Life Sciences Commons^™

Dendritic Cells In Hepatitis C Infection: Can They (Help) Win The Battle, Angela Dolganiuc, Gyongyi Szabo

Gyongyi Szabo

Infection with hepatitis C virus (HCV) is a public health problem; it establishes a chronic course in ~85% of infected patients and increases their risk for developing liver cirrhosis, hepatocellular carcinoma, and significant extrahepatic manifestations. The mechanisms of HCV persistence remain elusive and are largely related to inefficient clearance of the virus by the host immune system. Dendritic cells (DCs) are the most efficient inducers of immune responses; they are capable of triggering productive immunity and maintaining the state of tolerance to self- and non-self antigens. During the past decade, multiple research groups have focused on DCs, in hopes of …

Hypoxia And Hypoxia Inducible Factors: Diverse Roles In Liver Diseases, Bharath Nath, Gyongyi Szabo

Gyongyi Szabo

Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The hypoxia inducible factors (HIFs) are a family of evolutionarily conserved transcriptional regulators that affect a homeostatic response to low oxygen tension and have been identified as key mediators of angiogenesis, inflammation, and metabolism. In this review we summarize the evidence for a role of HIFs across a range of hepatic pathophysiology. We describe regulation of the HIFs and review investigations that demonstrate a role for HIFs in the development of liver fibrosis, activation of innate immune pathways, hepatocellular carcinoma, as well as …

Mitochondrial Antiviral Signaling Protein Defect Links Impaired Antiviral Response And Liver Injury In Steatohepatitis In Mice, Timea Csak, Angela Dolganiuc, Karen Kodys, Bharath Nath, Jan Petrasek, Shashi Bala, Dora Lippai, Gyongyi Szabo

Gyongyi Szabo

Mitochondrial dysfunction is a pathogenic feature of nonalcoholic steatohepatitis (NASH). NASH complicates hepatotropic viral disease. The mitochondrial antiviral signaling protein (MAVS) is the adapter of helicase receptors involved in sensing double-stranded RNA (dsRNA). We hypothesized that impaired MAVS function may contribute to insufficient antiviral response and liver damage in steatohepatitis. We identified reduced MAVS protein levels and increased MAVS association with the proteasome subunit alpha type 7 (PSMA7) in livers from mice given a methionine-choline-deficient (MCD) diet. Decreased association of MAVS with mitochondria and increased cytosolic cytochrome c indicated mitochondrial damage in steatohepatitis. In vivo administration of the synthetic dsRNA …

An Essential Role For Monocyte Chemoattractant Protein-1 In Alcoholic Liver Injury: Regulation Of Proinflammatory Cytokines And Hepatic Steatosis In Mice, Pranoti Mandrekar, Aditya Ambade, Arlene Lim, Gyongyi Szabo, Donna Catalano

Gyongyi Szabo

The importance of chemokines in alcoholic liver injury has been implicated. The role of the chemokine, monocyte chemoattractant protein-1 (MCP-1), elevated in patients with alcoholic liver disease is not yet understood. Here, we evaluated the pathophysiological significance of MCP-1 and its receptor, chemokine (C-C motif) receptor 2 (CCR2), in alcoholic liver injury. The Leiber-DeCarli diet containing alcohol or isocaloric control diets were fed to wild-type (WT) and MCP-1-deficient knockout (KO) mice for 6 weeks. In vivo and in vitro assays were performed to study the role of MCP-1 in alcoholic liver injury. MCP-1 was increased in Kupffer cells (KCs) as …

Lipopolysaccharide Induces And Activates The Nalp3 Inflammasome In The Liver, Michal Ganz, Timea Csak, Bharath D. Nath, Gyongyi Szabo

Gyongyi Szabo

AIM: To examine the activation of the Nalp3 inflammasome and its downstream targets following lipopolysaccharide (LPS)-induced stimulation in the liver. METHODS: Six-to-eight-week-old C57BL/6 chow fed mice were injected intraperitoneally with 0.5 mug/g bodyweight LPS and sacrificed 2, 4, 6, 18 or 24 h later. LPS-induced liver damage was confirmed by a biochemical assay to detect alanine aminotransferase (ALT) levels. To determine if LPS stimulation in the liver led to activation of the inflammasome, real-time quantitative polymerase chain reaction was used to evaluate the mRNA expression of components of the Nalp3 inflammasome. Enzyme-linked immunosorbent assays were used to determine the protein …

Fatty Acid And Endotoxin Activate Inflammasomes In Mouse Hepatocytes That Release Danger Signals To Stimulate Immune Cells, Timea Csak, Michal Ganz, Justin Pespisa, Karen Kodys, Angela Dolganiuc, Gyongyi Szabo

Gyongyi Szabo

The pathogenesis of nonalcoholic steatohepatitis (NASH) and inflammasome activation involves sequential hits. The inflammasome, which cleaves pro-interleukin-1beta (pro-IL-1beta) into secreted IL-1beta, is induced by endogenous and exogenous danger signals. Lipopolysaccharide (LPS), a toll-like receptor 4 ligand, plays a role in NASH and also activates the inflammasome. In this study, we hypothesized that the inflammasome is activated in NASH by multiple hits involving endogenous and exogenous danger signals. Using mouse models of methionine choline-deficient (MCD) diet-induced NASH and high-fat diet-induced NASH, we found up-regulation of the inflammasome [including NACHT, LRR, and PYD domains-containing protein 3 (NALP3; cryopyrin), apoptosis-associated speck-like CARD-domain containing …

