Medicine and Health Sciences Commons^™

Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo

Katherine A. Fitzgerald

Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of …

Binge Ethanol And Liver: New Molecular Developments, Shivendra Shukla, Stephen Pruett, Gyongyi Szabo, Gavin Arteel

Gyongyi Szabo

Binge consumption of alcohol is an alarming global health problem. Binge (acute) ethanol (EtOH) is implicated in the pathophysiology of alcoholic liver disease (ALD). New studies from experimental animals and from humans indicate that binge EtOH has profound effects on immunological, signaling, and epigenetic parameters of the liver. This is in addition to the known metabolic effects of acute EtOH. Binge EtOH alters the levels of several cellular components and dramatically amplifies liver injury in chronically EtOH exposed liver. These studies highlight the importance of molecular investigations into binge effects of EtOH for a better understanding of ALD and also …

Microrna-122 Regulates Hypoxia-Inducible Factor-1 And Vimentin In Hepatocytes And Correlates With Fibrosis In Diet-Induced Steatohepatitis, Timea Csak, Shashi Bala, Dora Lippai, Abhishek Satishchandran, Donna Catalano, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND and AIMS: miR-122 is the most abundant miRNA in the liver particularly in hepatocytes where it targets cholesterol metabolism. Steatosis, a key component of non-alcoholic fatty liver disease, is regulated by hypoxia-inducible factor-1alpha (HIF-1alpha). Here, we hypothesized that reduced miR-122 has a pathogenic role in steatohepatitis. METHODS: miR-122 and its target genes were evaluated in mouse livers and/or isolated hepatocytes after methionine-choline-deficient (MCD) or methionine-choline-supplemented (MCS) diet. RESULTS: Liver and hepatocyte miR-122 expression was significantly decreased in steatohepatitis. A maximum reduction in miR-122 occurred at the fibrosis stage (8 weeks of MCD diet). MAP3K3, a miR-122 target gene, was …

Acute Binge Drinking Increases Serum Endotoxin And Bacterial Dna Levels In Healthy Individuals, Shashi Bala, Miguel Marcos, Arijeet Gattu, Donna Catalano, Gyongyi Szabo

Gyongyi Szabo

Binge drinking, the most common form of alcohol consumption, is associated with increased mortality and morbidity; yet, its biological consequences are poorly defined. Previous studies demonstrated that chronic alcohol use results in increased gut permeability and increased serum endotoxin levels that contribute to many of the biological effects of chronic alcohol, including alcoholic liver disease. In this study, we evaluated the effects of acute binge drinking in healthy adults on serum endotoxin levels. We found that acute alcohol binge resulted in a rapid increase in serum endotoxin and 16S rDNA, a marker of bacterial translocation from the gut. Compared to …

Chronic Alcohol-Induced Microrna-155 Contributes To Neuroinflammation In A Tlr4-Dependent Manner In Mice, Dora Lippai, Shashi Bala, Timea Csak, Evelyn A. Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

INTRODUCTION: Alcohol-induced neuroinflammation is mediated by pro-inflammatory cytokines and chemokines including tumor necrosis factor-alpha (TNFalpha), monocyte chemotactic protein-1 (MCP1) and interleukin-1-beta (IL-1beta). Toll-like receptor-4 (TLR4) pathway induced nuclear factor-kappaB (NF-kappaB) activation is involved in the pathogenesis of alcohol-induced neuroinflammation. Inflammation is a highly regulated process. Recent studies suggest that microRNAs (miRNAs) play crucial role in fine tuning gene expression and miR-155 is a major regulator of inflammation in immune cells after TLR stimulation. AIM: To evaluate the role of miR-155 in the pathogenesis of alcohol-induced neuroinflammation. METHODS: Wild type (WT), miR-155- and TLR4-knockout (KO) mice received 5% ethanol-containing or isocaloric …

Another Armed Cd4(+) T Cell Ready To Battle Hepatocellular Carcinoma, Roniel Cabrera, Gyongyi Szabo

Gyongyi Szabo

No abstract provided.

