November-December 2010 l Vol 16 l No 11-12

Research Articles

A Longitudinal, Integrated, Clinical, Histological and mRNA Profiling Study of Resistance Exercise in Myositis
Gustavo A Nader, Maryam Dastmalchi, Helene Alexanderson, Cecilia Grundtman, Ramkishore Gernapudi, Mona Esbjörnsson, Zuyi Wang, Johan Rönnelid, Eric P Hoffman, Kanneboyina Nagaraju, and Ingrid E Lundberg
Polymyositis (PM) and dermatomyositis (DM) are chronic, autoimmune skeletal muscle disorders characterized by weakness, infiltration by mononuclear inflammatory cells and fibrosis. Despite current pharmacological treatment, many patients are left with impaired muscle function. While recent studies have shown moderate exercise training in combination with immunosuppressive drugs may improve muscle performance, the molecular mechanisms underlying the exercise-associated clinical improvements remain poorly understood. In the present study, Nader et al. investigate the underlying mechanisms responsible for the beneficial effects of resistance exercise in autoimmune inflammatory myopathy (AIM) patients using genome wide mRNA profiles. Changes in gene expression reported are in agreement with performance improvements induced by exercise and suggest resistance exercise training can induce a reduction in inflammation and fibrosis in skeletal muscle. High-throughput analysis of skeletal muscle gene expression may provide useful information for identification of new disease biomarkers and targets for pharmacological intervention of AIM patients.
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Overexpression of Interleukin-18 Aggravates Cardiac Fibrosis and Diastolic Dysfunction in Fructose-Fed Rats
Shan-Shan Xing, Xiu-Ping Bi, Hong-Wei Tan, Yun Zhang, Qi-Chong Xing, and Wei Zhang
Metabolic syndrome (MS) is a disorder characterized by a group of metabolic risk factors including obesity, type 2 diabetes, and hypertension, leading to an increased risk of cardiovascular disease. Inflammation plays an important role in the pathophysiology of MS. While it has been suggested that elevated serum levels of the proinflammatory cytokine interleukin-18 (IL-18) are involved in the pathogenesis of MS, the relationship remains unclear. In this work Xing et al. investigated the functional consequences of IL-18 overexpression in MS using an experimental model. Findings indicate overexpression of IL-18 leads to aggravated left ventricular diastolic dysfunction, suggesting an important role of IL-18 in myocardiac fibrosis in MS. Attenuation of the inflammatory process may represent an avenue for therapeutic strategy in treating metabolic cardiomyopathy.
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Altered mRNA Expression of Telomere-Associated Genes in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma
Julieta Panero, Jorge Arbelbide, Dorotea Beatriz Fantl, Hernán García Rivello, Dana Kohan, and Irma Slavutsky
Two of the most common plasma cell disorders are monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Clinical manifestations of MM include osteolytic lesions, anemia, hypercalcemia, immunodeficiency, and renal abnormalities. Telomere length and telomerase activity in cancer development have been extensively studied. Telomeres progressively shorten, lead to dysfunction and contribute to tumorigenesis. While several studies have evaluated telomere length and telomerase activity in MM patients, there is little information regarding this data in presymptomatic MGUS patients. Panero et al. examined mRNA expression in genes encoding telomere binding proteins to investigate the role of telomere dysfunction in the progression of MGUS to MM. Results show evidence of shortened telomeres, changes in telomere maintenance gene expression, and evidence of modified expression in telomere-associated genes between MGUS and MM. Understanding this process may aid in designing therapeutic approaches for patients with plasma cell disorders since many of them may be sensitive to interventions targeting telomere-damage.
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Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity
Daniel James Antoine, Dominic P Williams, Anja Kipar, Hugh Laverty, and B Kevin Park
Drug induced liver injury (DILI) is a major clinical concern and a leading cause of acute liver failure (ALF). Acetaminophen is a widely used analgesic which is safe at therapeutic doses. Acetaminophen hepatotoxicity following overdose contributes to a significant proportion of cases of ALF worldwide. While biochemical events leading to acetaminophen hepatotoxicity are well-defined, little is known about the cellular mechanism linking metabolic activation to clinical outcome. In this study, Antoine et al. investigated the effect of dietary restriction on cellular mechanisms during acetaminophen hepatotoxicity. Their findings indicate the inhibition of caspase driven apoptosis and HMGB1 oxidation by ATP depletion from fasting, promotes an inflammatory response during drug-induced hepatotoxicity. This work may aid the development of intervention therapies for cases of acetaminophen overdose and could improve the clinical management of drug induced liver injury.
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Phosphorylation of Extracellular Signal-Regulated Kinase (ERK)-1/2 Is Associated with the Downregulation of Peroxisome Proliferator–Activated Receptor (PPAR)-γ during Polymicrobial Sepsis
Jennifer M Kaplan, Paul W Hake, Alvin Denenberg, Marchele Nowell, Giovanna Piraino, and Basilia Zingarelli
