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Killing Of Human Melanoma Cells Induced By Activation Of Class I Interferon-Regulated Signaling Pathways Via Mda-7/Il-24, Suhendan Ekmekcioglu, John B Mumm, Malini Udtha, Sunil Chada, Elizabeth A Grimm

Faculty, Staff and Student Publications

Restoration of the tumor-suppression function by gene transfer of the melanoma differentiation-associated gene 7 (MDA7)/interleukin 24 (IL-24) successfully induces apoptosis in melanoma tumors in vivo. To address the molecular mechanisms involved, we previously revealed that MDA7/IL-24 treatment of melanoma cells down-regulates interferon regulatory factor (IRF)-1 expression and concomitantly up-regulates IRF-2 expression, which competes with the activity of IRF-1 and reverses the induction of IRF-1-regulated inducible nitric oxide synthase (iNOS). Interferons (IFNs) influence melanoma cell survival by modulating apoptosis. A class I IFN (IFN-alpha) has been approved for the treatment of advanced melanoma with some limited success. A class II IFN …

A New Model For Hemoglobin Ingestion And Transport By The Human Malaria Parasite Plasmodium Falciparum., Michelle D Lazarus, Timothy G Schneider, Theodore F Taraschi

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The current model for hemoglobin ingestion and transport by intraerythrocytic Plasmodium falciparum malaria parasites shares similarities with endocytosis. However, the model is largely hypothetical, and the mechanisms responsible for the ingestion and transport of host cell hemoglobin to the lysosome-like food vacuole (FV) of the parasite are poorly understood. Because actin dynamics play key roles in vesicle formation and transport in endocytosis, we used the actin-perturbing agents jasplakinolide and cytochalasin D to investigate the role of parasite actin in hemoglobin ingestion and transport to the FV. In addition, we tested the current hemoglobin trafficking model through extensive analysis of serial …

Rtr1 Is The Saccharomyces Cerevisiae Homolog Of A Novel Family Of Rna Polymerase Ii-Binding Proteins, Patrick A Gibney, Thomas Fries, Susanne M Bailer, Kevin A Morano

Faculty, Staff and Student Publications

Cells must rapidly sense and respond to a wide variety of potentially cytotoxic external stressors to survive in a constantly changing environment. In a search for novel genes required for stress tolerance in Saccharomyces cerevisiae, we identified the uncharacterized open reading frame YER139C as a gene required for growth at 37 degrees C in the presence of the heat shock mimetic formamide. YER139C encodes the closest yeast homolog of the human RPAP2 protein, recently identified as a novel RNA polymerase II (RNAPII)-associated factor. Multiple lines of evidence support a role for this gene family in transcription, prompting us to rename …

Neuromyelitis Optica Pathogenesis And Aquaporin 4, David J. Graber, Michael Levy, Douglas Kerr, William F. Wade

Dartmouth Scholarship

Neuromyelitis optica (NMO) is a severe, debilitating human disease that predominantly features immunopathology in the optic nerves and the spinal cord. An IgG1 autoantibody (NMO-IgG) that binds aquaporin 4 (AQP4) has been identified in the sera of a significant number of NMO patients, as well as in patients with two related neurologic conditions, bilateral optic neuritis (ON), and longitudinal extensive transverse myelitis (LETM), that are generally considered to lie within the NMO spectrum of diseases. NMO-IgG is not the only autoantibody found in NMO patient sera, but the correlation of pathology in central nervous system (CNS) with tissues that normally …

A Bacterial Cytotoxin Identifies The Rhoa Exchange Factor Net1 As A Key Effector In The Response To Dna Damage, Lina Guerra, Heather S. Carr, Agneta Richter-Dahlfors, Maria G Masucci, Monica Thelestam, Jeffrey A Frost, Teresa Frisan

