May-June 2011 l Vol 17 l No 5-6

HDAC Articles

Histone Deacetylase Inhibitors for Treating a Spectrum of Diseases Not Related to Cancer
Charles A Dinarello, Gianluca Fossati, and Paolo Mascagni
Page 333 l View article: PDF (143 KB) HTML

Pharmacokinetics, Safety and Inducible Cytokine Responses during a Phase 1 Trial of the Oral Histone Deacetylase Inhibitor ITF2357 (Givinostat)
Antonio Furlan, Valmen Monzani, Leonid L Reznikov, Flavio Leoni, Gianluca Fossati, Daniela Modena, Paolo Mascagni, and Charles A Dinarello
Page 353 l View article: PDF (2.8 MB) HTML

Effects of the Histone Deacetylase Inhibitor ITF2357 in Autoinflammatory Syndromes
Evelien J Bodar, Anna Simon, and Jos WM van der Meer
Page 363 l View article: PDF  (934 KB) HTML

The Oral Histone Deacetylase Inhibitor ITF2357 Reduces Cytokines and Protects Islet β Cells In Vivo and In Vitro
Eli C Lewis, Lykke Blaabjerg, Joachim Størling, Sif G Ronn, Paolo Mascagni, Charles A Dinarello, and Thomas Mandrup-Poulsen
Page 369 l View article: PDF (2.9 MB) HTML

Histone Deacetylase (HDAC) Inhibition as a Novel Treatment for Diabetes Mellitus
Dan P Christensen, Mattias Dahllöf, Morten Lundh, Daniel N Rasmussen, Mette D Nielsen, Nils Billestrup, Lars G Grunnet, and Thomas Mandrup-Poulsen
Page 378 l View article: PDF (2.6 MB) HTML

Inhibition of HDAC Activity by ITF2357 Ameliorates Joint Inflammation and Prevents Cartilage and Bone Destruction in Experimental Arthritis
Leo AB Joosten, Flavio Leoni, Sajeda Meghji, and Paolo Mascagni
Page 391 l View article: PDF (1.8 MB) HTML

HDAC Inhibition in Rheumatoid Arthritis and Juvenile Idiopathic Arthritis
Jelena Vojinovic and Nemanja Damjanov
Page 397 l View article: PDF (578 KB) HTML

HDAC Inhibition and Graft Versus Host Disease
Sung Choi and Pavan Reddy
Page 404 l View article: PDF (1.3 MB) HTML

HDAC Inhibition in Lupus Models
Christopher M Reilly, Nicole Regna, and Nilamadhab Mishra
Page 417 l View article: PDF (254 KB) HTML
 
Inhibition of Histone Deacetylases in Inflammatory Bowel Diseases
Rainer Glauben and Britta Siegmund
Page 426 l View article: PDF (270 KB) HTML

Targeting Inflammation in Heart Failure with Histone Deacetylase Inhibitors
Timothy A McKinsey
Page 434 l View article: PDF (2.7 MB) HTML

The Therapeutic Potential of HDAC Inhibitors in the Treatment of Multiple Sclerosis
Giuseppe Faraco, Leonardo Cavone, and Alberto Chiarugi
Page 442 l View article: PDF (492 KB) HTML

Histone Deacetylase Inhibitors as Therapeutic Agents for Acute Central Nervous System Injuries
Na'ama A Shein and Esther Shohami
Page 448 l View article: PDF (1.1 MB) HTML

Histone Deacetylase Inhibitors in the Treatment of Muscular Dystrophies: Epigenetic Drugs for Genetic Diseases
Silvia Consalvi, Valentina Saccone, Lorenzo Giordani, Giulia Minetti, Chiara Mozzetta, and Pier Lorenzo Puri
Page 457 l View article: PDF (1.1 MB) HTML

Histone Deacetylase Inhibitors for Purging HIV-1 from the Latent Reservoir
Shay Matalon, Thomas A Rasmussen, and Charles A Dinarello
Page 466 l View article: PDF (377 KB) HTML

