| Published by
|
March-April 2007 l Vol 13 l No 3-4
The Interleukin-8 (IL-8/CXCL8) Receptor Inhibitor Reparixin Improves Neurological Deficits and Reduces Long-term Inflammation in Permanent and Transient Cerebral Ischemia in Rats
Pia Villa, Sara Triulzi, Barbara Cavalieri, Rosa Di Bitondo, Riccardo Bertini, Sara Barbera, Paolo Bigini, Tiziana Mennini, Paolo Gelosa, Elena Tremoli, Luigi Sironi, and Pietro Ghezzi
Infiltration of neutrophils, or polymorphonuclear leukocytes (PMNs), contributes to the deleterious aspects of inflammation during stroke. Interleukin-8 (IL-8/CXCL8), in conjunction with other chemokines, is induced during stroke in patients and animals models of cerebral ischemia. Blocking inflammation by inhibiting these mediators is a plausible therapy for cerebral ischemia. Reparixin is an inhibitor of CXCR1 and CXCR2, the receptors for the CXCL8 family of chemokines implicated in the recruitment of PMNs. In this study, Villa et al. (125-133) evaluated the effects of reparixin in two cerebral ischemia models, transient and permanent middle cerebral artery occlusion, using varied treatment schedules and therapeutic windows. Data indicate that reparixin not only reduces short-term PMN infiltration and infarct size, but also decreases long-term inflammation and improves long-term neurological outcome in transient and permanent ischemia models. These results support the notion that CXCL8-mediated inflammation plays an important role in ischemic damage and CXCR1/2 inhibitors may represent a therapeutic strategy for the treatment of cerebral ischemia.
Page 125 l View article: PDF ( 1.6 MB) HTML
Erratum HTML
NF-kB is Persistently Activated in Continuously Stimulated Human Neutrophils
Veronika Miskolci, Janet Rollins, Hai Yen Vu, Chandra C Ghosh, Dennis Davidson, and Ivana Vancurova
Increased activation of the transcription factor NF-kB in neutrophils has been associated with the pathogenesis of sepsis, acute lung injury (ALI), bronchopulmonary dysplasia (BPD) and other neutrophil-mediated inflammatory disorders. Despite recent progress in analyzing early NF-kB activation in human neutrophils, mechanisms of NF-kB activation in persistently stimulated neutrophils remain unknown. Persistent NF-kB activation is believed to be involved in the host response to sepsis and the pathogenesis of ALI and BPD. Miskolci et al. (134-142) analyzed NF-kB activation and expression of IkB and NF-kB proteins during neutrophil stimulation with inflammatory signals for prolonged periods. Data suggest that NF-kB is persistently activated in human neutrophils during neutrophil-mediated inflammatory disorders. This persistent NF-kB activity may represent one of the underlying mechanisms for the continuous production of pro-inflammatory mediators. Understanding the mechanisms regulating initiation and persistence of NF-kB activation in human neutrophils may provide new information for the development of early detection and safer therapies for ALI, BPD, sepsis and other neutrophil-mediated inflammatory disorders.
Page 134 l View article: PDF (764 KB) HTML
Up-regulation of Rac1 by Epidermal Growth Factor Mediates COX-2 Expression in Recurrent Respiratory Papillomas
Rong Wu, Salvatore J Coniglio, Amanda Chan, Marc H Symons, and Bettie M Steinberg
Recurrent respiratory papillomas (RRP) are epithelial tumors of the airway caused by human papillomaviruses. Papilloma cells overexpress the epidermal growth factor receptor (EGFR) and signal transduction pathways linked to EGFR are altered in papilloma cells contributing to abnormal differentiation. Cyclooxygenase-2 (COX-2) expression is elevated in respiratory papilloma tissues and requires EGFR and phosphatidylinositol 3-kinase (PI3K) activity. However, the EGFR-Mek-Erk pathway plays no role in induction of COX-2 in papilloma cells, suggesting that one or more other pathways is involved in these cells. Wu et al. (143-150) postulated that a Rac1-dependent pathway may play a role in the induction of COX-2 in papilloma cells. Results show that Rac1 is overexpressed in papilloma cells, that overexpression is due to increased EGFR signaling and that Rac1 mediates induction of COX-2 in part through activation of p38. This pathway is specific to papilloma cells and does not function in normal laryngeal cells. A detailed understanding of this mechanism may lead to therapeutic targets for recurrent respiratory papillomas.