Human Ezrin-Moesin-Radixin Proteins Modulate Hepatitis C Virus Infection, Terence Bukong, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

Host cytoskeletal proteins of the ezrin-moesin-radixin (EMR) family have been shown to modulate single-stranded RNA virus infection through regulating stable microtubule formation. Antibody engagement of CD81, a key receptor for hepatitis C virus (HCV) entry, induces ezrin phosphorylation. Here we tested the role of EMR proteins in regulating HCV infection and explored potential therapeutic targets. We show that HCV E2 protein induces rapid ezrin phosphorylation and its cellular redistribution with F-actin by way of spleen tyrosine kinase (SYK). Therapeutically blocking the functional roles of SYK or F-actin reorganization significantly reduced Huh7.5 cell susceptibility to HCV J6/JFH-1 infection. Using gene regulation, …

Differences In Innate Immune Signaling Between Alcoholic And Non-Alcoholic Steatohepatitis, Jan Petrasek, Timea Csak, Michal Ganz, Gyongyi Szabo

Gyongyi Szabo

The similar histopathological characteristics of alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH), and the crucial role of the innate immune response in both conditions may lead to the assumption that ASH and NASH represent the same pathophysiological entities caused by different risk factors. In this review paper, we elaborate on the pathophysiological differences between these two entities and highlight the disease-specific involvement of signaling molecules downstream of the Toll-like receptor 4, and the differential mechanism by which the inflammasome contributes to ASH versus NASH. Our findings emphasize that ASH and NASH have disease-specific mechanisms and therefore represent distinct biological entities. …

Micro-Rna-155 Deficiency Prevents Alcohol-Induced Serum Endotoxin Increase And Small Bowel Inflammation In Mice, Dora Lippai, Shashi Bala, Donna Catalano, Karen Kodys, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND: Chronic alcohol impairs gut barrier function and induces inflammatory cytokines. The effects of acute alcohol binge on the gut are partially understood. Micro-RNA-155 (miR-155), a modulator of cytokine and T-cell immune response in the gut, stabilizes tumor necrosis factor-alpha (TNFalpha) mRNA. Here, we investigated the role of the inflammation modulator miR-155 as well as the effects of acute binge and chronic alcohol feeding in the small bowel (SB) in mice. METHODS: For the acute alcohol binge, wild-type (WT) mice received 5 g/kg 50% alcohol/d or equal amount of water oral gavage for 3 days. WT and miR-155-deficient (miR-155-knockout [KO]) …

Human Type 2 Myeloid Dendritic Cells Produce Interferon-Lambda And Amplify Interferon-Alpha In Response To Hepatitis C Virus Infection, Shuye Zhang, Karen Kodys, Kui Li, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND and AIMS: The type III interferons (IFN-lambdas: interleukin [IL]-28a, IL-28b, and IL-29) have important roles in hepatitis C virus (HCV) infection, but little is understood about what cells produce these cytokines or how production is activated. We investigated whether human immune cells recognize HCV-infected cells and respond by producing IFN-lambda. METHODS: We cultured healthy human peripheral blood mononuclear cells (PBMCs) with different populations of immune cells and Japanese fulminant hepatitis-1 (JFH-1) HCV-infected Huh7.5 (cell culture-derived HCV particles [HCVcc]/Huh7.5) cells. RESULTS: Human PBMCs recognized HCVcc/Huh7.5 cells and responded by producing IFN-alpha, IFN-gamma, and IFN-lambda. A rare subset of myeloid dendritic …

Converging Actions Of Alcohol On Liver And Brain Immune Signaling, Gyongyi Szabo, Dora Lippai

