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Interesting Target (interesting + target)
Selected AbstractsThe science of endothelin-1 and endothelin receptor antagonists in the management of pulmonary arterial hypertension: current understanding and future studiesEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2009N. J. Davie Abstract Pathological vascular remodelling is a key contributor to the symptomatology of pulmonary arterial hypertension (PAH), and reversing this process may offer the best hope for improving this debilitating condition. The vascular remodelling process is believed to be due to endothelial cell dysfunction and to involve altered production of endothelial cell-derived vasoactive mediators. The observation that circulating plasma levels of the vasoactive peptide endothelin (ET)-1 are raised in patients with PAH, and that ET-1 production is increased in the pulmonary tissue of affected individuals, makes it a particularly interesting target for a therapeutic intervention in PAH. Clinical trials with ET receptor antagonists (ETRAs) show that they provide symptomatic benefit in patients with PAH, thereby proving the clinical relevance of the ET system as a therapeutic target. In this paper, we review the role of ET-1 together with the available data on the roles of the specific ET receptors and ETRAs in PAH. In particular, we discuss the possible role of ET receptor selectivity in the vascular remodelling process in PAH and whether selective ETA or nonselective ETA/ETB blockade offers the greatest potential to improve symptoms and alter the clinical course of the disease. [source] Silencing MAT2A gene by RNA interference inhibited cell growth and induced apoptosis in human hepatoma cellsHEPATOLOGY RESEARCH, Issue 5 2007Quanyan Liu Aims:, A switch in gene expression from MAT1A to MAT2A was found in liver cancer, suggesting that MAT2A plays an important role in facilitating cancer growth. MAT2A is an interesting target for antineoplastic therapy. The molecular mechanisms of silencing MAT2A by RNA interference inhibited cell growth and induced apoptosis in hepatoma cells was studied. Methods:, We investigated the effects of MAT2A on S-adenosyl-methionine (SAM) production, cell growth and apoptotic cell death in hepatoma cell lines (Bel-7402, HepG2, and Hep3B) using an RNA interference approach. Results:, The treatment of three hepatoma cell lines with small interfering RNA (siRNA) targeting to the MAT2A gene resulted in reducing the MAT II activity, facilitating SAM production, increasing SAM : SAH ratio, inhibiting cell growth and inducing cell apoptosis in hepatoma cells. In addition, silencing MAT2A gene resulted in the stimulation of MAT1A mRNA production, which was blocked by 3-deazaadenosine and l -ethionine, but not d -ethionine, suggesting that such effect was specific and mediated by upregulation of SAM level and SAM : S-adenosylethionine (SAH) ratio. Conclusion:, Silencing MAT2A by sequence-specific small interfering RNA caused a switch of MAT gene expression from MAT2A to MAT1A, which led the content of SAM to change to a higher steady-state level that resulted in the inhibition of cell growth and the induction of apoptotic cell death in human hepatoma cells. These results also suggested that MAT2A may hold potential as a new target for liver cancer gene therapy. [source] Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental modelINTERNATIONAL JOURNAL OF CANCER, Issue 8 2007Sven A. Lang Abstract The mammalian target of rapamycin (mTOR) has become an interesting target for cancer therapy through its influence on oncogenic signals, which involve phosphatidylinositol-3-kinase and hypoxia-inducible factor-1, (HIF-1,). Since mTOR is an upstream regulator of HIF-1,, a key mediator of gastric cancer growth and angiogenesis, we investigated mTOR activation in human gastric adenocarcinoma specimens and determined whether rapamycin could inhibit gastric cancer growth in mice. Expression of phospho-mTOR was assessed by immunohistochemical analyses of human tissues. For in vitro studies, human gastric cancer cell lines were used to determine S6K1, 4E-BP-1 and HIF-1, activation and cancer cell motility upon rapamycin treatment. Effects of rapamycin on tumor growth and angiogenesis in vivo were assessed in both a subcutaneous tumor model and in an experimental model with orthotopically grown tumors. Mice received either rapamycin (0.5 mg/kg/day or 1.5 mg/kg/day) or diluent per intra-peritoneal injections. In addition, antiangiogenic effects were monitored in vivo using a dorsal-skin-fold chamber model. Immunohistochemical analyses showed strong expression of phospho-mTOR in 