Digital Commons Network^™

Bone Morphogenetic Protein-Focused Strategies To Induce Cytotoxicity In Lung Cancer Cells, A. Fotinos, N. Nagarajan, A. S. Martins, D. T. Fritz, D. Garsetti, A. T. Lee, C. C. Hong, M. B. Rogers

Journal Articles

Background: High bone morphogenetic protein (BMP)-2 expression in lung carcinoma correlates with poor patient prognosis. The present study explored strategies to repress BMP signaling. Materials and Methods: The cytotoxicity of BMP2-knockdown, dorsomorphin derivatives, and microRNAs was tested in transformed and non-transformed lung cells. Microarray analyses of 1,145 microRNAs in A549 lung adenocarcinoma cells and two other transformed lung cell types relative to BEAS-2B bronchial epithelial cells were performed. Results: Reduced BMP2 synthesis inhibited A549 cell growth. The dorsomorphin derivative LDN-193189, but not DMH1 or DMH4, was strongly cytotoxic towards A549 cells, but not towards BEAS-2B cells. Microarray analysis revealed that …

Suppression Of Aquaporin, A Mediator Of Water Channel Control In The Carcinogenic Liver Fluke, Opisthorchis Viverrini, Sirikanda Thanasuwan, Supawadee Piratae, Paul J. Brindley, Alex Loukas, Sasithorn Kaewkes, Thewarach Laha

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Background

Opisthorchiasis and Opisthorchis viverrini-associated bile duct cancer represent major public health threats in Thailand and Laos. The tegument of this food borne fluke plays pivotal roles in parasite metabolism, homeostasis and osmoregulation. Excretory/secretory products also pass from the fluke to the biliary environment, products that likely underlie pathogenesis of liver fluke infection. Aquaporins (AQPs), belong to the major intrinsic protein superfamily of integral plasma membrane channel proteins that selectively transport water across cell membranes. AQPs play key roles as water and ion transport channels through the tegument of helminth parasites.

Methods

Here, two forms of AQP mRNAs from the …

The Preliminary Study Of Effects Of Tolfenamic Acid On Cell Proliferation, Cell Apoptosis, And Intracellular Collagen Deposition In Keloid Fibroblasts In Vitro, Dan Yi, Mackenzie S. Newman, Yanfang Chen, Richard Simman

Pharmacology and Toxicology Faculty Publications

Keloid scarring is a fibroproliferative disorder due to the accumulation of collagen type I. Tolfenamic acid (TA), a nonsteroidal anti-inflammatory drug, has been found to potentially affect the synthesis of collagen in rats. In this preliminary study, we aimed to test the effects of TA on cell proliferation, cell apoptosis, and the deposition of intracellular collagen in keloid fibroblasts. Normal fibroblasts (NFs) and keloid fibroblasts (KFs) were obtained from human dermis tissue. Within the dose range 10−3–10−6 M and exposure times 24 h, 48 h, and 72 h, we found that 0.55 × 10−3 M TA at 48 h exposure …

Phenoxybenzamine Is Neuroprotective In A Rat Model Of Severe Traumatic Brain Injury, Thomas Rau, Aakriti Kothiwal, Annela Rova, Joseph F. Rhoderick, David J. Poulsen

Biomedical and Pharmaceutical Sciences Faculty Publications

Phenoxybenzamine (PBZ) is an FDA approved α-1 adrenergic receptor antagonist that is currently used to treat symptoms of pheochromocytoma. However, it has not been studied as a neuroprotective agent for traumatic brain injury (TBI). While screening neuroprotective candidates, we found that phenoxybenzamine reduced neuronal death in rat hippocampal slice cultures following exposure to oxygen glucose deprivation (OGD). Using this system, we found that phenoxybenzamine reduced neuronal death over a broad dose range (0.1 μM–1 mM) and provided efficacy when delivered up to 16 h post-OGD. We further tested phenoxybenzamine in the rat lateral fluid percussion model of TBI. When administered …

Decreased Langerhans Cell Responses To Il-36 Gamma: Altered Innate Immunity In Patients With Recurrent Respiratory Papillomatosis, J. Devoti, L. Hatam, A. Lucs, A. Afzal, A. Abramson, B. M. Steinberg, V. Bonagura