Sepsis, an overwhelming inflammatory response to infection or injury, may lead to shock, multiple organ failure and death. Peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor which regulates inflammation. Post-translational modifications to PPARγ regulate its function, potentially affecting inflammation. In this work, Kaplan et al. investigated the kinetics of altered PPARγ expression and activation in a model of polymicrobial sepsis. Data demonstrate PPARγ is reduced in immunomodulatory and parenchymal cells during polymicrobial sepsis. Restoration of PPARγ correlates with an increase in levels of the antiinflammatory adipokine, adiponectin. These results provide a mechanism through which a decrease in PPARγ in sepsis may be partially explained and support the notion that additional studies investigating the molecular link between adipokines and the inflammatory response in sepsis are warranted.
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Early Increase of Plasma Homocysteine in Sepsis Patients with Poor Outcome
Martin Ploder, Katharina Kurz, Andreas Spittler, Gabriele Neurauter, Erich Roth, and Dietmar Fuchs
Hyperhomocysteinaemia, or increased levels of homocysteine in the blood, is an established risk factor for coronary artery disease, which occurs when dietary supply with folate and/or vitamin B12 is inadequate. Increased homocysteine in the blood may lead to formation of blood clots, resulting in heart attack or stroke. Homocysteine also acts as a proinflammatory mediator and may therefore play a role when the immune system is stimulated, such as in trauma or sepsis. Since no major studies have investigated homocysteine concentrations in septic patients, Ploder et al. investigated whether hyperhomocysteinemia may develop in this cohort despite administration of enteral nutrition. Results indicate increased levels of homocysteine are associated with poor patient outcomes. This may be due to the increased demand of B-vitamins associated with immunopathogenetic mechanisms. Although preliminary, this work suggests B-vitamin supplementation during inflammatory conditions should be further explored.
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Prevention of Inflammation-Associated Preterm Birth by Knockdown of the Endothelin-1–Matrix Metalloproteinase-1 Pathway
Wei Wang, Haoting Yen, Chih-Hung Chen, Nitesh Jasani, Rimabahen Soni, Karen Koscica, and Sandra E Reznik
Premature birth is an increasing health problem and is the major cause of neonatal mortality in developed countries. Intrauterine infection is often associated with preterm labor. The matrix metalloproteinases (MMPs) are a family of zinc-dependant endopeptidases that aid in the degradation of the extracellular matrix, allowing for cell movement and tissue reorganization thereby supporting the growing fetus. Endothelin-1 (ET-1), an extremely potent vasoconstrictor peptide, has been shown to increase myometrial smooth muscle tone. Blockade of ET-1 through endothelin-converting enzyme 1 (ECE-1) inhibitor or endothelin receptor antagonists prevents preterm labor and delivery in mice. Wang et al. demonstrate that LPS-induced preterm labor is associated with increased levels of MMP-1. Using ECE-1 RNAi, they show that silencing the ECE-1/ET-1 pathway prevents both the onset of preterm labor and MMP-1 upregulation. Their data indicate that ET-1 and MMP-1 act in the same molecular pathway in preterm labor.
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Genome-Wide Association for Smoking Cessation Success in a Trial of Precessation Nicotine Replacement
George R Uhl, Tomas Drgon, Catherine Johnson, Marco F Ramoni, Frederique M Behm, and Jed E Rose
Cigarette smoking is a significant cause of premature death and disease. Although abstinence reduces risks to smokers, success rates following attempts to quit smoking remain modest. One year after unaided attempts to quit smoking, abstinence rates are less than 5%. In the current study, Uhl et al. report genome wide association studies of smoking cessation success in individually-genotyped European-American participants in a smoking cessation trial that examined effects of pre-cessation nicotine replacement therapy. Results identified a set of single nucleotide polymorphisms (SNPs) that overlap with prior datasets and likely identify a network of SNPs and genes with true biological relationships. Most of these genes are expressed in the brain and are related to neurotransmission processes, as may be expected for addiction-related traits. These results add to support for personalized approaches to smoking cessation treatment and contribute to studies that document molecular genetic contributions to the ability to quit smoking.
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Caveolin-1 as a Novel Indicator of Wound-Healing Capacity in Aged Human Corneal Epithelium
Ji Heon Rhim, Jae Hoon Kim, Eui-Ju Yeo, Jae Chan Kim, and Sang Chul Park
Postoperative care for the elderly requires special attention with respect to wound healing time. While several factors have been found to play roles during wound healing, the molecular mechanisms responsible for age-dependent delay in wound healing have not been well defined. Caveolin is a principal structural component of caveolae membranes. Levels of caveolin-1 have been found to increase with aging, and reduction of caveolin-1 using antisense oligonucleotides or siRNA recovers the epidermal growth factor response in senescent cells. Rhim et al. hypothesized that caveolin-1-dependent responses in aged corneal epithelial cells may be responsible for delayed wound healing. The authors evaluated corneal wound healing time after laser epithelial keratomileusis (LASEK) surgery in young, middle aged and elderly patients. Results indicate caveolin-1 status may be responsible for delayed wound healing in the elderly and act as a regulator for wound healing capacity. While downregulation of caveolin-1 may facilitate wound healing in the elderly post LASEK surgery, these results may also be applied to wound healing in other surgeries or traumas.
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Supplementary Data: PDF  (315 KB)

