July-August 2008 l Vol 14 l No 7-8

Successes of Molecular Medicine in Neuroscience
Bernhard Schaller and Nora Sandu
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1, 2-Dioleoyl-3-Trimethylammonium-Propane (DOTAP)- Formulated, Immune-Stimulatory Vascular Endothelial Growth Factor A Small Interfering RNA (siRNA) Increases Antitumoral Efficacy in Murine Orthotopic Hepatocellular Carcinoma with Liver Fibrosis
Miroslaw Kornek, Veronika Lukacs-Kornek, Andreas Limmer, Esther Raskopf, Ursula Becker, Maren Klöckner, Tilman Sauerbruch, and Volker Schmitz
Hepatocellular carcinoma (HCC) is a type of liver cancer that may occur in conjunction with cirrhosis, an accumulation of scar tissue in the liver. Vascular endothelial growth factor (VEGF) plays a role in tumor angiogenesis and in this work, Kornek et al. (365-373) sought to interrupt the VEGF pathway using gene silencing in a model of HCC with preexisting liver fibrosis. Treatment with VEGF-A small interfering RNA was efficient when combined with the cationic lipid DOTAP. These results may help direct and improve future experimental gene silencing approaches in order to establish more efficient anti-tumoral therapies against HCC.
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Genomic-Based High Throughput Screening Identifies Small Molecules that Differentially Inhibit the Antiviral and Immunomodulatory Effects of IFN-α
Bo Chen, Qin Zong, Ricardo Cibotti, Chad Morris, Juana Castaneda, Brian Naiman, Derong Liu, Anna Glodek, Gary P Sims, Ronald Herbst, Stephen K Horrigan, Peter A Kiener, Dan Soppet, Anthony J Coyle, and Laurent Audoly
Systemic Lupus Erythematosus (SLE) is an autoimmune disease which affects mainly women during their childbearing years. SLE is characterized by anti-nuclear autoantibodies and inflammatory lesions which target several tissues in the body. There remains an urgent need for novel, safe, effective therapies. Inhibition of type I interferons, such as IFN-α, may provide a therapeutic benefit for SLE and other autoimmune diseases. Chen et al. (374-382) screened a small compound library to identify modulators of IFN-α biological effects. A high throughput genomic-based screen was applied to prioritize small molecule inhibitors targeting various intracellular signaling pathways. This work describes a novel strategy to identify small molecule inhibitors for the treatment of autoimmune disorders.
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Proteomic Analysis Permits the Identification of New Biomarkers of Arterial Wall Remodeling in Hypertension
Sandrine Delbosc, Mounsif Haloui, Liliane Louedec, Morgan Dupuis, Myriam Cubizolles, Vladimir N Podust, Eric T Fung, Jean-Baptiste Michel, and Olivier Meilhac
Hypertension is one of the main risk factors for vascular disease. To explore markers of hypertension-related morbidity, Delbosc et al. (383-394) investigated changes in proteins released by the aorta in two models with differing susceptibility to hypertension. Results indicate a greater susceptibility to endothelial dysfunction is associated with aortic wall hypertrophic remodeling. The authors also identified SM22α as a potential marker of susceptibility to hypertension-induced arterial wall remodeling.
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Felodipine Reduces Cardiac Expression of IL-18 and Perivascular Fibrosis in Fructose-Fed Rats
Shan-Shan Xing, Hong-Wei Tan, Xiu-Ping Bi, Ming Zhong, Yun Zhang, and Wei Zhang
High dietary intake of fructose has rapidly become an important causative factor in the development of metabolic syndrome. Metabolic syndrome is associated with accelerated macrovascular and microvascular coronary disease, cardiomyopathy and elevated inflammatory status. Xing et al. (395-402) fed rats fructose to investigate whether metabolic syndrome-associated elevation of IL-18, an inflammatory cytokine associated with increased adiposity and insulin resistance could be pharmacologically attenuated. Results show the calcium channel blocker felodipine attenuated serum levels of IL-18, cardiac IL-18 mRNA, and coronary perivascular fibrosis suggesting IL-18 may contribute to the pathological sequelae of this disease.
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Rosiglitazone Attenuates Insulin-Like Growth Factor 1 Receptor Survival Signaling In PC-3 Cells
Efstathia Papageorgiou, Nea Pitulis, Menelaos Manoussakis, Peter Lembessis, and Michael Koutsilieris
Prostate cancer is the most common malignancy in men over 60 and is associated with significant cancer-related mortality in its advanced stage.  PPARγ is overexpressed in prostate cancer and PPARγ ligands promote cell cycle arrest and apoptosis in prostate cancer cells.  Papageorgiou et al. (403-411) analyzed the ability of two PPARγ ligands to increase cytotoxicity and suppress survival in PC-3 prostate cancer cells. While both ligands induced cytostasis, only the synthetic ligand inhibited the survival factor action of IGF-1 on chemotherapy-induced apoptosis of PC-3 cells via a non-genomic action.  This attenuation of IGF-1-dependent signaling in PC-3 cells could have clinical implications for the management of androgen ablation-refractory and chemotherapy-resistant advanced prostate cancer patients with bone metastasis.