Journal Articles

Recurrent respiratory papillomatosis (RRP) is a rare, chronic disease caused by human papillomaviruses (HPVs) types 6 and 11 that is characterized by the polarization of adaptive immune responses that support persistent HPV infection. Respiratory papillomas express elevated mRNA levels of IL-36 gamma, a proinflammatory cytokine in comparison to autologous clinically normal laryngeal tissues; however there is no evidence of inflammation in these lesions. Consistent with this, respiratory papillomas do not contain T(H)1-like CD4(+) T-cells or cytotoxic CD8(+) T-cells, but instead contain a predominance of T(H)2-like and T regulatory cells (Tregs). In addition, papillomas also are infiltrated with immature Langerhans cells …

Alpha 7 Nicotinic Acetylcholine Receptor Signaling Inhibits Inflammasome Activation By Preventing Mitochondrial Dna Release, B. Lu, K. Kwan, Y. A. Levine, P. S. Olofsson, H. Yang, J. H. Li, S. Joshi, H. C. Wang, U. Andersson, S. S. Chavan, K. J. Tracey

Journal Articles

The mammalian immune system and the nervous system coevolved under the influence of cellular and environmental stress. Cellular stress is associated with changes in immunity and activation of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, a key component of innate immunity. Here we show that alpha 7 nicotinic acetylcholine receptor (alpha 7 nAchR)-signaling inhibits inflammasome activation and prevents release of mitochondrial DNA, an NLRP3 ligand. Cholinergic receptor agonists or vagus nerve stimulation significantly inhibits inflammasome activation, whereas genetic deletion of alpha 7 nAchR significantly enhances inflammasome activation. Acetylcholine accumulates in macrophage cytoplasm after adenosine triphosphate (ATP) stimulation …

Probiotics: Achieving A Better Regulatory Fit, Diane E. Hoffmann, Claire M. Fraser, Francis Palumbo, Jacques Ravel, Virginia Rowthorn, Jack Schwartz

Faculty Scholarship

In 2007, the National Institutes of Health (NIH) launched the Human Microbiome Project (HMP), a $150 million initiative to characterize the microbial communities found at several different sites on the human body and to analyze the role of these microbes in human health and disease. Many lines of research have demonstrated the significant role of the microbiota in human physiology. The microbiota is involved, for example, in the healthy development of the immune system, prevention of infection from pathogenic or opportunistic microbes, and maintenance of intestinal barrier function. The HMP findings are helping us understand the role and variation of …

The Relationship Of Neurocognition And Negative Symptoms To Social And Role Functioning Over Time In Individuals At Clinical High Risk In The First Phase Of The North American Prodrome Longitudinal Study, E. C. Meyer, Ricardo Carrion, Barbara Cornblatt, J. Addington, K. S. Cadenhead, T. D. Cannon, T. H. Mcglashan, D. O. Perkins, M. T. Tsuang, L. J. Seidman, +3 Additional Authors

Journal Articles

OBJECTIVES: Impaired social, role, and neurocognitive functioning are preillness characteristics of people who later develop psychosis. In people with schizophrenia, neurocognition and negative symptoms are associated with functional impairment. We examined the relative contributions of neurocognition and symptoms to social and role functioning over time in clinically high-risk (CHR) individuals and determined if negative symptoms mediated the influence of cognition on functioning. METHODS: Social, role, and neurocognitive functioning and positive, negative, and disorganized symptoms were assessed in 167 individuals at CHR for psychosis in the North American Prodrome Longitudinal Study Phase 1 (NAPLS-1), of whom 96 were reassessed at 12 …

Circulating Complexes Of The Vitamin D Binding Protein With G-Actin Induce Lung Inflammation By Targeting Endothelial Cells, L. Y. Ge, G. Trujillo, E. J. Miller, R. R. Kew

Journal Articles

This study investigated the actin scavenger function of the vitamin D binding protein (DBP) in vivo using DBP null (-/-) mice. Intravenous injection of G-actin into wild-type (DBP+/+) and DBP-/- mice showed that contrary to expectations, DBP+/+ mice developed more severe acute lung inflammation. Inflammation was restricted to the lung and pathological changes were clearly evident at 1.5 and 4 h post-injection but were largely resolved by 24 h. Histology of DBP+/+ lungs revealed noticeably more vascular leakage, hemorrhage and thickening of the alveolar wall. Flow cytometry analysis of whole lung homogenates showed significantly increased neutrophil infiltration into DBP+/+ mouse …