Gyongyi Szabo

Chronic excessive alcohol consumption results in inflammation in multiple organs, including the brain. While the contribution of neuroinflammation to alcohol-related cognitive dysfunction and behavioral alterations is established, the mechanisms by which alcohol triggers inflammation in the brain are only partially understood. There are acute and long-term alterations in brain function due to intercellular and intracellular changes of different cell types as a result of alcohol consumption. This review focuses on the alcohol-induced proinflammatory cellular and molecular changes in the central nervous system. Alcohol passes through the blood-brain barrier and alters neurotransmission. Alcohol use activates microglia and astrocyte, contributing to neurodegeneration …

Both Bone Marrow-Derived And Non-Bone Marrow-Derived Cells Contribute To Aim2 And Nlrp3 Inflammasome Activation In A Myd88-Dependent Manner In Dietary Steatohepatitis, Timea Csak, Arun Pillai, Michal Ganz, Dora Lippai, Jan Petrasek, Jin-Kyu Park, Karen Kodys, Angela Dolganiuc, Evelyn Kurt-Jones, Gyongyi Szabo

Gyongyi Szabo

BACKGROUND and AIMS: Inflammation promotes the progression of non-alcoholic steatohepatitis (NASH). Toll-like receptor 4 (TLR4) and TLR9 activation through myeloid differentiation primary response gene 88 (MyD88) and production of mature interleukin-1beta (IL-1beta) via inflammasome activation contribute to steatohepatitis. Here, we investigated the inter-relationship between TLR signalling and inflammasome activation in dietary steatohepatitis.

METHODS: Wild type (WT), TLR4- and MyD88-deficient (KO) mice received methionine-choline-deficient (MCD) or -supplemented (MCS) diets for 5 weeks and a subset was challenged with TLR9 ligand CpG-DNA.

RESULTS: TLR4, TLR9, AIM2 (absent in melanoma 2) and NLRP3 (NLR family pyrin domain containing 3) inflammasome mRNA, and mature …

Toll-Like Receptors In Liver Disease, Jan Petrasek, Timea Csak, Gyongyi Szabo

Gyongyi Szabo

Activation of inflammatory signaling pathways is of central importance in the pathogenesis of alcoholic liver disease (ALD) and nonalcoholic steatohepatitis (NASH). Recent studies demonstrated that Toll-like receptors, the sensors of microbial and endogenous danger signals, are expressed and activated in innate immune cells as well as in parenchymal cells in the liver and thereby contribute to ALD and NASH. In this review, we emphasize the importance of gut-derived endotoxin and its recognition by TLR4 in the liver. The significance of TLR-induced intracellular signaling pathways and cytokine production as well as the contribution of individual cell types to the inflammation is …

Exosome-Mediated Delivery Of Functionally Active Mirna-155 Inhibitor To Macrophages, Fatemeh Momen-Heravi, Shashi Bala, Terence Bukong, Gyongyi Szabo

Gyongyi Szabo

Exosomes, membranous nanovesicles, naturally carry bio-macromolecules and play pivotal roles in both physiological intercellular crosstalk and disease pathogenesis. Here, we showed that B cell-derived exosomes can function as vehicles to deliver exogenous miRNA-155 mimic or inhibitor into hepatocytes or macrophages, respectively. Stimulation of B cells significantly increased exosome production. Unlike in parental cells, baseline level of miRNA-155 was very low in exosomes derived from stimulated B cells. Exosomes loaded with a miRNA-155 mimic significantly increased miRNA-155 levels in primary mouse hepatocytes and the liver of miRNA-155 knockout mice. Treatment of RAW macrophages with miRNA-155 inhibitor loaded exosomes resulted in statistically …

High Fat Diet Feeding Results In Gender Specific Steatohepatitis And Inflammasome Activation, Michal Ganz, Timea Csak, Gyongyi Szabo

