July-Aug 2006 l Vol 12 l No 7-8

Immunolocalization and Expression of Vascular Endothelial Growth Factor Receptors (VEGFRs) and Neuropilins (NRPs) on Keratinocytes in Human Epidermis
Xiao-Yong Man, Xiao-Hong Yang, Sui-Qing Cai, Yong-Gang Yao, and Min Zheng
Endothelial cell growth factors have been studied extensively due to their angiogenic behavior in physiological and pathological conditions.  In particular, vascular endothelial growth factor (VEGF) plays an important role in normal and pathological angiogenesis.  VEGF receptors (VEGFRs) and neuropilins (NRPs), traditionally found specifically on endothelial cells, bind VEGF with high affinity and are traditionally considered to be specific for endothelial cells.  Here, Man et al. (127-136) found expression of VEGFRs and NRPs on cultured epidermal keratinocytes at mRNA and protein levels.  Further, VEGFRs and NRPs were localized by immunofluorescence to the epidermis of surgical skin specimens.  These results suggest that the expression of VEGFRs and NRPs on keratinocytes may be significant in the regulation and activity of autocrine signaling in the epidermis.
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Intracellular Evaluation of ER Targeting Elucidates a Mild Form of Inherited Coagulation Deficiency
Lara Rizzotto, Mirko Pinotti, Paolo Pinton, Rosario Rizzuto, and Francesco Bernard
Genetic investigations in patients have revealed a mutational pattern for several hemorrhagic coagulation factor disorders which are mainly characterized by a reduction in circulating protein levels in plasma. The molecular mechanisms through which the mutations elicit their effects and their relationship with plasma and clinical phenotypes in patients have been poorly investigated.  Here, Rizzotto et al. (137-142) investigated the altered targeting to the endoplasmic reticulum due to missense mutations.  Through in vitro expression of native and chimeric proteins, the authors determined the effect of mutations on factor VII (FVII), the serine protease which triggers the clotting cascade.  They suggest that pre-peptide mutations associated with the residual expression of normal FVII explained the mild form of FVII deficiency in patients.  This approach, which may be extended to other coagulation serine proteases, clearly contributed to elucidate the relationship of genotype with plasma and clinical phenotype.
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Activation of the Poly (ADP-ribose) Polymerase Pathway in Human Heart Failure
Andrea Molnár, Attila Tóth, Zsolt Bagi, Zoltán Papp, István Édes, Miklós Vaszily, Zoltán Galajda, Julius Gy. Papp,3András Varró, Viktória Szüts, Zsombor Lacza, Domokos Gerö, and Csaba Szabó Hepatocellular carcinomaAcute and chronic heart failure are major causes of hospitalization, morbidity and mortality worldwide. The pathological mechanism of heart failure is complex and can include the activation of numerous secondary pathways, resulting in structural alterations that further exacerbate heart failure. Recent animal models of heart failure have provided pathogenetic evidence that poly(ADP-ribose) polyermase (PARP) may play a role in oxidative and nitrosative stress as well as downstream mechanisms leading to various forms of heart failure. Here, Molnar et al. (143-152) compare healthy human myocardial samples with myocardial samples from failing human hearts and found evidence of oxidative and nitrosative stress and PARP activation. Pharmacological exploitation of these pathways may allow for the identification of new targets for therapeutic intervention.
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Non-hematopoietic Erythropoietin Derivatives Prevent Motoneuron Degeneration in Vitro and in Vivo
Tiziana Mennini, Massimiliano De Paola, Paolo Bigini, Cristina Mastrotto, Elena Fumagalli, Sara Barbera, Manuela Mengozzi, Barbara Viviani, Emanuela Corsini, Marina Marinovich, Lars Torup, Johan Van Beek, Marcel Leist, Michael Brines, Antony Cerami, and Pietro Ghezzi
Amyotrophic Lateral Sclerosis (ALS) is a degenerative disease of the upper and lower motoneurons that leads to progressive motor dysfunction and death within 3-5 years of diagnosis. Currently, only one drug, riluzole, is approved by the FDA for the treatment of ALS and the search for new therapeutic agents is ongoing.  Erythropoietin (EPO), a hematopoietic growth factor, exhibits protective effects in various models of neurodegenerative disease. However, EPO administration increases hematocrit which may have undesirable effects, such as increased risk of thrombosis.  Derivatives of EPO, carbamylated EPO (CEPO) and asialo EPO (ASIALO-EPO), retain the neuroprotective activities of EPO without the potentially harmful effects. Here, Mennini et al. (153-160) extend their in vitro studies and tested the effect of EPO derivative treatment in an animal model of ALS, the wobbler mouse.  Results indicate that EPO derivatives have significant potential as therapeutics for prevention of motoneuron degeneration.