Nudging The Fda, W. Nicholson Price Ii, I. Glenn Cohen

Law Faculty Scholarship

[Excerpt] "The FDA’s regulation of drugs is frequently the subject of policy debate, with arguments falling into two camps. On the one hand, a libertarian view of patients and the health care system holds high the value of consumer choice. Patients should get all the information and the drugs they want; the FDA should do what it can to enforce some basic standards but should otherwise get out of the way. On the other hand, a paternalist view values the FDA’s role as an expert agency standing between patients and a set of potentially dangerous drugs and potentially unscrupulous or …

The Omega-3 Fatty Acid Eicosapentaenoic Acid Is Required For Normal Alcohol Response Behaviors In C. Elegans, Richard C. Raabe, Laura D. Mathies, Andrew G. Davies, Jill C. Bettinger

Pharmacology and Toxicology Publications

Alcohol addiction is a widespread societal problem, for which there are few treatments. There are significant genetic and environmental influences on abuse liability, and understanding these factors will be important for the identification of susceptible individuals and the development of effective pharmacotherapies. In humans, the level of response to alcohol is strongly predictive of subsequent alcohol abuse. Level of response is a combination of counteracting responses to alcohol, the level of sensitivity to the drug and the degree to which tolerance develops during the drug exposure, called acute functional tolerance. We use the simple and well-characterized nervous system of Caenorhabditis …

Complement Expression In The Retina Is Not Influenced By Short-Term Pressure Elevation, Konstantin Astafurov, Cecilia Q. Dong, Lampros Panagis, Gautam Kamtham, Lizhen Ren, Anna Rozenboym, Tarique D. Perera, Jeremy D. Coplan, John Danias

Publications and Research

Purpose: To determine whether short-term pressure elevation affects complement gene expression in the retina in vitro and in vivo.

Methods: Muller cell (TR-MUL5) cultures and organotypic retinal cultures from adult mice and monkeys were sub- jected to either 24-h or 72-h of pressure at 0, 15, 30, and 45 mmHg above ambient. C57BL/6 mice were subjected to microbead-induced intraocular pressure (IOP) elevation for 7 days. RNA and protein were extracted and used for analysis of expression levels of complement component genes and complement component 1, q subcomponent (C1q) and comple- ment factor H (CFH) immunoblotting. …

Identification Of A Treatment-Resistant, Ketamine-Sensitive Genetic Line In The Chick Anxiety-Depression Model, Stephen Walter White

Electronic Theses and Dissertations

Approximately 60% of Major Depressive Disorder (MDD) patients do not respond to FDA-approved antidepressants. Introducing effective pharmacotherapies for this treatment-resistant population is hindered by the lack of pre-clinical screening assays that accurately model the clinical features of TRD. The purpose of this research was to screen representatives of different classes FDA-approved antidepressants and one novel antidepressant in two genetic lines of domestic fowl chicks that have previously been identified as stress-vulnerable and stress-resilient in the chick anxiety depression model. Separate groups of socially raised Black Australorp (stress-vulnerable) and Production Red (stress-resilient) chicks were administered the tricyclic antidepressant imipramine (0-20 mg/kg), …

Pharmacological Basis For The Medicinal Use Of Rhus Coriaria In Hyperactive Gut Disorders, Khalid Hussain Janbaz, Arham Shabbir, Hassan Mehmood, Anwarul Hassan Gilani

Department of Biological & Biomedical Sciences

This study was aimed at providing the pharmacological basis for the medicinal use of Rhus coriaria in diarrhea. In mice, the crude of R. coriaria demonstrated antisecretory and antidiarrheal effects against castor oil-induced fluid accumulation and diarrhea at at 100 and 300 mg/kg, respectively, and was found safe up to tested dose of 5 g/kg. In isolated rabbit jejunum, R. coriaria exhibited concentration-dependent (0.01-3.0 mg/mL) relaxation of spontaneous and high K⁺ (80 mM)-induced contractions, similar to verapamil. The Ca⁺⁺ antagonist activity was confirmed when pretreatment of R. coriaria shifted Ca⁺⁺ concentration-response curves to the right with suppression …