Review  Articles

Endoplasmic Reticulum Stress in Age-Related Macular Degeneration: Trigger for Neovascularization
Antero Salminen, Anu Kauppinen, Juha MT Hyttinen, Elisa Toropainen and Kai Kaarniranta
Age-related macular degeneration (AMD) can cause a progressive loss of central vision in elderly individuals. AMD may be classified into two categories: the atrophic dry form and the exudative wet form. The crucial difference between dry and wet AMD is the development of choroidal neovascularization in the wet form. In this review, Salminen et al. discuss the role of endoplasmic reticulum stress in neovascularization regulation and the conversion of dry age-related macular degeneration to its detrimental wet counterpart.
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D-Chiro-Inositol Glycans in Insulin Signaling and Insulin Resistance
Joseph Larner, David L Brautigan, and Michael O Thorner
Classical actions of insulin involve increased glucose uptake from the bloodstream and its metabolism in peripheral tissues. However, non-oxidative and oxidative glucose disposal remain incompletely explained by current models for insulin action. In this work, Larner et al. review the possible role of second messengers in responses and resistance to insulin. The authors postulate that inositol glycans, particularly of the D-chiroinositol class, are insulin mimetic and may serve as insulin second messengers.
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Interleukin-1β and Interleukin-6 in Arthritis Animal Models: Roles in the Early Phase of Transition from Acute to Chronic Inflammation and Relevance for Human Rheumatoid Arthritis
Gianfranco Ferraccioli, Luisa Bracci-Laudiero, Stefano Alivernini, Elisa Gremese, Barbara Tolusso, and Fabrizio De Benedetti
Tumor necrosis factor is the major target of therapeutic approaches in rheumatoid arthritis. A key issue in chronic arthritis is understanding the crucial molecules driving the transition from the acute phase to the chronic irreversible phase of the disease. In this review, Ferraccioli et al. examine five experimental models of rheumatoid arthritis and review cytokines necessary for driving the condition from acute to chronic.
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 Author Index - Volume 16, 2010 PDF

Subject Index - Volume 16, 2010  PDF