Faculty, Staff and Student Publications

BACKGROUND: Exposure of adherent cells to DNA damaging agents, such as the bacterial cytolethal distending toxin (CDT) or ionizing radiations (IR), activates the small GTPase RhoA, which promotes the formation of actin stress fibers and delays cell death. The signalling intermediates that regulate RhoA activation and promote cell survival are unknown. PRINCIPAL FINDINGS: We demonstrate that the nuclear RhoA-specific Guanine nucleotide Exchange Factor (GEF) Net1 becomes dephosphorylated at a critical inhibitory site in cells exposed to CDT or IR. Expression of a dominant negative Net1 or Net1 knock down by iRNA prevented RhoA activation, inhibited the formation of stress fibers, …

Cif Is Negatively Regulated By The Tetr Family Repressor Cifr, Daniel P. Maceachran, Bruce A. Stanton, George A. O'Toole

Dartmouth Scholarship

We previously reported that the novel Pseudomonas aeruginosa toxin Cif is capable of decreasing apical membrane expression of the cystic fibrosis transmembrane conductance regulator (CFTR). We further demonstrated that Cif is capable of degrading the synthetic epoxide hydrolase (EH) substrate S-NEPC [(2S,3S)-trans-3-phenyl-2-oxiranylmethyl 4-nitrophenol carbonate], suggesting that Cif may be reducing apical membrane expression of CFTR via its EH activity. Here we report that Cif is capable of degrading the xenobiotic epoxide epibromohydrin (EBH) to its vicinal diol 3-bromo-1,2-propanediol. We also demonstrate that this epoxide is a potent inducer of cif gene expression. We show that the predicted TetR family transcriptional …

A Distinct Role For B1b Lymphocytes In T Cell-Independent Immunity, Kishore R. Alugupalli

Department of Microbiology and Immunology Faculty Papers

Pathogenesis of infectious disease is not only determined by the virulence of the microbe but also by the immune status of the host. Vaccination is the most effective means to control infectious diseases. A hallmark of the adaptive immune system is the generation of B cell memory, which provides a long-lasting protective antibody response that is central to the concept of vaccination. Recent studies revealed a distinct function for B1b lymphocytes, a minor subset of mature B cells that closely resembles that of memory B cells in a number of aspects. In contrast to the development of conventional B cell …

Serum Proteomic Profiles In Inflammatory And Non-Inflammatory Cardiomyopathies: A Novel Approach For Diagnostic Biomarker Discovery, Oyere Onuma

Yale Medicine Thesis Digital Library

The aim of this project is to develop a noninvasive serum test that predicts histologic forms of myocarditis (inflammatory) and dilated (non-inflammatory) cardiomyopathy using proteomic techniques to analyze serum proteins. Idiopathic dilated cardiomyopathy (DCM) and myocarditis (myocardial inflammation) represent a spectrum of heart muscle disease of various etiologies that usually present with progressive heart failure. Together, they constitute the leading cause of heart transplantation in the United States. Currently, the gold standard of diagnosis of myocarditis is by endomyocardial biopsy (EMB) and histopathological classification according to the Dallas Criteria ; however this diagnostic technique is severely limited by its invasiveness, …

The State Of The Art In Evaluating The Performance Of Assistant And Associate Deans As Seen By Deans And Assistant And Associate Deans., David G. Dunning, Timothy M. Durham, Mert N. Aksu, Brian M. Lange

Journal Articles: College of Dentistry

This study explores the little-understood process of evaluating the performance of assistant and associate deans at dental colleges in the United States and Canada. Specifically, this research aimed to identify the methods, processes, and outcomes related to the performance appraisals of assistant/associate deans. Both deans and assistant/associate deans were surveyed. Forty-four of sixty-six deans (66.7 percent) and 227 of 315 assistant/associate deans (72.1 percent) completed surveys with both close-ended and open-ended questions. In addition, ten individuals from each group were interviewed. Results indicate that 75-89 percent of assistant/associate deans are formally evaluated, although as many as 27 percent may lack …