Prevalence And Prevention Of The Female Athlete Triad, Elizabeth Dachenhaus

Honors Projects

A study was composed to analyze the three components of the female athlete triad: disordered eating, amenorrhea, and osteoporosis. The cyclic behavior of these three components and determination of which of the pillars of the triad is the most dangerous was also focused on. In order to test the prevalence of disordered eating among women’s collegiate teams, a brief survey was distributed and analyzed among athletes at Bowling Green State University. In addition to confirming that women in aesthetic sports experience a greater amount of disordered eating on the team, the survey also identified women that participated in sports perceived …

"Synthesis Of 4-Aryl-6-Indolylpyridine-3-Carbonitriles And Evaluation Of Their Antiproliferative Activity" Data Files, Naglaa Salem El-Sayed, Amir Nasrolahi Shirazi, Magda Goda El-Meligy, Ahmed Kamel El-Ziaty, Zenat Adeeb Nagib, Keykavous Parang

Pharmacy Faculty Data Sets

No abstract provided.

Risk Factors For Early Childhood Infection Of Human Herpesvirus-8 In Zambian Children: The Role Of Early Childhood Feeding Practices, Kay L. Crabtree, Janet M. Wojcicki, Veenu Minhas, David R. Smith, Chipepo Kankasa, Charles D. Mitchell, Charles Wood

Nebraska Center for Virology: Faculty Publications

Background—Human herpesvirus-8 (HHV-8) infection in early childhood is common throughout sub-Saharan Africa with prevalence increasing throughout childhood. Specific routes of transmission have not been clearly delineated, though HHV-8 is present in high concentrations in saliva.

Methods—To understand the horizontal transmission of HHV-8 within households to children we enrolled for cross-sectional analysis, 251 households including 254 children, age two and under, in Lusaka, Zambia. For all children, plasma was screened for HHV-8 and HIV-1 and health and behavioral questionnaires were completed. Multi-level logistic regression analysis was conducted to assess independent factors for HHV-8 infection in children.

Results—Risk factors for HHV-8 infection …

Turnip Crinkle Virus Coat Protein Inhibits The Basal Immune Response To Virus Invasion In Arabidopsis By Binding To The Nac Transcription Factor Tip, Teresa Donze, Feng Qu, Paul Twigg, T. Jack Morris

Nebraska Center for Virology: Faculty Publications

Turnip crinkle virus (TCV) has been shown to interact with a NAC transcription factor, TIP, of Arabidopsis thaliana, via its coat protein (CP). This interaction correlates with the resistance response manifested in TCV-resistant Arabidopsis ecotype Di-17. We report that failure of a mutated CP to interact with TIP triggered the corresponding TCV mutant (R6A) to cause more severe symptoms in the TCV-susceptible ecotype Col-0. We hypothesized that TCV regulates antiviral basal immunity through TIP-CP interaction. Consistent with this hypothesis, we found that the rate of accumulation of R6A was measurably slower than wild-type TCV over the course of an …

Cyclic Peptide-Capped Gold Nanoparticles For Enhanced Sirna Delivery, Amir Nasrolahi Shirazi, Karissa L. Paquin, Niall G. Howlett, Dindyal Mandal, Keykavous Parang

Pharmacy Faculty Articles and Research

Previously, we have reported the synthesis of a homochiral L-cyclic peptide [WR]5 and its use for delivery of anti-HIV drugs and biomolecules. A physical mixture of HAuCl4 and the peptide generated peptide-capped gold nanoparticles. Here, [WR]5 and [WR]5-AuNPs were tested for their efficiency to deliver a small interfering RNA molecule (siRNA) in human cervix adenocarcinoma (HeLa) cells. Flow cytometry investigation revealed that the intracellular uptake of a fluorescence-labeled non-targeting siRNA (200 nM) was enhanced in the presence of [WR]5 and [WR]5-AuNPs by 2- and 3.8-fold when compared with that of siRNA alone after 24 h incubation. Comparative toxicity results showed …