Page 143 l View article: PDF (612 KB) HTML
PRL-3-siRNA Inhibits the Metastasis of B16-BL6 Mouse Melanoma Cells in vitro and in vivo
Feng Qian, Yu-Pei Li, Xia Sheng, Zi-Chao Zhang, Ran Song, Wei Dong, Shao-Xian Cao, Zi-Chun Hua, and Qiang Xu
Metastasis is a leading cause of cancer mortality involving a complex, multi-step progress by which tumor cells disseminate to distant sites to establish discontinuous secondary colonies. Many factors have been validated in the process of metastasis; however, mechanisms of regulating the multi-step progression from primary tumor initiation to proliferation in metastatic sites remain poorly elucidated. Phosphatase of regenerating liver (PRL), a newly identified tyrosine phosphatase family, plays a causative role in tumor metastasis. PRL-3 plays a notable role in metastatic cancer cells and Qian et al. (151-159) investigated the role of endogenous PRL-3 in the metastatic process as well as the clinical ability of PRL-3-siRNA to prolong the survival time of mice in the spontaneous metastasis model. Results indicate that PRL-3 plays a critical role in promoting the process of spontaneous metastasis and tumor growth initiation. Inhibiting PRL-3 may improve malignant tumor therapy.
Page 151 l View article: PDF (768 KB) HTML
Eratum: View Figure 5 PDF
Expression of the Neural Stem Cell Markers NG2 and L1 in Human Angiomyolipoma- Are angiomyolipomas neoplasms of stem cells?
So Dug Lim, William Stallcup, Benjamin Lefkove, Baskaran Govindarajan, Kit Sing Au, Hope Northrup, Deborah Lang, David E Fisher, Avani Patel, Mahul B Amin, and Jack L Arbiser
Angiomyolipomas are benign tumors of the kidney which express phenotypes of smooth muscle, fat, and melanocytes. These tumors appear with increased frequency in the autosomal dominant disorder tuberous sclerosis, and are the leading cause of morbidity in adults with tuberous sclerosis. While benign, these tumors are capable of provoking life threatening hemorrhage and replacement of the kidney parenchyma, resulting in renal failure. The histogenesis of these tumors is currently unclear. Recently, stem cell precursors have been recognized that can give rise to smooth muscle and melanocytes. These precursors have been shown to express the neural stem cell marker NG2 and L1. To determine whether angiomyolipomas express NG2 and L1, Lim et al. (160-165) performed immunocytochemistry on a cell line derived from a human angiomyolipoma. Results revealed uniform staining of tumor cells while renal cell carcinomas revealed positivity only of angiogenic vessels. These results support a novel histogenesis of angiomyolipoma as a defect in differentiation of stem cell precursors. An understanding of the embryonic basis of angiomyolipoma may be beneficial in therapy of this common tumor.
Page 160 l View article: PDF (364 KB) HTML
Survivin Expression in Tuberous Sclerosis Complex Cells
Emily Baechler, Jason Stephana Carelli, Elena Lesma, Simona Paratore, Vera Grande, Giorgia Zadra, Silvano Bosari, Anna Maria Di Giulio, and Alfredo Gorio
Tuberous Sclerosis Complex (TSC) is a genetic tumor suppressor-gene disorder inducing mutations in TSC1/TSC2 genes. TSC is characterized by multi-organ development of mainly benign tumors which affect the central nervous system, kidney and skin. Kidney tumors include angiomyolipomas and renal cell carcinomas which are masses made up of muscle cells, adipose tissues, and disorganized vascular channels. Survivin is a member of the inhibitors of apoptosis gene family and one of the most pursued targets among the regulators of apoptosis. A significant feature of survivin is its expression in cancers. Here Carelli et al. (166-177) isolated and characterized two cell populations from an angiomyolipoma in a patient affected by TSC2. Results show that TSC2 -/- angiomyolipoma-derived human smooth muscle cells express the apoptosis inhibitor protein, survivin, when exposed to insulin-like growth factor 1 (IGF-1) or when various culture conditions were disturbed. The TSC2 -/- cells release IGF-1 through a negative feedback mechanism which is further activated when cells are exposed to IGF-1 receptor antibodies. The autocrine release of IGF-1 may be a powerful mechanism of survival of the tightly packed cells in the thick-walled vessels of TSC angiomyolipoma and in lymphangioleiomyomatosis (LAM) nodules. Targeted inhibition of survivin may enhance sensitivity to TSC2 therapy, and thus may be an effective target for future LAM therapies.