17beta-Estradiol Increases Basal But Not Bradykinin-Stimulated Release Of Active T-Pa In Young Postmenopausal Women, Mias Pretorius, Gary Van Guilder, Raul J Guzman, James M Luther, Nancy J Brown

Health and Nutritional Sciences Faculty Publications

Angiotensin-converting enzyme inhibition potentiates basal and bradykinin-stimulated tissue-type plasminogen activator (t-PA) release to a greater extent in women than in men. This study tested the hypothesis that 17beta-estradiol enhances the effect of angiotensin-converting enzyme inhibition on t-PA release in young postmenopausal women. We conducted a double-blind, prospective, crossover study in 14 young postmenopausal women (mean age 48.2+/-2.3 years) who were randomized to receive 17beta-estradiol (1 mg/d) or matching placebo for 4 weeks. At the end of each treatment period, we measured the effect of intraarterial infusion of bradykinin, methacholine, and nitroprusside on forearm blood flow and net t-PA release, before …

Drinking-Water Arsenic Exposure Modulates Gene Expression In Human Lymphocytes From A U.S. Population, Angeline S. Andrew, David A. Jewell, Rebecca A. Mason, Michael L. Whitfield, Jason H. Moore, Margaret R. Karagas

Dartmouth Scholarship

Background:

Arsenic exposure impairs development and can lead to cancer, cardiovascular disease, and diabetes. The mechanism underlying these effects remains unknown. Primarily because of geologic sources of contamination, drinking-water arsenic levels are above the current recommended maximum contaminant level of 10 μg/L in the northeastern, western, and north central regions of the United States.

Objectives:

We investigated the effects of arsenic exposure, defined by internal biomarkers at levels relevant to the United States and similarly exposed populations, on gene expression.

Methods:

We conducted separate Affymetrix microarray-based genomewide analyses of expression patterns. Peripheral blood lymphocyte samples from 21 controls interviewed (1999–2002) …

Drug Metabolism In Human Brain: High Levels Of Cytochrome P4503a43 In Brain And Metabolism Of Anti-Anxiety Drug Alprazolam To Its Active Metabolite, Varsha Agarwal, Reddy P. Kommaddi, Khader Valli, Daniel Ryder, Thomas M. Hyde, Joel E. Kleinman, Henry W. Strobel, Vijayalakshmi Ravindranath

Faculty, Staff and Student Publications

Cytochrome P450 (P450) is a super-family of drug metabolizing enzymes. P450 enzymes have dual function; they can metabolize drugs to pharmacologically inactive metabolites facilitating their excretion or biotransform them to pharmacologically active metabolites which may have longer half-life than the parent drug. The variable pharmacological response to psychoactive drugs typically seen in population groups is often not accountable by considering dissimilarities in hepatic metabolism. Metabolism in brain specific nuclei may play a role in pharmacological modulation of drugs acting on the CNS and help explain some of the diverse response to these drugs seen in patient population. P450 enzymes are …

The Effect Of Dexmedetomidine On The Mini-Cog Score And High-Mobility Group Box 1 Levels In Elderly Patients With Postoperative Neurocognitive Disorders Undergoing Orthopedic Surgery, Joan M Mastrobattista, Mark A Klebanoff, J Christopher Carey, John C Hauth, Cora A Macpherson, J Ernest, Margaret Cotroneo, Kenneth J Leveno, Ronald Wapner, Michael Varner, Jay D Iams, Atef Moawad, Baha M Sibai, Menachem Miodovnik, Mitchell Dombrowski, Mary J O'Sullivan, J Peter Vandorsten, Oded Langer

