efficient delivery of the peptide into the …

Co-Targeting Of Cyclooxygenase-2 And Foxm1 Is A Viable Strategy In Inducing Anticancer Effects In Colorectal Cancer Cells, Maqbool Ahmed, Azhar Hussain, Abdul K. Siraj, Shahab Uddin, Nasser Al-Sanea, Fouad Al-Dayel, Mohammed Al-Assiri, Shaham Beg, Khawla S. Al-Kuraya

Centre for Regenerative Medicine & Stem Cell Research

Background: Cross-talk between deregulated signaling pathways in cancer cells causes uncontrolled growth and proliferation. These cancers cells become more aggressive and quickly develop resistance to therapy. Therefore targeting of these deregulated pathways simultaneously can result in efficient cell death of cancer cells. In this study we investigated co-expression of Cox-2 and FoxM1 in a cohort of colorectal carcinoma (CRC) samples and also examined whether inhibition of Cox-2 and FoxM1 simultaneously can lead to inhibition of cell viability and induction of apoptosis in colorectal cancer cell lines and in vivo xenograf
Methods: Protein expression of Cox-2 and FoxM1 was determined …

Expression Of Interferon Gamma By A Recombinant Rabies Virus Strongly Attenuates The Pathogenicity Of The Virus Via Induction Of Type I Interferon., Darryll A Barkhouse, Samantha A Garcia, Emily K Bongiorno, Aurore Lebrun, Milosz Faber, D Craig Hooper, Phd

Department of Cancer Biology Faculty Papers

UNLABELLED: Previous animal model experiments have shown a correlation between interferon gamma (IFN-γ) expression and both survival from infection with attenuated rabies virus (RABV) and reduction of neurological sequelae. Therefore, we hypothesized that rapid production of murine IFN-γ by the rabies virus itself would induce a more robust antiviral response than would occur naturally in mice. To test this hypothesis, we used reverse engineering to clone the mouse IFN-γ gene into a pathogenic rabies virus backbone, SPBN, to produce the recombinant rabies virus designated SPBNγ. Morbidity and mortality were monitored in mice infected intranasally with SPBNγ or SPBN(-) control virus …

Antidiarrhoeal, Antisecretory And Antispasmodic Activities Of Matricaria Chamomilla Are Mediated Predominantly Through K+-Channels Activation, Hassan Mehmood, Siraj Munir, Uzair Ali Khalid, Mudassir Asrar, Anwarul Hassan Gilani

Department of Biological & Biomedical Sciences

Background: Matricaria chamomilla commonly known as “Chamomile” (Asteraceae) is a popular medicinal herb widely used in indigenous system of medicine for a variety of ailments. However, there is no detailed study available showing its effectiveness in hyperactive gut disorders like, abdominal colic and diarrhoea. This study was designed to determine the pharmacological basis for the folkloric use of Matricaria chamomilla in diarrhoea.
Methods: The crude aqueous-methanolic extract of Matricaria chamomilla (Mc.Cr) was studied for its protective effect in mice against castor oil-induced diarrhoea and intestinal fluid accumulation. The isolated rabbit jejunum was selected for the in-vitro experiments using tissue bath …

Effects Of Aggregated Alpha-Synuclein On Cultured Neuronal Cells, David Freeman

Dissertations

α-synuclein dysregulation is a critical aspect of Parkinson's disease pathology. Recent studies have observed that α-synuclein aggregates are cytotoxic to cells in culture and that this toxicity can be spread between cells. However, the molecular mechanisms governing this cytotoxicity and spread are poorly characterized. Recent studies of viruses and bacteria, which achieve their cytoplasmic entry by rupturing intracellular vesicles, have utilized the redistribution of galectin proteins as a tool to measure vesicle rupture by these organisms. Using this approach, we demonstrate that α-synuclein aggregates can induce the rupture of lysosomes following their endocytosis in neuronal cell lines. This rupture can …

Extended Treatment Window Exists For Improving Sensorimotor Recovery Using Anti-Nogo A Immunotherapy In Adult Rats With Chronic Stroke Deficits, Katherine Marie Podraza

Dissertations

Stroke related death ranks as the fourth most common cause of mortality in the United States. Current therapeutic options following stroke are limited. One potential therapy involves the use of anti-Nogo-A immunotherapy post-stroke. Our laboratory has shown that the administration of this novel treatment results in sensorimotor recovery in adult and aged rats. This therapy has been shown to be efficacious when applied immediately, 24 hours, and 1 week post-stroke in rats with mild to moderate sensorimotor deficits. In addition, recent results suggest that administration of anti-Nogo-A immunotherapy up to 9 weeks after stroke still induces functional recovery and neuroanatomical …

A Novel Codon-Optimized Siv Gag-Pol Immunogen For Genebased Vaccination, Catherine M. Crosby, Eric A. Weaver, Reeti Khare, Michael A. Barry

Nebraska Center for Virology: Faculty Publications

Simian immunodeficiency virus (SIV) is a robust pathogen used in non-human primates to model HIV vaccines. SIV encodes a number of potential vaccine targets. By far the largest and most conserved protein target in SIV is its gag-pol protein that bears many epitopes to drive multivalent immune T cell responses. While gag-pol is an attractive antigen, it is only translated after a frame shift between gag and pol with the effect that gag and pol are expressed at an approximate 10/1 ratio. The codon bias of native lentiviral genes are also mismatched with the abundance of tRNAs in mammalian cells …

Role Of 5'Tg3'-Interacting Factors (Tgifs) In Vorinostat (Hdac Inhibitor)-Mediated Corneal Fibrosis Inhibition, Ajay Sharma, Nishant R. Sinha, Saad Siddiqui, Rajiv R. Mohan

Pharmacy Faculty Articles and Research

Purpose: We have previously reported that vorinostat, an FDA-approved, clinically used histone deacetylase (HDAC) inhibitor, attenuates corneal fibrosis in vivo in rabbits by blocking transforming growth factor β (TGFβ). The 5′TG3′-interacting factors (TGIFs) are transcriptional repressors of TGFβ1 signaling via the Smad pathway. The present study was designed to explore the expression of TGIFs in human corneal fibroblasts and to investigate their role in mediating the antifibrotic effect of vorinostat.

Methods: Human corneal fibroblast cultures were generated from donor corneas. RNA isolation, cDNA preparation, and PCR were performed to detect the presence of TGIF1 and TGIF2 transcripts. The cultures were …