Page 166 l View article: PDF (1.6 MB) HTML
RR Interval Variability is Inversely Related to Inflammatory Markers: The CARDIA Study
Richard P Sloan, Heather McCreath, Kevin J Tracey, Stephen Sidney, Kiang Liu, and Teresa Seeman
Recent evidence reveals that the immune system is under the direct control of the vagus nerve via the “cholinergic anti-inflammatory pathway. Stimulation of vagus nerve activity significantly inhibits cytokine levels in animal models, and cholinergic agents inhibit cytokine release by human macrophages. Moreover, when vagus nerve activity is decreased or absent, cytokines are overproduced. Atherosclerosis is an inflammatory disease characterized by elevated levels of the proinflammatory mediators C reactive protein (CRP) and interleukin six (IL-6). The relationship between cardiac vagal activity and cytokine levels in healthy humans is not well understood. Here, Sloan et al. (178-184) measured RR interval variability, an index of cardiac vagal modulation, and CRP and IL-6 in 757 subjects participating in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Analysis showed that all RR variability indices were strongly and inversely related to CRP and IL-6. These results demonstrate the inverse relationship between inflammatory markers and indices of cardiac autonomic regulation in a large sample of healthy young adults. These findings are consistent with the hypothesis that diminished descending vagal anti-inflammatory signals can allow cytokine overproduction in humans.
Page 178 l View article: PDF (156 KB) HTML
Serum Levels of Soluble Form of Receptor for Advanced Glycation End Products (sRAGE) are Associated with Inflammatory Markers in Patients with Type 2 Diabetes
Kazuo Nakamura, Sho-ichi Yamagishi, Hisashi Adachi, Yayoi Kurita-Nakamura, Takanori Matsui, Takafumi Yoshida, and Tsutomu Imaizumi
The receptor for advanced glycation end products (RAGE) plays an important role in accelerated atherosclerosis in diabetes and levels of the soluable form, sRAGE, are significantly higher in type 2 diabetic patients when compared with non-diabetic subjects. Levels of sRAGE are also positively associated with the presence of coronary artery disease in diabetes. Here, Nakamura et al. (185-189) examined whether serum levels of sRAGE were correlated to inflammatory biomarkers in patients with type 2 diabetes. The results demonstrated that serum levels of sRAGE were positively associated with monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor (TNF) levels in type 2 diabetic patients. These observations suggest the possibility that sRAGE may serve as a biomarker of vascular inflammation in type 2 diabetic patients.
Page 185 l View article: PDF ( 128 KB) HTML
Phosphorothioate Oligonucleotides Reduce PrPSc Levels and Prion Infectivity in Cultured Cells
Marcela J Karpuj, Kurt Giles, Sagit Gelibter, Michael R Scott, Vishwanath R Lingappa, Francis C Szoka, David Peretz, Wilfred Denetclaw, and Stanley B Prusiner
The prion diseases, like other neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases, are characterized by clinical manifestations that include depression and dementia. Posttranslational modifications convert the native cellular protein PrC into the pathogenic prion protein PrPSc , the sole infectious particle of the disease. Several therapeutic approaches to prion disease have been investigated with varying success. Here, Karpuj et al. (190-198) investigated oligonucleotides as potential pharmacotherapeutics for the treatment of prion disease. Results show that short phosphorothioate DNA (PS-DNA) oligonucleotides diminished the levels of both PrPC and PrPSc in prion-infected neuroblastoma cells. The effect of PS-DNA on PrP levels was independent of the nucleotide sequence and the effective concentration necessary to inhibit PrPC was more than 50-fold greater than that required to inhibit PrPSc. Bioassays in transgenic mice demonstrated a substantial diminution in the prion infectivity after neuroblastoma cells were exposed to PS-DNA. Whether PS-DNA will be useful in the treatment of prion disease in people or livestock remains to be established.
Page 190 l View Full Supplement: PDF (832 KB) HTML
Imbalance in the Seminal Fluid MIF Indicates Male Infertility
Bayan Aljabari, Aldo E Calogero, Anna Perdichizzi, Enzo Vicari, Raja Karaki, Tarek Lahloub, Rashed Zatari, Khaleel El-Abed, Ferdinando Nicoletti, Edmund J Miller, Valentin A Pavlov, and Yousef Al-Abed
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine with important pathogenic roles in diseases such as sepsis, septic shock and diabetes. Recent studies have indicated a broader scope for MIF activities including a role in reproduction. MIF affects sperm maturation, spermatozoa motility, is a constituent of seminal fluid, and is a cytoskeleton element of the sperm tail. Aljabari et al. (199-202) hypothesized that MIF levels in seminal fluid may be indicative of spermatozoa quality and therefore male fertility. Indeed, the authors discovered a correlation between MIF levels in human seminal fluid and fertility status. These findings may open the door for the development of a diagnostic method for fertility status.