Faculty, Staff and Student Publications

Our objective was to determine the effect of body mass index (BMI) on response to bacterial vaginosis (BV) treatment. A secondary analysis was conducted of two multicenter trials of therapy for BV and TRICHOMONAS VAGINALIS. Gravida were screened for BV between 8 and 22 weeks and randomized between 16 and 23 weeks to metronidazole or placebo. Of 1497 gravida with asymptomatic BV and preconceptional BMI, 738 were randomized to metronidazole; BMI was divided into categories: < 25, 25 to 29.9, and > or = 30. Rates of BV persistence at follow-up were compared using the Mantel-Haenszel chi square. Multiple logistic regression was used to evaluate the effect …

Ly2109761, A Novel Transforming Growth Factor Beta Receptor Type I And Type Ii Dual Inhibitor, As A Therapeutic Approach To Suppressing Pancreatic Cancer Metastasis, Davide Melisi, Satoshi Ishiyama, Guido M Sclabas, Jason B Fleming, Qianghua Xia, Giampaolo Tortora, James L Abbruzzese, Paul J Chiao

Faculty, Staff and Student Publications

Most pancreatic cancer patients present with inoperable disease or develop metastases after surgery. Conventional therapies are usually ineffective in treating metastatic disease. It is evident that novel therapies remain to be developed. Transforming growth factor beta (TGF-beta) plays a key role in cancer metastasis, signaling through the TGF-beta type I/II receptors (TbetaRI/II). We hypothesized that targeting TbetaRI/II kinase activity with the novel inhibitor LY2109761 would suppress pancreatic cancer metastatic processes. The effect of LY2109761 has been evaluated on soft agar growth, migration, invasion using a fibroblast coculture model, and detachment-induced apoptosis (anoikis) by Annexin V flow cytometric analysis. The efficacy …

Clinical And Microbiological Aspects Of Linezolid Resistance Mediated By The Cfr Gene Encoding A 23s Rrna Methyltransferase, Cesar A Arias, Martha Vallejo, Jinnethe Reyes, Diana Panesso, Jaime Moreno, Elizabeth Castañeda, Maria V Villegas, Barbara E Murray, John P Quinn

Faculty, Staff and Student Publications

The cfr (chloramphenicol-florfenicol resistance) gene encodes a 23S rRNA methyltransferase that confers resistance to linezolid. Detection of linezolid resistance was evaluated in the first cfr-carrying human hospital isolate of linezolid and methicillin-resistant Staphylococcus aureus (designated MRSA CM-05) by dilution and diffusion methods (including Etest). The presence of cfr was investigated in isolates of staphylococci colonizing the patient's household contacts and clinical isolates recovered from patients in the same unit where MRSA CM-05 was isolated. Additionally, 68 chloramphenicol-resistant Colombian MRSA isolates recovered from hospitals between 2001 and 2004 were screened for the presence of the cfr gene. In addition to erm(B), …

Computational Models Of Tandem Src Homology 2 Domain Interactions And Application To Phosphoinositide 3-Kinase, Dipak Barua, James R. Faeder, Jason M. Haugh

Chemical and Biochemical Engineering Faculty Research & Creative Works

Intracellular signal transduction proteins typically utilize multiple interaction domains for proper targeting, and thus a broad diversity of distinct signaling complexes may be assembled. Considering the coordination of only two such domains, as in tandem Src homology 2 (SH2) domain constructs, gives rise to a kinetic scheme that is not adequately described by simple models used routinely to interpret in vitro binding measurements. To analyze the interactions between tandem SH2 domains and bisphosphorylated peptides, we formulated detailed kinetic models and applied them to the phosphoinositide 3-kinase p85 regulatory subunit/platelet-derived growth factor β-receptor system. Data for this system from different in …

Activation Of Heat Shock And Antioxidant Responses By The Natural Product Celastrol: Transcriptional Signatures Of A Thiol-Targeted Molecule, Amy Trott, James D West, Lada Klaić, Sandy D Westerheide, Richard B Silverman, Richard I Morimoto, Kevin A Morano