Altered Mucins (Muc) Trafficking In Benign And Malignant Conditions., Suhasini Joshi, Sushil Kumar, Amit Choudhury, Moorthy P. Ponnusamy, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Mucins are high molecular weight O-glycoproteins that are predominantly expressed at the apical surface of epithelial cells and have wide range of functions. The functional diversity is attributed to their structure that comprises of a peptide chain with unique domains and multiple carbohydrate moieties added during posttranslational modifications. Tumor cells aberrantly overexpress mucins, and thereby promote proliferation, differentiation, motility, invasion and metastasis. Along with their aberrant expression, accumulating evidence suggest the critical role of altered subcellular localization of mucins under pathological conditions due to altered endocytic processes. The mislocalization of mucins and their interactions result in change in the density …

Cystatin C As Biomarker Of Contrast-Induced Nephropathy In Pediatric Cardiac Angiography, Osman Özdemi̇r, Ayşe Deni̇z Oğuz, Abdülkadi̇r Eren, Ci̇hat Şanli, Hüsnü Oğuz Söylemezoğlu, Ayşe Banu Çayci

Turkish Journal of Medical Sciences

The purpose of this study is to find the frequency of contrast-induced nephropathy (CIN) and to show the risk factors in the development of CIN and the diagnostic utility of serum cystatin C (CysC) and serum and urine neutrophil gelatinase-associated lipocalin (NGAL) during childhood following cardiac angiography. Materials and methods: In this prospective study, we studied 46 children with congenital heart disease. The levels of serum creatinine, serum CysC, and serum NGAL were measured at 4, 24, and 48 h, while levels of urine NGAL and urine creatinine were measured at 4 to 8 and 48 h following cardiac angiography. …

Targeting Tau-Mediated Nmdar Hypofunction Reverses Deficits In A Mouse Model Of Frontotemporal Dementia, Brian Andrew Warmus

All ETDs from UAB

Frontotemporal dementia (FTD) is a rapidly progressive and lethal disease, with no disease-modifying treatments. It is known that tau mutations cause FTD, but the underlying neurobiology is undefined. We sought to identify how tau affects the neurobiology in order to find potential treatment targets. Here, we address this question using a new mouse model expressing human tau with an FTD-associated mutation. We studied behavior, physiology, biochemistry, and neuropathology in several cohorts of mice at different ages. These mutant tau mice had abnormal repetitive behavior characteristic of FTD and synaptic deficits selectively in regions associated with FTD (ventral striatum and insula). …

Copper Homeostasis In Mycobacteria, Jennifer L. Rowland

All ETDs from UAB

Mycobacterium tuberculosis, the causative agent on tuberculosis in humans, is a globally important pathogen. In 2013, nearly 1.2 million people died from tuberculosis. Drug treatments and effective vaccines are lacking for this pathogen. A better understanding of the basic physiology of M. tuberculosis is required to improve disease outcomes. Upon inhalation into the lungs, M. tuberculosis is taken up by macrophages, in a process called phagocytosis, which normally destroys invading bacteria. As the phagosome inside the macrophage matures, bactericidal mechanisms are activated including: lowering pH, and introducing reactive oxygen and nitrogen species and hydrolytic enzymes to degrade bacterial cell walls. …

Protein O-Glcnac Modification In Diabetic Vascular Calcification, Jack Heath

All ETDs from UAB

Vascular calcification is prevalent in patients of diabetes mellitus, which represents an independent risk factor that positively correlated with morbidity and mortality in these patients. Vascular calcification is now recognized as a cell-regulated process of osteogenic differentiation of vascular smooth muscle cells (VSMC) in response to stress, such as hyperglycemia and oxidative stress. Both hyperglycemia and oxidative stress have been shown to induce protein modification by O-linked ß-N-acetylglucosamine modification (O-GlcNAcylation), which is also elevated in diabetes. The present studies aimed to determine the effects of protein O-GlcNAcylation on vascular calcification in diabetes, and uncover the underlying molecular mechanisms. With the …

Innate Immune Defense Against The Fungal Pathogen Aspergillus Fumigatus, Melissa Ann Gessner