Page 199 l View article: PDF (196 KB) HTML
Paraoxonase 1 Response to a High-fat Diet. Gender Differences in the Factors Involved
Elena Thomàs-Moyà, Magdalena Gianotti, Ana M Proenza, and Isabel Lladó
Diets consumed in industrialized countries are rich in fat and increase the incidence of atherosclerosis, a process reported to be influenced by gender. Paraoxonase 1 (PON1) is an esterase closely associated with high-density lipoprotein (HDL) and believed to confer antioxidant properties to HDL. While the consumption of high-fat diets has been associated with reduced PON1 activity in animals, gender distinctions of this mechanism have not been described. Thomàs-Moyà et al. (203-209) investigate the effect a high-fat diet has on serum PON1 and other inflammatory markers in male and female rats. Results showed that while the high-fat diet did not affect proinflammatory adipokines, lipid profiles or peroxidation, it did cause a reduction in serum paraoxonase activity. The authors also found that diminished PON1 levels were caused by different mechanisms in male and female rats reflecting varied PON1 adaptive mechanisms in response to the consumption of a high-fat diet. Ongoing studies are examining the role of PON1 in fatty diet-related diseases.
Page 203 l View article: PDF (72 KB) HTML
Cholinergic Anti-Inflammatory Pathway Activity and High Mobility Group Box-1 (HMGB1) Serum Levels in Patients with Rheumatoid Arthritis
Richard S Goldstein, Annette Bruchfeld, Lihong Yang, Abdul R Qureshi, Margot Gallowitsch-Puerta, Nirav B Patel, Brett J Houston, Sangeeta Chavan, Mauricio Rosas-Ballina, Peter K Gregersen, Christopher J Czura, Richard P Sloan, Andrew E Sama, and Kevin J Tracey
Rheumatoid arthritis (RA) is a chronic autoimmune disease with affected individuals exhibiting a diminished quality of life as well as decreased life expectancy. High mobility group box-1 (HMGB1) is a pro-inflammatory cytokine which has been implicated in the pathogenesis of arthritis. HMGB1 expression is increased in the synovium of patients with RA and anti-HMGB1 antibodies confer significant protection against the development of experimental arthritis in animals. The cholinergic anti-inflammatory pathway is a neural mechanism that inhibits the expression of HMGB1 and other cytokines in various models of inflammation. The activity of the principal nerve in this pathway, the vagus nerve, can be determined non-invasively by measuring heart rate variability. Here, Goldstein et al. (210-215) investigated whether RA patients exhibited decreased activity in the cholinergic anti-inflammatory pathway. Results show that elevated levels of the pro-inflammatory cytokine HMGB1 correlate with depressed levels of vagus nerve activity. In the future it may be possible to increase the activity of the vagus nerve using biofeedback, vagus nerve stimulation or other measures in order to decrease pro-inflammatory cytokines and improve disease.
Page 210 l View article: PDF (156 KB) HTML
Changing Viral Tropism Using Immunoliposomes Alters the Stability of Gene Expression: Implications for Viral Vector Design
Peng H Tan, Shao-An Xue, Bin Wei, Angelika Holler, Ralf-Holger Voss, and Andrew J T George
Viral and non-viral vectors can be manipulated to increase the efficiency and specificity for vascular cell transduction. Many strategies for re-directing the tropism of murine Moloney leukaemia virus (MMLV) have been described. Pre-formed virion-liposome complexes, termed virosomes, are reported to be relatively stable. Virosomes mediate envelope-independent transduction that allows efficient super-infection of resistant cell lines, but is not target-specific. Here, Tan et al. (216-226) developed a novel method using antibodies to direct MMLV to vascular endothelium. They have termed the complexes that form between viruses, liposomes and antibodies ‘immunovirosomes.’ These immunovirosomes improve the transduction efficiency of the viruses and alter their tropism. However, the enhancement of the transduction efficiency was transient; suggesting that re-routing the entry pathway of viruses alters the expression properties of the viruses. These findings may improve specificity and efficiency in future viral vector designs.
Page 216 l View article: PDF (344 KB) HTML |