60% of intestinal- and 64% of diffuse-type human gastric adenocarcinomas. In vitro, rapamycin-treatment effectively blocked S6K1, 4E-BP-1 and HIF-1, activation, and significantly impaired tumor cell migration. In vivo, rapamycin-treatment led to significant inhibition of subcutaneous tumor growth, decreased CD31-positive vessel area and reduced tumor cell proliferation. Similar significant results were obtained in an orthotopic model of gastric cancer. In the dorsal-skin-fold chamber model, rapamycin-treatment significantly inhibited tumor vascularization in vivo. In conclusion, mTOR is frequently activated in human gastric cancer and represents a promising new molecular target for therapy. © 2007 Wiley-Liss, Inc. [source] Lymphatics at the crossroads of angiogenesis and lymphangiogenesisJOURNAL OF ANATOMY, Issue 6 2004Claudio Scavelli Abstract The lymphatic system is implicated in interstitial fluid balance regulation, immune cell trafficking, oedema and cancer metastasis. However, the sequence of events that initiate and coordinate lymphatic vessel development (lymphangiogenesis) remains obscure. In effect, the understanding of physiological regulation of lymphatic vasculature has been overshadowed by the greater emphasis focused on angiogenesis, and delayed by a lack of specific markers, thereby limiting this field to no more than a descriptive characterization. Recently, new insights into lymphangiogenesis research have been due to the discovery of lymphatic-specific markers and growth factors of vascular endothelial growth factor (VEGF) family, such as VEGF-C and VEGF-D. Studies using transgenic mice overexpressing VEGF-C and VEGF-D have demonstrated a crucial role for these factors in tumour lymphangiogenesis. Knowledge of lymphatic development has now been redefined at the molecular level, providing an interesting target for innovative therapies. This review highlights the recent insights and advances into the field of lymphatic vascular research, outlining the most important aspects of the embryo development, structure, specific markers and methods applied for studying lymphangiogenesis. Finally, molecular mechanisms involved in the regulation of lymphangiogenesis are described. [source] Gender-dependent association of the GNAS1 T393C polymorphism with early aseptic loosening after total hip arthroplastyJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 12 2008Hagen S. Bachmann Abstract The G-protein G,s is involved in the physiology and pathophysiology of bone. Especially, G,s is a key regulator of interleukin-6, which is a potent promoter of aseptic loosening. We hypothesized that the common single nucleotide polymorphism GNAS1 T393C could also affect time to aseptic loosening. Caucasian patients were genotyped for the GNAS1 T393C polymorphism. Time and median time to aseptic loosening were analyzed for dependency on GNAS1 genotypes. Time and median time were not significantly associated with genotypes. Additional analysis corrected for gender revealed, that the TT genotype was associated with significantly longer time (p,=,0.048) as well as median time (p,=,0.022) to aseptic loosening in female patients. In contrast to the findings in females, male TT genotype carriers had significantly shorter time (p,=,0.018) and median time (p,=,0.023) to aseptic loosening. Compared with TT genotype carriers heterozygous patients had a 6.25-fold lower risk with a hazard ratio of 0.160 (p,=,0.016) and male patients carrying the CC genotype had an 11-fold lower risk with a hazard ratio of 0.088 (p,=,0.006) in multivariate analysis. The present study suggests a significant gender-dependent role of the T393C polymorphism in aseptic loosening. The apparently contradictory results in women and men and the finding that the GNAS1 T393C genotype is an independent factor for time to aseptic loosening in male patients assigned this polymorphism as an interesting target for further investigations in bone diseases. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source] Carbonic anhydrase IX: A new druggable target for the design of antitumor agentsMEDICINAL RESEARCH REVIEWS, Issue 3 2008Jean-Yves Winum Abstract Carbonic anhydrases (CAs, EC 4.2.1.1) are a family of enzymes widespread in all life kingdoms. In mammals, isozyme CA IX is highly overexpressed in many cancer types being present in few normal tissues. Its expression is strongly induced by hypoxia present in many tumors, being regulated by the HIF transcription factor and correlated with a poor response to classical chemo- and radiotherapies. CA IX was recently shown to contribute to acidification of the tumor environment, by efficiently catalyzing the