Gyongyi Szabo

AIM: To develop an animal model that encompasses the different facets of non-alcoholic steatohepatitis (NASH), which has been a challenge. METHODS: In this study, we used a high fat diet (HFD) feeding supplemented with fructose and sucrose in the water mimicking the high-fructose corn syrup that is abundant in the diet in the United States. We used C57Bl/6 wild-type mice for short and long-term feedings of 6 and 16 wk respectively, and evaluated the extent of liver damage, steatosis, and inflammasome activation. Our methods included histopathological analysis to assess liver damage and steatosis, which involved H and E and oil-red-o …

Immune And Inflammatory Pathways In Nash, Michal Ganz, Gyongyi Szabo

Gyongyi Szabo

Immune and inflammatory pathways have a central role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Both the innate and adaptive immune systems contribute to the development of NAFLD. Pathogen-associated molecular patterns and danger-associated molecular patterns are known to activate a variety of pattern-recognition receptors that result in inflammation. The key features of the immune system and inflammatory pathways in the development of NAFLD are discussed in this review.

Innate Immune Cell Networking In Hepatitis C Virus Infection, Banishree Saha, Gyongyi Szabo

Gyongyi Szabo

Persistent viral infection, such as HCV infection, is the result of the inability of the host immune system to mount a successful antiviral response, as well as the escape strategies devised by the virus. Although each individual component of the host immune system plays important roles in antiviral immunity, the interactive network of immune cells as a whole acts against the virus. The innate immune system forms the first line of host defense against viral infection, and thus, virus elimination or chronic HCV infection is linked to the direct outcome of the interactions between the various innate immune cells and …

Sting-Irf3 Pathway Links Endoplasmic Reticulum Stress With Hepatocyte Apoptosis In Early Alcoholic Liver Disease, Jan Petrasek, Arvin Iracheta-Vellve, Timea Csak, Abhishek Satishchandran, Karen Kodys, Evelyn A. Kurt-Jones, Katherine A. Fitzgerald, Gyongyi Szabo

Gyongyi Szabo

Emerging evidence suggests that innate immunity drives alcoholic liver disease (ALD) and that the interferon regulatory factor 3 (IRF3),a transcription factor regulating innate immune responses, is indispensable for the development of ALD. Here we report that IRF3 mediates ALD via linking endoplasmic reticulum (ER) stress with apoptotic signaling in hepatocytes. We found that ethanol induced ER stress and triggered the association of IRF3 with the ER adaptor, stimulator of interferon genes (STING), as well as subsequent phosphorylation of IRF3. Activated IRF3 associated with the proapoptotic molecule Bax [B-cell lymphoma 2 (Bcl2)-associated X protein] and contributed to hepatocyte apoptosis. Deficiency of …

Applying Novel Tree-Based Frameworks To Big Data For Classification Of Heart Failure Patients And Prediction Of Clinical Responses, Yan Zhang, Nicholas Downing, Emily Bucholz, Suganthi Balasubramanian, Shu-Xia Li, Tara Liptak, Harlan Krumholz, Mark Gerstein

Yale Day of Data

Over 5 million Americans suffer from heart failure, a condition with a 5-year survival that eclipses all cancers apart from that of lung cancer. Conventional understanding of heart failure is simplistic: it is viewed as a single syndrome, despite real heterogeneity. In addition, models predicting outcomes focus on dichotomous results, like 30-day readmission. A novel approach to classification of heart failure may improve our ability to target interventions, improve patient experiences, and predict outcomes.

The Healthcare Cost and Utilization Project is a family of administrative claims databases that describes patient demographics, comorbidities, procedures, acute care utilization and outcomes, such as …

Inpp4b Suppresses Prostate Cancer Cell Invasion, Myles C. Hodgson, Elena I. Deryugina, Egla Suarez, Sandra M. Lopez, Dong Lin, Hui Xue, Ivan P. Gorlov

Dartmouth Scholarship

INPP4B and PTEN dual specificity phosphatases are frequently lost during progression of prostate cancer to metastatic disease. We and others have previously shown that loss of INPP4B expression correlates with poor prognosis in multiple malignancies and with metastatic spread in prostate cancer.