All ETDs from UAB

The opportunistic fungal pathogen Aspergillus fumigatus is a ubiquitous mold that causes severe, invasive life-threatening infections in patients that are severely immunocompromised. Major risk factors include neutropenia, neutrophil dysfunction and immunosuppressive therapies. Recently, however, rising incidences of colonizing A. fumigatus have been reported in patients without classical risk factors. We sought out to elucidate non-classical pre-disposing conditions that may render a lung environment susceptible to fungal colonization as well as mechanisms involved in immune defense against the invading fungal pathogen. Further defining a role for Dectin-1 in an Aspergillus fumigatus infection, we demonstrated a critical role for Dectin-1 dependent interleukin-22 …

The Role Of Il-7 And C-Kit Signaling Pathways In Specification Of B Lymphocytes, Oleg Kolupaev

All ETDs from UAB

B-lymphocyte commitment from common lymphoid progenitors (CLP) is orchestrated by a number of transcription factors and extracellular developmental cues. Most prominently, IL-7 signaling acts as a critical factor for promotion of B cell differentiation through its role in upregulation of the B-cell commitment factor, Ebf1, by activation of Jak-Stat5 signaling. Other cytokines and growth factors secreted by bone marrow stromal cells, such as Flt3 ligand, are known to modulate developmental outcomes by regulating the IL-7R-Jak-Stat5 pathway. The role of stem cell factor (SCF), the ligand of the receptor tyrosine kinase (RTK) c-Kit, and the mechanism by which it affects cell …

Osteomimmunology Of Bone Fracture Healing And Cell And Gene Therapy Approaches For Nonunion Bone Defects, Seth G. Levy

All ETDs from UAB

Despite the body's ability to repair bone fractures under normal circumstances, up to 10% of the 7.9 million fractures suffered in the United States each year do not achieve bony union. Bone fractures heal with overlapping phases of inflammation, cell proliferation, and bone remodeling. Osteogenesis and angiogenesis are known to work in concert to control many stages of this process, but when one is impaired it leads to failure of bone healing, referred to as a nonunion. Such nonunion fractures often result from critical-size defects that will not completely heal over the natural lifetime of the animal. Based on this …

Engineering Fibroblast-Remodeled Electrospun Matrices For Full-Thickness Skin Regeneration, Paul Bonvallet

All ETDs from UAB

Skin is often severely damaged, resulting in the need for surgical intervention. There are many limitations to current therapies, therefore a synthetic skin graft would be invaluable for skin regeneration. The focus of the current study is on developing engineered scaffolds with embedded dermal fibroblasts that can be remodeled into native skin tissue upon implantation. To achieve this goal we created electrospun scaffolds composed of collagen I and polycaprolactone (PCL), and then introduced pores to allow fibroblast infiltration. In initial experiments performed to optimize pore size and collagen to PCL concentration, we determined that a 160 µm pore diameter, and …

Il-8 Is Necessary And Sufficient For X-Ray Radiation Enhanced Endothelial Adhesion., Stephen Kyle Babitz

All ETDs from UAB

Ionizing radiation (IR) is a potent inflammatory stimulus to the human body. In the vasculature, inflammation is a major contributing factor for atherosclerosis. In addition, radiation from several sources has been linked with increased risk for multiple cardiovascular complications. A key compnent of radiation associated inflammation is an increase in the adhesiveness of the endothelium which leads to a pathogenic accumulation of leukocytes in the vascular wall. This is one of the initial steps in vascular inflammation and leads to a number of adverse complications such as heart disease and stroke. The molecular mechanisms behind radiaton enhanced endothelial adhesion have …

Effects Of Storage On The Red Blood Cell And Its Implications For Transfusion, Ryan D. Stapley

All ETDs from UAB

Transfusion with red blood cells (RBC) remains a frontline therapy in critically ill patients. Recent studies have documented an association between storage duration and an increased incidence of transfusion-related toxicities. This transfusion-related toxicity is characterized by both a pro-inflammatory state and a microcirculatory dysfunction and is associated with changes that occur to the RBC and its media during storage referred to as the storage lesion. These changes that occur to the RBC include an increase in cell-free hemoglobin, heme, free iron, microparticles, as well as changes to the RBC itself. This thesis explores how these elements could contribute to transfusion-related …