hydration of carbon dioxide to bicarbonate and protons with its extracellularly situated active site, leading both to the acquisition of metastasic phenotypes and to chemoresistance with weakly basic anticancer drugs. Inhibition of this enzymatic activity by specific and potent inhibitors was shown to revert these acidification processes, establishing a clear-cut role of CA IX in tumorigenesis. The development of a wide range of potent and selective CA IX inhibitors belonging to diverse chemical classes, such as membrane-impermeant, fluorescent or metal-containing such agents, could thus provide useful tools for highlighting the exact role of CA IX in hypoxic cancers, to control the pH (im)balance of tumor cells, and to develop novel diagnostic or therapeutic applications for the management of tumors. Indeed, both fluorescent inhibitors or positively charged, membrane impermeant sulfonamides have been recently developed as potent CA IX inhibitors and used as proof-of-concept tools for demonstrating that CA IX constitutes a novel and interesting target for the anticancer drug development. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 3, 445,463, 2008 [source] Eosinophils and atopic dermatitisALLERGY, Issue 6 2004D. Simon In spite of the progress regarding the description of immunological phenomena associated with atopic dermatitis (AD), the pathogenesis of this disease still remains unclear. The presence of eosinophils in the inflammatory infiltrate of AD has long been established. Eosinophil numbers as well as eosinophil granule protein levels in peripheral blood are elevated in most AD patients and appear to correlate with disease activity. Moreover, eosinophil granule proteins, which possess cytotoxic activity, are deposited in the skin lesions. These observations indicate a role of eosinophils in the pathogenesis of AD. Furthermore, AD is associated with increased production of T helper 2 cytokines including interleukin (IL)-5, which specifically acts on eosinophils, resulting in accelerated eosinophilopoiesis, chemotaxis, cell activation, and delayed apoptosis. Therefore, IL-5 is an interesting target for experimental therapy in this inflammatory disorder of the skin. Such studies might result in new insights into the pathogenetic role of eosinophils in AD. [source] Proteomic analysis of the E2F1 response in p53-negative cancer cells: New aspects in the regulation of cell survival and deathPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 21 2006Zhenpeng Li Abstract E2F1 is an essential transcription factor that regulates cell-cycle progression and apoptosis. Overexpression of E2F1 sensitizes neoplastic cells to apoptosis and leads to tumor growth suppression, making it an interesting target for anticancer therapy. Use of E2F1 as a therapeutic, however, requires a detailed knowledge of the mechanisms by which it controls cellular proliferation and apoptosis, and of other potential E2F1 activities. In this study, a differential proteome analysis was performed to identify proteins associated with E2F1 activity in inducible p53-deficient Saos-2ERE2F1 osteosarcoma cells. 2-DE revealed a distinct protein profile at 32,h after E2F1 activation. Thirty-three proteins were reproducibly identified as either up-regulated or down-regulated. Proteins were identified by MALDI-MS. They included hitherto unknown E2F1 target proteins of cytoskeletal origin, chaperones, enzymes, proteasomal proteins, and several heterogeneous nuclear ribonucleoproteins, suggesting its role in the ER-stress response, protein degradation, and modulation of pre-mRNA splicing. Protein analysis-derived results were verified by Western blot using representative protein candidates. Thirteen identified proteins were the products of genes known to be cancer related. Thus, proteome analysis provides new information about the complexity of E2F1 activities in human cancer cells that may be considered when using E2F1 as a drug. [source] The small ubiquitin-like modifier mediates the resistance of prosthesis-loosening fibroblast-like synoviocytes against fas-induced apoptosisARTHRITIS & RHEUMATISM, Issue 7 2009Ingmar Meinecke Objective To study the expression of small ubiquitin-like modifier 1 (SUMO-1) in aseptic loosening of prosthesis implants and to investigate its role in regulating the susceptibility of prosthesis-loosening fibroblast-like synoviocytes (FLS) to Fas-induced apoptosis. Methods Specimens of aseptically loosened tissue were obtained at revision surgery, and the expression of SUMO-1 was analyzed by in situ hybridization. SUMO-1 levels in FLS were determined by quantitative polymerase chain reaction and Western blot