Research Articles

Impact of Genotyping on Outcome of Prostatic Biopsies: A Multicenter Prospective Study
Jean-Nicolas Cornu, Sarah Drouin, Géraldine Cancel-Tassin, Pierre Bigot, Abdel-Rahmène Azzouzi, Nicolas Koutlidis, Luc Cormier, Cécile Gaffory, Morgan Rouprêt, Philippe Sèbe, Marc-Olivier Bitker, François Haab, and Olivier Cussenot
Prostate cancer (PCa) is a highly incident disease and an estimated 200,000 new cases were diagnosed in the US last year. Genotyping single-nucleotide polymorphisms (SNPs) has been extensively used in research to characterize genetic variability. However, currently used predictive and prognostic models in localized prostate cancer do not integrate genotyping. To assess its value in a clinical setting, Cornu et al. prospectively evaluated the correlation between three genotypes and prostatic biopsy outcome in Caucasian men. The most significant SNPs were found to correlate with Gleason score and cancer aggressiveness. This inaugural prospective evaluation underscores the potential usefulness of genotyping in PCa assessment. Ongoing clinical evaluation of larger panels of SNPs will detail the actual impact of genetic markers on clinical practice.
Page 473 l View article: PDF (246 KB) HTML

A Four-Gene Signature Predicts Disease Progression in Muscle Invasive Bladder Cancer
Wun-Jae Kim, Seon-Kyu Kim, Pildu Jeong, Seok-Joong Yun, In-Chang Cho, Isaac Yi Kim, Sung-Kwon Moon, Hong-Duck Um, and Yung Hyun Choi
Bladder cancer is responsible for 150,000 deaths annually and is the seventh most prevalent type of cancer worldwide. Although only 20% of bladder cancer patients are diagnosed with muscle invasive bladder cancer (MIBC), the vast majority of cancer-specific deaths are due to MIBC. Conventional histopathological parameters have been investigated as prognostic indicators of MIBC, however, there are no reliable parameters that can adequately predict disease progression or metastasis of MIBC. In the present study, Kim et al. investigate putative genetic signatures associated with disease progression in patients with MIBC. The authors demonstrate a  four-gene expression signature is a reliable prognostic indicator of progression in MIBC, independent of traditional pathologic prognostic parameters. Identification of patients with high-risk MIBC may improve the effectiveness of currently available treatments and provide opportunities for the development of new treatment modalities.
Page 478 l View article: PDF (1.3 MB) HTML
Supplementary Data l View article: PDF (1.5 MB)

GNMT Expression Increases Hepatic Folate Contents and Folate-Dependent Methionine Synthase-Mediated Homocysteine Remethylation
Yi-Cheng Wang, Yi-Ming Chen, Yan-Jun Lin, Shih-Ping Liu, and En-Pei Isabel Chiang
Glycine N-methyltransferase (GNMT) is an abundant hepatic folate binding protein, which can regulate mediating methyl group availability in mammalian cells. GNMT is commonly diminished in human hepatoma and is believed to be a susceptibility gene and a potential tumor suppressor. Wang et al. investigated the impacts of GNMT expression on cell growth, folate status, methylfolate-dependent reactions and antifolate cytotoxicity. The authors demonstrated that expression of GNMT improves folate status while destruction of GNMT reduces hepatic folate and decreases methylfolate-dependent methionine synthase expression in the liver. The data indicate normal GNMT function is important for reducing liver cytotoxicity and the impact of GNMT on folate metabolism may account for the protective role of GNMT against liver tumorigenesis.
Page 486 l View article: PDF (868 KB) HTML

Autonomic Contribution to Endothelin-1 Increase during Laboratory Anger-Recall Stress in Patients with Coronary Artery Disease
Matthew M Burg, Aaron Soufer, Rachel Lampert, Dorothea Collins, and Robert Soufer
Coronary artery disease (CAD) is a disease of chronic inflammation characterized in part by macrophage infiltration of atherosclerotic plaques. Macrophages continuously release inflammatory cytokines that provoke endothelial cell dysfunction. Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor that can be rapidly released by activated macrophages and the vascular endothelium in response to stimuli of short duration, including those triggered by emotional stress. This may lead to coronary plaque rupture and triggered cardiac events.  Here, Burg et al. examine the contribution of changes in autonomic activity provoked by a laboratory stressor to changes in circulating ET-1 among patients with CAD.  The recall of a previously anger-provoking incident by CAD patients induced sympathetic arousal and parasympathetic withdrawal, the latter of which predicted an associated increase in circulating ET-1. These results suggest future examination of autonomic influences on atherosclerotic leukocytes, endothelial cell function, and the dynamics of ET-1 are warranted.
Page 495 l View article: PDF (70 KB) HTML