Characterization Of Secretory Sphingomyelinase Activity, Lipoprotein Sphingolipid Content And Ldl Aggregation In Ldlr-/- Mice Fed On A High-Fat Diet, Gergana M. Deevska, Manjula Sunkara, Andrew J. Morris, Mariana N. Nikolova‑Karakashian

Physiology Faculty Publications

The propensity of LDLs (low-density lipoproteins) for aggregation and/or oxidation has been linked to their sphingolipid content, specifically the levels of SM (sphingomyelin) and ceramide. To investigate this association in vivo, ldlr (LDL receptor)-null mice (ldlr-/-) were fed on a modified (atherogenic) diet containing saturated fats and cholesterol. The diet led to significantly elevated SM content in all serum lipoproteins. In contrast, ceramide increased only in the LDL particles. MS-based analyses of the lipid acyl chain composition revealed a marked elevation in C16:0 fatty acid in SM and ceramide, consistent with the prevalence of palmitic acid in the modified diet. …

Atovaquone Ameliorate Gastrointestinal Toxoplasmosis Complications In A Pregnancy Model, Helieh S. Oz, Thomas Tobin

Physiology Faculty Publications

Background: Toxoplasma is an important source of foodborne hospitalization with no safe and effective therapy against chronic or congenital Toxopalsmosis. Atovaquone is a drug of choice but not approved for use in congenital Toxoplasmosis. We hypothesized atovaquone to be safe and effective against feto-maternal Toxoplasmosis.

Material/Methods: Programmed pregnant mice were i.p. infected with 50–2400 Tachyzoites from Type II strain (clone PTG). Dams were treated daily with atovaquone or sham and monitored for pain, and complications.

Results: Dams developed pain related abdominal hypersensitivity (allodynia) to mechanical stimuli in a Tachyzoites dose dependent manner. Infected dams were anemic and exhibited ascities and …

Early Stage Drug Treatment That Normalizes Proinflammatory Cytokine Production Attenuates Synaptic Dysfunction In A Mouse Model That Exhibits Age-Dependent Progression Of Alzheimer's Disease-Related Pathology, Adam D. Bachstetter, Christopher M. Norris, Pradoldej Sompol, Donna M. Wilcock, Danielle Goulding, Janna H. Neltner, Daret St. Clair, D. Martin Watterson, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

Overproduction of proinflammatory cytokines in the CNS has been implicated as a key contributor to pathophysiology progression in Alzheimer's disease (AD), and extensive studies with animal models have shown that selective suppression of excessive glial proinflammatory cytokines can improve neurologic outcomes. The prior art, therefore, raises the logical postulation that intervention with drugs targeting dysregulated glial proinflammatory cytokine production might be effective disease-modifying therapeutics if used in the appropriate biological time window. To test the hypothesis that early stage intervention with such drugs might be therapeutically beneficial, we examined the impact of intervention with MW01-2-151SRM (MW-151), an experimental therapeutic that …

Two Boundaries Separate Borrelia Burgdorferi Populations In North America, Gabriele Margos, Jean I. Tsao, Santiago Castillo-Ramirez, Yvette A. Girard, Anne G. Hoen

Dartmouth Scholarship

Understanding the spread of infectious diseases is crucial for implementing effective control measures. For this, it is important to obtain information on the contemporary population structure of a disease agent and to infer the evolutionary processes that may have shaped it. Here, we investigate on a continental scale the population structure of Borrelia burgdorferi, the causative agent of Lyme borreliosis (LB), a tick-borne disease, in North America. We test the hypothesis that the observed d population structure is congruent with recent population expansions and that these were preceded by bottlenecks mostly likely caused by the near extirpation in the 1900s …

Corneal Replication Is An Interferon Response-Independent Bottleneck For Virulence Of Herpes Simplex Virus 1 In The Absence Of Virion Host Shutoff, Tracy J. Pasieka, Vineet D. Menachery, Pamela C. Rosato, David A. Leib

Dartmouth Scholarship

Herpes simplex viruses lacking the virion host shutoff function (Δvhs) are avirulent and hypersensitive to type I and type II interferon (IFN). In this study, we demonstrate that even in the absence of IFN responses in AG129 (IFN-αβγR^−/−) mice, Δvhs remains highly attenuated via corneal infection but is fully virulent via intracranial infection. The data demonstrate that the interferon-independent inherent replication defect of Δvhs has a significant impact upon peripheral replication and neuroinvasion.

Inhibition Of Fatty Acid Synthase Attenuates Cd44-Associated Signaling And Reduces Metastasis In Colorectal Cancer, Yekaterina Y. Zaytseva, Piotr G. Rychahou, Pat Gulhati, Victoria Allison Elliott, William Conan Mustain, Kathleen O'Connor, Andrew J. Morris, Manjula Sunkara, Heidi L. Weiss, Eun Young Lee, B. Mark Evers

Markey Cancer Center Faculty Publications

Fatty acid synthase (FASN) and ATP-citrate lyase, key enzymes of de novo lipogenesis, are significantly upregulated and activated in many cancers and portend poor prognosis. Even though the role of lipogenesis in providing proliferative and survival advantages to cancer cells has been described, the impact of aberrant activation of lipogenic enzymes on cancer progression remains unknown. In this study, we found that elevated expression of FASN is associated with advanced stages of colorectal cancer (CRC) and liver metastasis, suggesting that it may play a role in progression of CRC to metastatic disease. Targeted inhibition of lipogenic enzymes abolished expression of …