We demonstrate that de novo expression of INPP4B in highly invasive human prostate carcinoma PC-3 cells suppresses their invasion both in vitro and in vivo. Using global gene expression analysis, we found that INPP4B regulates a number of genes associated with cell adhesion, the extracellular matrix, and the cytoskeleton. Importantly, de novo expressed INPP4B suppressed the proinflammatory chemokine …

Atypical Multisensory Integration In Niemann-Pick Type C Disease – Towards Potential Biomarkers, Gizely N. Andrade, Sophie Molholm, John S. Butler, Alice Brown Brandwein, Steven U. Walkley, John J. Foxe

Publications and Research

Background: Niemann-Pick type C (NPC) is an autosomal recessive disease in which cholesterol and glycosphingolipids accumulate in lysosomes due to aberrant cell-transport mechanisms. It is characterized by progressive and ultimately terminal neurological disease, but both pre-clinical studies and direct human trials are underway to test the safety and efficacy of cholesterol clearing compounds, with good success already observed in animal models. Key to assessing the effectiveness of interventions in patients, however, is the development of objective neurobiological outcome measures. Multisensory integration mechanisms present as an excellent candidate since they necessarily rely on the fidelity of long-range neural connections between the …

Mapping Regions Of Rnf168 Required For Its Degradation By Icp0, Andrea Cyr, Matthew Weitzman

e-Research: A Journal of Undergraduate Work

Viruses establish infection by overtaking host cell processes and developing mechanisms that promote viral replication. Herpes simplex virus undergoes lytic and latent cycles of infection throughout the lifespan of its host. The viral genome is transcriptionally silent during latency, but viral proteins are produced upon reactivation. Herpes simplex virus type 1 encodes the ICP0 protein, an E3 ubiquitin ligase required for reactivation from latency of the infectious virus. The immediate-early protein ICP0 regulates the herpes simplex virus by activating viral gene expression thereby initiating lytic infection. Cellular proteins are degraded by ICP0, promoting the virus to enter the lytic cycle. …

The Ebola Epidemic: A Public Health Emergency Of International Concern, Lawrence O. Gostin, Daniel Lucey, Alexandra Phelan

Georgetown Law Faculty Publications and Other Works

On August 8, 2014, the World Health Organization (WHO) Director-General Margaret Chan declared the West Africa Ebola crises a “public health emergency of international concern,” triggering powers under the 2005 International Health Regulations (IHR).

The most affected West African states have attempted classic public health measures with varied success, including quarantine and isolation, social distancing, risk communication, and travel restrictions. These have involved a trade off between population health and human rights; sometimes to the disadvantage of both. At the same time, the countries’ health systems and human resources are fragile, impeding an effective response.

Beyond the public health and …

Outrage Over Video Of Police’S Rough Handling Of Man With Huntington's Disease Spurs Calls For Justice, Awareness, Kenneth P. Serbin

At Risk for Huntington's Disease

No abstract provided.

Inpatient Admissions And Costs Of Congenital Heart Disease From Adolescence To Young Adulthood, Yang Lu, Garima Agrawal, Chia-Wei Lin, Roberta Williams

Yang Lu

Background. Health care utilization patterns and associated costs of congenital heart disease (CHD) in young adulthood are not well understood.

Methods. California State Inpatient Databases 2005 to 2009 were used to conduct a retrospective study on inpatient admissions of CHD patients 10 to 29 years old (n = 7,419) and of all patients of the same age (n = 1,195,233).