Faculty, Staff and Student Publications

Stress response pathways allow cells to sense and respond to environmental changes and adverse pathophysiological states. Pharmacological modulation of cellular stress pathways has implications in the treatment of human diseases, including neurodegenerative disorders, cardiovascular disease, and cancer. The quinone methide triterpene celastrol, derived from a traditional Chinese medicinal herb, has numerous pharmacological properties, and it is a potent activator of the mammalian heat shock transcription factor HSF1. However, its mode of action and spectrum of cellular targets are poorly understood. We show here that celastrol activates Hsf1 in Saccharomyces cerevisiae at a similar effective concentration seen in mammalian cells. Transcriptional …

Sp1 Up-Regulates Camp-Response-Element-Binding Protein Expression During Retinoic Acid-Induced Mucous Differentiation Of Normal Human Bronchial Epithelial Cells, Jeong Soo Hong, Seung-Wook Kim, Ja Seok Koo

Faculty, Staff and Student Publications

CREB [CRE (cAMP-response element)-binding protein] is an important transcription factor that is differentially regulated in cells of various types. We recently reported that RA (retinoic acid) rapidly activates CREB without using RARs (RA receptors) or RXRs (retinoid X receptors) in NHTBE cells (normal human tracheobronchial epithelial cells). However, little is known about the role of RA in the physiological regulation of CREB expression in the early mucous differentiation of NHTBE cells. In the present study, we report that RA up-regulates CREB gene expression and that, using 5'-serial deletion promoter analysis and mutagenesis analyses, two Sp1 (specificity protein 1)-binding sites located …

Celecoxib Concentration Predicts Decrease In Prostaglandin E2 Concentrations In Nipple Aspirate Fluid From High Risk Women, Edward R. Sauter, Wenyi Qin, John E. Hewett, Rachel L. Ruhlen, John T. Flynn, George Rottinghaus, Yin-Chieh Chen

Department of Molecular Physiology and Biophysics Faculty Papers

BACKGROUND: Epidemiologic studies suggest that long term low dose celecoxib use significantly lowers breast cancer risk. We previously demonstrated that 400 mg celecoxib taken twice daily for 2 weeks lowered circulating plasma and breast nipple aspirate fluid (NAF) prostaglandin (PG)E2 concentrations in post- but not premenopausal high risk women. We hypothesized that circulating concentrations of celecoxib influenced PGE2 response, and that plasma levels of the drug are influenced by menopausal status. To address these hypotheses, the aims of the study were to determine: 1) if circulating plasma concentrations of celecoxib correlated with the change in plasma or NAF PGE2 concentrations …

Medulloblastomas Overexpress The P53-Inactivating Oncogene Wip1/Ppm1d, Robert C. Castellino, Massimiliano De Bortoli, Xiongbin Lu, Sung-Hwan Moon, Thuy-Ai Nguyen, Mark A. Shepard, Pulivarthi H. Rao, Lawrence A. Donehower, John Y H Kim

Faculty, Staff and Students Publications

Medulloblastoma is the most common malignant brain tumor of childhood. Despite numerous advances, clinical challenges range from recurrent and progressive disease to long-term toxicities in survivors. The lack of more effective, less toxic therapies results from our limited understanding of medulloblastoma growth. Although TP53 is the most commonly altered gene in cancers, it is rarely mutated in medulloblastoma. Accumulating evidence, however, indicates that TP53 pathways are disrupted in medulloblastoma. Wild-type p53-induced phosphatase 1 (WIP1 or PPM1D) encodes a negative regulator of p53. WIP1 amplification (17q22-q23) and its overexpression have been reported in diverse cancer types. We examined primary medulloblastoma specimens …

Bifidobacteria In Feces And Environmental Waters, Regina Lamendella, Jorge W. Santo Domingo, Catherine A. Kelty, Daniel B. Oerther

Civil, Architectural and Environmental Engineering Faculty Research & Creative Works