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Differential Reactions of Microglial to Brain Metastasis of Lung Cancer
Bei Ping He, Jian Jun Wang, Xian Zhang, Yan Wu, Miao Wang, Boon-Huat Bay, and Alex Yuang-Chi Chang
Patients with brain metastases have a poor prognosis in spite of radio- and/or chemotherapy.  Immune cells in the brain, such as microglia, may play a major role in cancer metastasis, dormancy and relapse.  Microglia serve as a major component in the brain immune system, however, the mechanism by which they interact with metastatic cancer cells remains unknown.  He et al. (161-170) investigated microglial reactions with metastatic lung cancer cells in brain tissues and evaluated the cytotoxic effects of lipopolysaccharide-activated microglia on metastatic lung cancer cells in vitro.  Microglia showed significant activation in the vicinity of a metastatic lung cancer mass in the brain and formed a clear boundary between the tumor mass and normal brain tissue.  Together with the observation that TNF-α alone induced proliferation of the tumor cells, these findings provide possible clues to the mechanism of activation of central microglia involved in the metastasis of lung cancer cells to the brain.  
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Expression of Adamalysin Proteases (A Disintegrin And Metalloprotease) and their Inhibitors in Sputum from Asthmatics
Geneviève Paulissen, Natacha Rocks, Florence Quesada-Calvo, Philippe Gosset, Jean-Michel Foidart, Agnès Noel, Renaud Louis, and Didier D Cataldo
Asthma, a complex inflammatory disease of the conducting airways, leads to progressive lung function impairment and morphological changes in the airways.  Histological studies have shown that asthmatic patients display structural changes in bronchial trees such as increased muscle mass and inflammatory cell infiltration.  These changes have clinical repercussions that may be responsible for airway hyperresponsiveness and decreases in forced expiratory volume.  Paulissen et al. (171-179) investigated ADAMs (A disintegrin and metalloprotease) and ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs), proteases which have been extensively studied in asthmatic pathology and been reported to be asthma-associated genes. The authors conclude that members of the ADAM and ADAMTS families are modulated in sputum from asthmatics and, due to their varied potentialities, may play a role in the control of inflammation, airway remodeling and bronchoconstriction.
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Limited Dynamic Range of Immune Response Gene Expression Observed in Healthy Blood Donors Using RT-PCR
Kevin McLoughlin, Ken Turteltaub, Danute Bankaitis-Davis, Richard Gerren, Lisa Siconolfi, Kathleen Storm, John Cheronis, David Trollinger, Dennis Macejak, Victor Tryon, and Michael Bevilacqua
Recent developments in gene and protein expression analysis technology suggest that gene expression may be a key indicator of an individual’s pathophysiologic status.  Consequently, the clinical application of gene expression technology has the potential to vastly improve upon current approaches for monitoring health and diagnosing disease.  A key requirement for clinical application of gene expression technology is determining natural variations in healthy subjects to establish a normal range of expression or “reference range”.  McLoughlin et al. (185-195) characterized the natural variations of immune response genes in the whole blood of apparently healthy subjects.  Additionally, whole blood gene expression in volunteers injected with lipopolysaccharide was also analyzed.  Results suggest that the dynamic range of expression of immune response genes is limited among healthy subjects and individuals exposed to bacterial endotoxin show expression profiles that can be readily distinguished from those of a healthy population.
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Oral Adsorbent AST-120 Decreases Serum Levels of AGEs in Patients with Chronic Renal Failure
Seiji Ueda, Sho–ichi Yamagishi, Masayoshi Takeuchi, Keisuke Kohno, Ryo Shibata, Yuriko Matsumoto, Utako Kaneyuki, Toshiko Fujimura, Ayako Hayashida, and Seiya Okuda
Advanced glycation end products (AGEs) are senescent macroprotein derivatives, the formation and accumulation of which have been shown to progress at an accelerated rate in diabetes and chronic renal failure (CRF).  AGE formation and accumulation in plasma and vascular tissues contribute to the pathogenesis of accelerated atherosclerosis that occurs in these devastating disorders.  AST-120 is an oral adsorbent that attenuates the progression of CRF by removing uremic toxins.  Here, Ueda et al. (180-184) tested serum levels of AGE before and after AST-120 administration in non-diabetic CRF patients.  AST-120 administration significantly decreased patient serum levels of AGEs.  Additionally, in vitro, AST-120 adsorbed carboxymethyllysine, a well-characterized digested food-derived AGE.  The authors conclude that the atheroprotective properties of AST-120 are ascribed in part to its AGE-lowering ability via adsorption of carboxymethyllysine.
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