Results. Compared with all patients, annual admission costs of CHD patients monotonically decreased, from $13.9 million at age 10 to 14 years to $7.2 million at age 25 to 29 years, which were due to lower costs per admission and …

The Epidemic Of Mental And Neurological Health, Mohsyn I. Malik

Psychology Publications

This paper composes an image of modern mental and neurological health issues and looks to draw links to the current epidemic based on research and studies found online the internet and off-line. The goal is to examine what may be the underlying problem for a lot of these increases in mental health issues and neurodegenerative diseases and what are some promising clinical and sociocultural advances that may help. It explores problems such as the negative impact of the pharmaceutical giants, the increase in apathy in the work place and the general stigma towards mental disease. Through current research, the use …

Vitamin D Status Is Associated With Early Markers Of Cardiovascular Disease In Prepubertal Children, Benjamin U. Nwosu, Louise Maranda, Karen Cullen, Carol A. Ciccarelli, Mary M. Lee

Mary M. Lee

Background: The associations of 25-hydroxyvitamin D [25(OH)D], non-high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL), and related markers of early cardiovascular disease (CVD) are unclear in prepubertal children. Objective: To investigate the association of 25(OH)D with markers of CVD. The hypothesis was that 25(OH)D would vary inversely with non-HDL-C. Subjects and methods: A prospective cross-sectional study of children (n=45; 26 males, 19 females) of mean age 8.3 ± 2.5 years to investigate the relationships between 25(OH)D and glucose, insulin, high-sensitivity C-reactive protein, and lipids. Vitamin D deficiency was defined as 25(OH)D/mL; overweight as body mass index (BMI) ≥ 85 th but …

Parental Mastery Of Continuous Subcutaneous Insulin Infusion Skills And Glycemic Control In Youth With Type 1 Diabetes, Kathleen Mitchell, Kimberley Johnson, Karen Cullen, Mary M. Lee, Olga T. Hardy

Mary M. Lee

OBJECTIVE: The purpose of this study is to determine whether parental knowledge of the continuous subcutaneous insulin infusion (CSII) device affects glycemic control as measured by hemoglobin A1c (A1C) level. SUBJECTS AND METHODS: Parents of children with type 1 diabetes mellitus (T1DM) using CSII completed a 14-item questionnaire. Questions 1-10 were knowledge-based questions that required the parent to extract specific information from their child's CSII device. Questions 11-14 asked parents to provide a self-assessment of their CSII knowledge. RESULTS: Twenty-two parents of youth with T1DM participated in the study. Ten of the youth were in the Low-A1C group (A1C/=8%). Parents …

Farm Residence And Reproductive Health Among Boys In Rural South Africa, Rene English, Melissa Perry, Mary Lee, Elaine Hoffman, Steven Delport, Mohamed Dalvie

Mary M. Lee

BACKGROUND: Few studies have investigated reproductive health effects of contemporary agricultural pesticides in boys. OBJECTIVES: To determine the association between pesticide exposure and reproductive health of boys. METHODS: We conducted a cross-sectional study in rural South Africa of boys living on and off farms. The study included a questionnaire (demographics, general and reproductive health, phyto-estrogen intake, residential history, pesticide exposures, exposures during pregnancy); and a physical examination that included sexual maturity development ratings; testicular volume; height, weight, body mass index; and sex hormone concentrations. RESULTS: Among the 269 boys recruited into the study, 177 (65.8%) were categorized as farm (high …

Virus Sharing, Genetic Sequencing, And Global Health Security, Lawrence O. Gostin, Alexandra Phelan, Michael A. Stoto, John D. Kraemer, K. Srinath Reddy

Georgetown Law Faculty Publications and Other Works

The WHO’s Pandemic Influenza Preparedness (PIP) Framework was a milestone global agreement designed to promote the international sharing of biological samples to develop vaccines, while that ensuring poorer countries would have access to those vaccines. Since the PIP Framework was negotiated, scientists have developed the capacity to use genetic sequencing data (GSD) to develop synthetic viruses rapidly for product development of life-saving technologies in a time-sensitive global emergency—threatening to unravel the Framework. Access to GSD may also have major implications for biosecurity, biosafety, and intellectual property (IP).

By rendering the physical transfer of viruses antiquated, GSD may also undermine the …