Bifidobacteria have been recommended as potential indicators of human fecal pollution in surface waters even though very little is known about their presence in nonhuman fecal sources. The objective of this research was to shed light on the occurrence and molecular diversity of this fecal indicator group in different animals and environmental waters. Genus- and species-specific 16S rRNA gene PCR assays were used to study the presence of bifidobacteria among 269 fecal DNA extracts from 32 different animals. Twelve samples from three wastewater treatment plants and 34 water samples from two fecally impacted watersheds were also tested. The species-specific assays …

Inhibition Of Signal Transducer And Activator Of Transcription 3 Expression By Rna Interference Suppresses Invasion Through Inducing Anoikis In Human Colon Cancer Cells, Yu Fan, You-Li Zhang, Ying Wu, Wei Zhang, Yin-Huan Wang, Zhao-Ming Cheng, Hua Li

Dartmouth Scholarship

AIM: To investigate the roles and mechanism of signal transducer and activator of transcription 3 (STAT3) in invasion of human colon cancer cells by RNA interference.

A Neuroanatomically Grounded Hebbian-Learning Model Of Attention-Language Interactions In The Human Brain., Max Garagnani, Thomas Wennekers, Friedemann Pulvermüller

School of Engineering, Computing and Mathematics

Meaningful familiar stimuli and senseless unknown materials lead to different patterns of brain activation. A late major neurophysiological response indexing 'sense' is the negative component of event-related potential peaking at around 400 ms (N400), an event-related potential that emerges in attention-demanding tasks and is larger for senseless materials (e.g. meaningless pseudowords) than for matched meaningful stimuli (words). However, the mismatch negativity (latency 100-250 ms), an early automatic brain response elicited under distraction, is larger to words than to pseudowords, thus exhibiting the opposite pattern to that seen for the N400. So far, no theoretical account has been able to reconcile …

Amp-Activated Protein Kinase Regulates Co2-Induced Alveolar Epithelial Dysfunction In Rats And Human Cells By Promoting Na,K-Atpase Endocytosis, István Vadász, Laura A. Dada, Arturo Briva, Humberto E. Trejo, Lynn C. Welch, Jiwang Chen, Peter T. Toth, Emilia Lecuona, Lee A. Witters, Paul T. Schumacker, Navdeep S. Chandel, Werner Seeger, Jacob I. Sznajder

Dartmouth Scholarship

Hypercapnia (elevated CO₂ levels) occurs as a consequence of poor alveolar ventilation and impairs alveolar fluid reabsorption (AFR) by promoting Na,K-ATPase endocytosis. We studied the mechanisms regulating CO₂-induced Na,K-ATPase endocytosis in alveolar epithelial cells (AECs) and alveolar epithelial dysfunction in rats. Elevated CO₂ levels caused a rapid activation of AMP-activated protein kinase (AMPK) in AECs, a key regulator of metabolic homeostasis. Activation of AMPK was mediated by a CO₂-triggered increase in intracellular Ca²⁺ concentration and Ca²⁺/calmodulin-dependent kinase kinase-β (CaMKK-β). Chelating intracellular Ca²⁺ or abrogating CaMKK-β function by gene silencing or …

Fak, Pdz-Rhogef And Rockii Cooperate To Regulate Adhesion Movement And Trailing-Edge Retraction In Fibroblasts, M. P. Iwanicki, T. Vomastek, R. W. Tilghman, K. H. Martin, J. Banerjee, P. B. Wedegaertner, J. T. Parsons

Faculty & Staff Scholarship

No abstract provided.