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p16INK4a Gene Promoter Hypermethylation in Mucosa as a Prognostic Factor for Patients with Colorectal Cancer
Yvonne Wettergren, Elisabeth Odin, Staffan Nilsson, Göran Carlsson, and Bengt Gustavsson
Colorectal cancer (CRC) is the third leading cause of cancer deaths in Western countries. Development of distant metastases by tumor cells spread from the primary tumor site is a major cause of death. Using biomarkers to identify CRC patients who would benefit from adjuvant treatment may decrease the risk of recurrence. Low folate levels are seen in CRC patients with poor survival. Folate levels affect gene-specific hypermethylation, and in this work Wettergren et al. (412-421) investigated whether hypermethylation of the p16 promoter in mucosa could be detected and related to survival of CRC patients.  Patients with p16 hypermethylation in the mucosa had an increased risk of cancer-related death and shorter disease-free survival. Hypermethylation of p16 was identified as an independent prognostic parameter for cancer-specific survival and an independent predictor of disease free survival.  
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Lysophosphatidic Acid Inhibits Bacterial Endotoxin-Induced Pro-Inflammatory Response: Potential Anti-Inflammatory Signaling Pathways
Hongkuan Fan, Basilia Zingarelli, Vashaunta Harris, George E Tempel, Perry V Halushka, and James A Cook
Overactivity of the innate immune system results in systemic inflammatory response syndrome (SIRS) and septic shock. Lack of the Gi protein results in augmented inflammatory responses to lipopolysaccharide (LPS).  Since lysophosphatidic acid (LPA) activates Gi proteins, Fan et al. (422-428) hypothesized that LPA could inhibit LPS-induced inflammatory responses through activation of Gi-coupled anti-inflammatory signaling pathways.  Results demonstrate LPA has an anti-inflammatory effect on LPS-induced systemic inflammation through ERK1/2, serine/threonine phosphatases and P13 kinase signaling pathways. Targeting LPA and the corresponding signaling pathways may result in potential therapeutic treatments for sepsis.
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Association of Urinary N-Domain Angiotensin I-Converting Enzyme with Plasma Inflammatory Markers and Endothelial Function
Fernanda B Fernandes, Frida L Plavnik, Andressa MS Teixeira, Dejaldo M deJesus Christofalo, Sergio A Ajzen, Elisa MS Higa, Fernanda A Ronchi, Ricardo de Castro Cintra Sesso, and Dulce E Casarini
Hypertension, or high blood pressure, is a critical public health problem. Hypertensive patients often do not exhibit symptoms, leaving them unaware of their risk. Development of early biomarkers for hypertension may help identify those at risk before an adverse outcome such as heart attack or stroke may occur. Fernandes et al. (429-435) examined the association between urinary angiotension I-converting enzyme (ACE), a vascular regulator, and other hypertensive elements including C-reactive protein, homocysteine plasma levels, urinary nitric oxide and endothelial function. Findings suggest that healthy subjects with the 90kDa isoform of ACE and a family history of hypertension exhibited endothelial dysfunction. This data may lead to the development of a biomarker to assess future hypertension risks.
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Soluble FcγRIIIa^Mφ Levels in Plasma Correlate with Carotid Maximum Intima-Media Thickness (IMT) in Subjects Undergoing an Annual Medical Checkup
Midori Masuda, Katsuya Amano, Shi Yan Hong, Noriko Nishimura, Masayoshi Fukui, Masamichi Yoshika, Yutaka Komiyama, Hiroya Masaki, Toshiji Iwasaka, and Hakuo Takahashi
Atherosclerosis is the buildup of plaque deposits in the arteries. Macrophages play a major role in this vascular lesion development. The FcγRIIIa(CD16) receptor is expressed in a minor subset of peripheral blood monocytes and is present in human atherosclerotic plaques. Soluble FcγRIIIa^Mφ found in plasma is significantly increased in patients with coronary artery disease. Masuda et al. (436-442) investigated the potential of FcγRIIIa^Mφ as biomarker for atherosclerosis. Results showed the soluble FcγRIIIa^Mφ levels were related to the number of risk factors for atherosclerosis including aging, smoking, diabetes, hypertension and cholesterolemia as well as carotid maximum intima-media thickness. This indicates macrophage activation during the incipient stage of atherosclerosis and the potential use of soluble FcγRIIIa^Mφ as a predictive marker for this disease.
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Purification and Characterization of Human Adrenomedullin Binding Protein-1
Xiaoling Qiang, Rongqian Wu, Youxin Ji, Mian Zhou, and Ping Wang
Vascular responsiveness to adrenomedullin (AM), a potent vasoactive peptide, decreases during sepsis and hemorrhage and improves after administration of its binding protein (AMBP-1). While AM/AMBP-1 may be a leading candidate for sepsis and hemorrhage treatment, the high cost of commercial AMBP-1 has limited the development of human AM and AMBP-1 as therapeutic agents.  In this work Qiang et al. (443-450) successfully isolated and purified AMBP-1 from human serum and demonstrated its stability and biological activity in vitro and in vivo. This technique allows further development of human AM/AMBP-1 as a therapy for safe and effective treatment of hemorrhagic shock, sepsis, and ischemic injury.