Milk Fat Globule-EGF Factor 8 Is a Critical Protein for Healing of Dextran Sodium Sulfate–Induced Acute Colitis in Mice
Ashish Chogle, Heng-Fu Bu, Xiao Wang, Jeffrey B Brown, Pauline M Chou, and Xiao-Di Tan
Inflammatory bowel disease (IBD) describes the inflammatory conditions of the large and small intestine including Crohn's disease and Ulcerative colitis. The pathogenesis of IBD is gradually being unraveled and may be the result of a combination of genetic, environmental, and immunological factors. Milk fat globule–EGF factor 8 (MFG-E8) plays an important role in maintaining the integrity of the intestinal mucosa and accelerates its healing in experimental models of sepsis. In the present study, Chogle et al. examined the role of MFG-E8/lactadherin in a model of IBD pathogenesis, tested its protective effects, and explored the therapeutic roles of MFG-E8 in experimental colitis. Their data suggest that MFG-E8 is an essential protective factor for gut epithelial homeostasis and exogenous administration of MFG-E8 may represent a novel therapeutic target in inflammatory bowel disease.
Page 502 l View article: PDF (3.2 MB) HTML
Supplementary Data l View article: PDF  (537 KB)

Peptide-Based Inhibition of NF-κB Rescues Diaphragm Muscle Contractile Dysfunction in a Murine Model of Duchenne Muscular Dystrophy
Jennifer M Peterson, William Kline, Benjamin D Canan, Daniel J Ricca, Brian Kaspar, Dawn A Delfín, Kelly DiRienzo, Paula R Clemens, Paul D Robbins, Albert S Baldwin, Pat Flood, Pravin Kaumaya, Michael Freitas, Joe N Kornegay, Jerry R Mendell, Jill A Rafael-Fortney, Denis C Guttridge, and Paul ML Janssen
Duchenne Muscular Dystrophy (DMD) is a deadly genetic disease mainly characterized by progressive weakness of the skeletal musculature. In one specific manifestation, the deterioration of diaphragm muscles leads to infection and respiratory failure. The nuclear factor kappa β (NF-Κβ) signaling pathway has been implicated as a contributing factor in this process. Here, Peterson et al. explore the clinical potential of various formulations of an NF-Κβ inhibitor, the NEMO Binding Domain (NBD) peptide. Results indicate a water-soluble NBD peptide significantly restored diaphragm contractile function and improved histopathological indices of disease in experimental models. Current treatment options for DMD are limited and this effort may provide a needed treatment strategy for these patients.
Page 508 l View article: PDF (831 KB) HTML

Insulin Protects against Hepatic Damage Postburn
Marc G Jeschke, Robert Kraft, Juquan Song, Gerd G Gauglitz, Robert A Cox, Natasha C Brooks, Celeste C Finnerty, Gabriela A Kulp, David N Herndon, and Darren Boehning
As one of the most severe forms of trauma occurring in over two million people in the United States of America per year, burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). Insulin has been shown to attenuate hepatic damage and to improve liver function, however, the underlying mechanisms by which insulin exerts its effects on liver structure and function are not understood. In this study, Jeschke et al. investigated the molecular mechanisms by which insulin administration improves hepatic structure and function post-burn. Results indicate Insulin significantly alleviates burn induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation, leading to improved hepatic structure and function. Their results support the use of insulin therapy after traumatic injury to improve patient outcomes.
Page 516 l View article: PDF (2.8 MB) HTML

Involvement of Leptin Receptor Long Isoform (LepRb)-STAT3 Signaling Pathway in Brain Fat Mass– and Obesity-Associated (FTO) Downregulation during Energy Restriction
Pei Wang, Feng-Jiao Yang, Hui Du, Yun-Feng Guan, Tian-Ying Xu, Xue-Wen Xu, Ding-Feng Su, and Chao-Yu Miao
Obesity has reached epidemic proportions worldwide, and accumulating evidence indicates that obesity is a heterogeneous disorder affected by both genetic and non-genetic factors. The fat mass– and obesity-associated (FTO) gene is tightly associated with the pathophysiology of obesity, however, the exact role of FTO remains poorly understood. Here, Wang et al. used a model of energy restriction to investigate expression levels of FTO mRNA and protein in peripheral metabolic tissues and in the brain, and to explore the involvement of the leptin signaling pathway in FTO regulation. Their results provide evidence that the LepRb-STAT3 signaling pathway is involved in the brain FTO downregulation during energy restriction. This work further extends our understanding of FTO's role in obesity. 
Page 523 l View article: PDF (3.1 MB) HTML

