Digestive System Diseases Commons^™

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 …

Circulating Microrna Profiles In Human Patients With Acetaminophen Hepatotoxicity Or Ischemic Hepatitis, Jeanine Ward, Chitra Kanchagar, Isana Veksler-Lublinsky, Rosalind C. Lee, Mitchell R. Mcgill, Hartmut Jaeschke, Steven C. Curry, Victor R. Ambros

Victor R. Ambros

We have identified, by quantitative real-time PCR, hundreds of miRNAs that are dramatically elevated in the plasma or serum of acetaminophen (APAP) overdose patients. Most of these circulating microRNAs decrease toward normal levels during treatment with N-acetyl cysteine (NAC). We identified a set of 11 miRNAs whose profiles and dynamics in the circulation during NAC treatment can discriminate APAP hepatotoxicity from ischemic hepatitis. The elevation of certain miRNAs can precede the dramatic rise in the standard biomarker, alanine aminotransferase (ALT), and these miRNAs also respond more rapidly than ALT to successful treatment. Our results suggest that miRNAs can serve as …

The Vitamin D Status In Inflammatory Bowel Disease, Lauren Veit, Louise Maranda, Jay G. Fong, Benjamin U. Nwosu

Benjamin U. Nwosu

CONTEXT: There is no consensus on the vitamin D status of children and adolescents with inflammatory bowel disease (IBD).

AIM: To determine the vitamin D status of patients with IBD by comparing their serum 25(OH)D concentration to that of healthy controls.

HYPOTHESIS: Serum 25(OH)D concentration will be lower in patients with IBD compared to controls.

SUBJECTS AND METHODS: A case-controlled retrospective study of subjects with IBD (n = 58) of 2-20 years (male n = 31, age 16.38±2.21 years; female n = 27, age16.56±2.08 years) and healthy controls (n = 116; male n = 49, age 13.90±4.59 years; female n …

Data From: The Vitamin D Status In Inflammatory Bowel Disease, Lauren Veit, Louise S. Maranda, Jay G. Fong, Benjamin U. Nwosu

Benjamin U. Nwosu

Manuscript abstract: Context: There is no consensus on the vitamin D status of children and adolescents with inflammatory bowel disease (IBD). Aim: To determine the vitamin D status of patients with IBD by comparing their serum 25(OH)D concentration to that of healthy controls. Hypothesis: Serum 25(OH)D concentration will be lower in patients with IBD compared to controls. Subjects and Methods: A case-controlled retrospective study of subjects with IBD (n=58) of 2-20 years (male n=31, age 16.38 ± 2.21 years; female n=27, age16.56 ± 2.08 years) and healthy controls (n=116; male n=49, age 13.90 ± 4.59 years; female n=67, age 15.04 …

Cytokine Changes In Colonic Mucosa Associated With Blastocystis Spp. Subtypes 1 And 3 In Diarrhoea-Predominant Irritable Bowel Syndrome, Javed Yakoob, Zaigham Abbas, Muhammad Waqas Usman, Aisha Sultana, Muhammad Islam, Safia Awan, Zubair Ahmad, Saeed Hamid, Wasim Jafri

Section of Gastroenterology

We determined cytokines (e.g. interleukin-8, 10, 12 and TNF-α) expression by peripheral blood mononuclear cells (PBMCs) and in rectal mucosa in diarrhoea-predominant irritable bowel syndrome (D-IBS) with Blastocystis spp. Eighty patients with D-IBS and Blastocystis spp. infection were classified as 'cases' and 80 with D-IBS without Blastocystis spp. infection were classified as 'control'. Cases were subdivided into D-IBS and Blastocystis sp. defined type 1 (subtype-specific primer SB83) and type 3 (SB227). Stool microscopy and culture were performed. Rectal biopsies were obtained for histology and cytokines by real-time PCR for mRNA expression of cytokines. PBMCs IL-8 was similar in different groups …

Lrh1 As A Driving Factor For Cancer Development, Alissa M. Margraf

Senior Honors Projects

LRH1 as a driving factor for cancer development

Alissa Margraf, Qi Tang, Qiushi Lin, Xiaoqun Dong

Department of Biomedical and Pharmaceutical Science, College of Pharmacy, The University of Rhode Island, Pharmacy Building, 7 Greenhouse Road, Kingston, RI 02881 USA

Cancer is a major public health problem worldwide. Colon cancer ranks as the third most common causes of cancer mortality in the United States, with an estimated 96,830 new cases and 50,310 deaths in 2014. Colon cancer develops in the digestive tract where benign growths called polyps transform into malignant tumors. Colon cancer cells invade and destroy nearby tissue and can …

Endoscopic Pancreatic Pseudo-Cyst Drainage, Judith Dorsam Rn

Patient Care Services / Nursing

No abstract provided.