Targeting Nf-Kappab: A Promising Molecular Therapy In Inflammatory Arthritis., Jorge A. Roman-Blas, Sergio A. Jimenez

Scleroderma Center Faculty Papers

The nuclear factor-kappa B family of transcription factors is intimately involved in the regulation of the inflammatory responses that play a fundamental role in the damage of articular tissues. Thus, many studies have examined the important contributions of components of the NF-kappaB signaling pathways to the pathogenesis of various rheumatic diseases and their pharmacologic modulation. Currently available therapeutic agents including nonsteroidal anti-inflammatory drugs, corticosteroids, nutraceuticals, and disease-modifying antirheumatic drugs, as well as novel specific small-molecule inhibitors have been employed. In addition, promising nucleic acid-based strategies have shown encouraging results. However, further research will be needed before NF-kappaB-aimed strategies become an …

Devices In Heart Failure: Potential Methods For Device-Based Monitoring Of Congestive Heart Failure, Shahzeb M Munir, Roberta C Bogaev, Ed Sobash, K J Shankar, Sreedevi Gondi, Igor V Stupin, Jillian Robertson, M Alan Brewer, S Ward Casscells, Reynolds M Delgado, Amany Ahmed

Faculty, Staff and Student Publications

Congestive heart failure has long been one of the most serious medical conditions in the United States; in fact, in the United States alone, heart failure accounts for 6.5 million days of hospitalization each year. One important goal of heart-failure therapy is to inhibit the progression of congestive heart failure through pharmacologic and device-based therapies. Therefore, there have been efforts to develop device-based therapies aimed at improving cardiac reserve and optimizing pump function to meet metabolic requirements. The course of congestive heart failure is often worsened by other conditions, including new-onset arrhythmias, ischemia and infarction, valvulopathy, decompensation, end-organ damage, and …

Suicides Among Farmers In Three Southeastern States, 1990-1998, Steven R. Browning, Susan C. Westneat, Robert H. Mcknight

Epidemiology and Environmental Health Faculty Publications

Several studies have documented higher rates of suicide among farmers in comparison to other occupational groups, both in the U.S. and internationally. The purpose of this study is to describe the epidemiology of farmer suicides in three southeastern states (Kentucky, North Carolina, and South Carolina) during the nine-year period 1990-1998. Electronic death certificate data were obtained from the National Center for Health Statistics. Over the nine-year period, there were 590 deaths related to suicide (E-codes: 950-959) among farmers (occupation codes: 473, 474, 475, 477, and 479) in the states of Kentucky, North Carolina, and South Carolina. The results of this …

Nf-Kappab Mediates The Survival Of Human Bronchial Epithelial Cells Exposed To Cigarette Smoke Extract, Xiangde Liu, Shinsaku Togo, Mona Al-Mugotir, Huijung Kim, Qiuhong Fang, Tetsu Kobayashi, Xingqi Wang, Lijun Mao, Peter Bitterman, Stephen I. Rennard

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: We have previously reported that low concentrations of cigarette smoke extract induce DNA damage without leading to apoptosis or necrosis in human bronchial epithelial cells (HBECs), and that IL-6/STAT3 signaling contributes to the cell survival. Since NF-kappaB is also involved in regulating apoptosis and cell survival, the current study was designed to investigate the role of NF-kappaB in mediating cell survival in response to cigarette smoke exposure in HBECs.

METHODS: Both the pharmacologic inhibitor of NF-kappaB, curcumin, and RNA interference targeting p65 were used to block NF-kappaB signaling in HBECs. Apoptosis and cell survival were then assessed by various …

Micrornas (Mirnas) In Neurodegenerative Diseases, Peter T. Nelson, Wang-Xia Wang, Bernard W. Rajeev

Sanders-Brown Center on Aging Faculty Publications

Aging-related neurodegenerative diseases (NDs) are the culmination of many different genetic and environmental influences. Prior studies have shown that RNAs are pathologically altered during the inexorable course of some NDs. Recent evidence suggests that microRNAs (miRNAs) may be a contributing factor in neurodegeneration. miRNAs are brain-enriched, small (~22 nucleotides) non-coding RNAs that participate in mRNA translational regulation. Although discovered in the framework of worm development, miRNAs are now appreciated to play a dynamic role in many mammalian brain-related biochemical pathways, including neuroplasticity and stress responses. Research about miRNAs in the context of neurodegeneration is accumulating rapidly, and the goal of …