Mammal Cells Double Their Total RNAs against Diabetes, Ischemia Reperfusion and Malaria-Induced Oxidative Stress
Zhong-Wei Zhang, Jian Cheng, Fei Xu, Ming Yuan, Jun-Bo Du, Jing Shang, Yong Wang, Lei Du, Zi-Lin Li, and Shu Yuan
While total cellular RNA may increase or decrease gradually during growth or as a result of stress, overall levels usually remain stable. However, in this work Zhang et al. observed mammalian cell RNAs double within 24 hours in response to free heme accumulation (ischemia reperfusion and malaria infection) or a high level of sugar treatment (diabetes). Pretreatment with either glucose or heme for 24 hours subsequently alleviated oxidative damage caused by diabetes, ischemia reperfusion or malarial infection. The authors postulate the rapid RNA amplification may play an important role in mammalian response to diabetes, ischemia reperfusion and malaria infection-derived oxidative stress and manipulation of RNA may offer a new direction for treatment.
Page 533 l View article: PDF (1.1 MB) HTML
Supplementary Data l View article: PDF  (1.5 MB)

Aging Influences Cardiac Mitochondrial Gene Expression and Cardiovascular Function following Hemorrhage Injury
Bixi Jian, Shaolong Yang, Dongquan Chen, Luyun Zou, John C Chatham, Irshad Chaudry, and Raghavan Raju
Aging is a significant factor that contributes to mitochondrial damage and dysfunction. A progressive decline in mitochondrial respiratory pathway activity is associated with the progression to heart failure. Specific molecular pathways responsible for mitochondrial functional alterations after injury in relation to aging are largely unknown. Here, Jian et al. use experimental models to further investigate these mechanisms. Results point to c-Myc as a potential target gene in injury and aging.  A further understanding of c-Myc and its relationship to mitochondrial function may unravel new pathways in age-related injury.
Page 542 l View article: PDF (1 MB) HTML
Supplementary Data l View article: PDF (1.6 MB)

Functional Evaluation of GJB2 Variants in Nonsyndromic Hearing Loss
Soo-Young Choi, Kyu Yup Lee, Hyun-Jin Kim, Hyo-Kyeong Kim, Qing Chang, Hong-Joon Park, Chang-Jin Jeon, Xi Lin, Jinwoong Bok, and Un-Kyung Kim
Hearing loss (HL) is one of the most common sensory disorders, affecting about 2 out of 1000 newborns. Mutations in the gap junction beta 2 (GJB2) gene are responsible for approximately 50% of autosomal recessive nonsyndromic HL and more than 150 different variants have been reported in the GJB2 gene. In this study, Choi et al. performed functional analyses and population study for two variants of GJB2 to clarify the possible roles of these variants in HL. Results indicate the variants affect the rate of intracellular substrate transfer and calcium ion transfer along with hemichannel permeability. Based upon these findings, the authors suggest HL may be associated with these variants and additional research is needed to extend the findings.
Page 553 l View article: PDF (954 KB) HTML
Supplementary Data l View article: PDF (905 KB)

Validation of the Glaucoma Filtration Surgical Mouse Model for Antifibrotic Drug Evaluation
Li-Fong Seet, Wing Sum Lee, Roseline Su, Sharon N Finger, Jonathan G Crowston, and Tina T Wong
Glaucoma is a disease of the eye resulting in optic nerve damage, leading to progressive, irreversible loss of vision. Elevated intraocular pressure (IOP) is the most common risk factor in glaucoma which can be surgically managed by glaucoma filtration surgery (GFS). However, the major obstacle to achieving long-term surgical success is the post-operative subconjunctival scarring response. Several experimental models for studying the scarring response after GFS have been described but they all have limitations. In this study, Seet et al. have developed a murine model of GFS and discussed the validity of their model and its similarity to human glaucoma filtration surgery. The authors also demonstrated the key mechanisms whereby mitomycin c treatment modulates the antiscarring response in this model.
Page 557 l View article: PDF (6.4 MB) HTML

Review  Article

Novel Aspects of Fibrin(ogen) Fragments during Inflammation
Carla Jennewein, Nguyen Tran, Patrick Paulus, Peter Ellinghaus, Johannes Andreas Eble, and Kai Zacharowski
Coagulation is a process of blood clot formation that is initiated not only by a complex cascade upon injury to a blood vessel, but also in response to inflammation. Uncontrolled activation of the coagulation system contributes to inflammation. Coagulation is initiated by the activation of thrombin that triggers fibrin formation, while fibrin is cleaved by plasmin resulting in the lysis of clots that is accompanied by the generation of fibrin D and E fragments. Coagulation is not only affected by inflammation, but various coagulation factors including fibrin(ogen) and fibrin degradation products modulate the inflammatory response by affecting leukocyte migration and cytokine production. In this review article, Jennewein et al. discuss the interaction between inflammation and coagulation and the modulation of inflammation by fibrin(ogen) and fibrin fragments.
Page 568 l View article: PDF (2.6 MB) HTML

Erratum
Page 576 l View article: PDF (213 KB)