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Protein Aggregation in the Brain: The Molecular Basis for Alzheimer’s and Parkinson’s Diseases
G Brent Irvine, Omar M El-Agnaf, Ganesh M Shankar, and Dominic M Walsh
Developing effective treatments for neurodegenerative diseases is one of the greatest medical challenges of the 21st century.  Protein aggregation is a common feature of many neurodegenerative diseases and is assumed to play a central role in pathogenesis.  Irvine et al. (451-464) discuss this theme as it relates to Alzheimer’s and Parkinson’s diseases. 
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Epithelial Cell Apoptosis and Neutrophil Recruitment in Acute Lung Injury - A Unifying Hypothesis? What We Have Learned from Small Interfering RNAs
Mario Perl, Joanne Lomas-Neira, Chun-Shiang Chung, and Alfred Ayala
Acute Lung Injury (ALI) is associated with high morbidity and mortality.  ALI is a co-morbid event associated with a diverse family of diseases and the lack of therapeutic options for ALI may result from distinct pathological processes.  Activated neutrophil induced tissue injury and epithelial cell apoptosis-mediated lung damage represent two potentially important candidate pathomechanisms in ALI.  In this review, Perl et al. (465-475) focus on these pathogenic mechanisms as well as the role of small interfering RNA as a potential therapeutic for ALI.
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HMGB1: Endogenous Danger Signaling
John R Klune, Rajeev Dhupar, Jon Cardinal, Timothy R Billar, and Allan Tsung
Recent advances in understanding the mechanisms of innate immune system activation have pointed to certain pattern recognition receptors as a common pathway for immune identification of both microbial invasion and tissue injury.  By sensing either pathogens or endogenous danger signals released upon cellular stress or damage, these pattern recognition receptors, or alarmins, are capable of alerting the host to danger by activating the innate immune system.  Klune et al. (476-484) describe the role of an archetypical alarmin, HMGB1, and its potential therapeutic role in various disease states.
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Epidemic Inflammation: Pondering Obesity
Carl Nathan
Over the past few decades more than half of Americans were among the billion people worldwide who had become overweight or obese.  Inflammation has been recognized as a major driver in the pathogenesis of common diseases, such as diabetes and cancer, in which obesity is a major risk factor.  While it is not suggested that obesity’s initial cause is inflammation, it does frequently lead to inflammation that appears to arise first in certain fat deposits.  Nathan (485-492) reviews evidence that reactive oxygen and nitrogen intermediates help drive chronic inflammation in the obese.   
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Sex Steroids and Stem Cell Function
Rinki Ray, Nathan M Novotny, Paul R Crisostomo, Tim Lahm, Aaron Abarbanell, and Daniel R Meldrum
Gender dimorphisms exist in a variety of disorders. Estrogens influence myocardial remodeling following insult, facilitate mobilization of endothelial progenitor cells to the ischemic myocardium and enhance neovascularization at the ischemic border zone. Stem cell transplantation has improved treatment for several disorders; however a greater understanding of the effects of sex hormones on stem cell populations is required to improve clinical efficacy.  In this review, Ray et al. (493-501) summarize current knowledge regarding the effects of estrogens and androgens on various stem cell populations.
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Renal Hypoxia and Dysoxia After Reperfusion of the Ischemic Kidney
Mattieu Legrand, Egbert Mik, Tanja Johannes, Didier Payen, and Can Ince
Ischemia is the most common cause of acute renal failure – a common condition that develops in 5% of hospitalized patients.  Recent investigations have identified a central role of microvascular dysfunction leading to decreased renal oxygen supply and changes in oxygen consumption during the ischemia-reperfusion injury process. Legrand et al. (502-516) provide an overview of how renal oxygenation pathways are affected by I/R in the kidney and how these processes affect organ failure. 
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Estrogen, NFκB and the Heat Shock Response
James P Stice and Anne A Knowlton
Estrogen is known to induce a number of beneficial physiological effects, particularly in the neurological and cardiovascular systems. These benefits can be attributed to the antioxidant and vasodilatory effects of E2, the most biologically active metabolite of estrogen.  E2 interacts with and modulates NFκB activity, inducing expression of the protective class of proteins, HSPs.  Stice and Knowlton (517-527) focus on the molecular mechanisms and biological relevance of cross-talk between E2, NFκB, and HSPs.
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Host Defense Peptides in Wound Healing
Lars Steinstraesser, Till Koehler, Frank Jacobsen, Adrien Daigeler, Ole Goertz, Stefan Langer, Marco Kesting, Hans Steinau, Elof Eriksson, and Tobias Hirsch
Skin and soft tissue infections account for 7-10% of hospitalizations and represent one of the most common indications for antimicrobial therapy in the United States.  Wound infections and sepsis are an increasing cause of death in severely ill patients, and the treatment of chronic and complex wounds puts a significant burden on the health care system and on the economy as a whole.  In this review, Steinstraesser et al. (528-537) focus on the current knowledge of host defense peptides affecting wound healing and infection.
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Erratum
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