analysis. Immunohistochemistry and confocal microscopy were used to study the subcellular localization of SUMO-1. The functional role of SUMO-1 in Fas-induced apoptosis of prosthesis-loosening FLS was investigated by small interfering RNA,mediated knockdown of SUMO-1 and by gene transfer of the nuclear SUMO-specific protease SENP1. Results SUMO-1 was expressed strongly in aseptically loosened tissue and was found prominently at sites adjacent to bone. Prosthesis-loosening FLS expressed levels of SUMO-1 similar to the levels expressed by rheumatoid arthritis (RA) FLS, with SUMO-1 being found mainly in promyelocytic leukemia protein nuclear bodies. Knockdown of SUMO-1 had no effect on spontaneous apoptosis but significantly increased the susceptibility of prosthesis-loosening FLS to Fas-induced apoptosis. Gene transfer of the nuclear SUMO-specific protease SENP1 reverted the apoptosis-inhibiting effects of SUMO-1. Conclusion These data suggest that SUMO-1 is involved in the activation of both RA FLS and prosthesis-loosening FLS by preventing these cells from undergoing apoptosis. Modification of nuclear proteins by SUMO-1 contributes to the antiapoptotic effects of SUMO-1 in prosthesis-loosening FLS, providing evidence for the specific activation of sumoylation during their differentiation. Therefore, SUMO-1 may be an interesting target for novel strategies to prevent aseptic prosthesis loosening. [source] Increased neuronal cell number in the dorsal motor nucleus of the vagus in schizophreniaACTA NEUROPSYCHIATRICA, Issue 1 2010Hubertus Axer Axer H, Bernstein H-G, Keiner S, Heronimus P, Sauer H, Witte OW, Bogerts B, Bär K-J. Increased neuronal cell number in the dorsal motor nucleus of the vagus in schizophrenia. Objective: Recently, a reduction in efferent vagal regulation has been found in schizophrenic patients. Methods: Therefore, the brainstems of nine schizophrenic patients and nine normal controls were stereologically analysed. The number of neurons using the optical fractionator method and nuclear volumes applying the Cavalieri principle was estimated in Nissl stained sections of the dorsal motor nucleus of the vagus (DMNV) and the hypoglossal nucleus. Results: The neurons in the right DMNV were significantly increased in the schizophrenic group compared to normal controls (p = 0.047), while the volumes of the DMNV did not differ. In contrast, no such differences were found in the hypoglossal nucleus. Conclusion: Although this pilot study is limited by its small sample size, the analysis of the solitarius,ambiguus,vagus system in schizophrenic patients is an interesting target in schizophrenia research. The most reasonable background for increased neuron numbers in the DMNV could be a system-specific neurodevelopmental disturbance in schizophrenia. [source] An unbiased pilot survey for Galactic water masersMONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 4 2010J. L. Caswell ABSTRACT The Australia Telescope Compact Array has been used in a fast surveying mode to study the 22-GHz transition of water in two small sample regions of the southern Galactic plane. The observations allow an unbiased search for water masers, including any that may have no association with masers from other molecules (or indeed, no association with any other detectable celestial object). Positions with arcsecond accuracy were obtained from the original survey data for detected sources, and these were re-observed at an epoch more than two years later. Variability of the spectra between the epochs was considerable: our total of 32 masers comprises 24 detected at both epochs, two detected at only the first epoch and six detected at only the follow-up epoch. The success of our surveying mode shows it to be a practical strategy for the difficult task of extending unbiased water maser surveys to a large portion of the Galactic plane. Our results show quantitatively the effect of variability on the completeness of surveys conducted at a single epoch. Most of our maser detections are new discoveries. Only four had previously been detected (in searches towards interesting targets in the survey area). The high density of water masers from our unbiased survey supports earlier suggestions that they are the most populous maser species, and one of the most sensitive and reliable tracers of massive young stellar objects , newly forming massive young stars. The spectra of nine masers show high-velocity emission, and they show a striking preponderance of blueshifted high-velocity features. This is compatible with such blueshifts being a characteristic of populations dominated by masers at the earliest evolutionary stage of star formation, in some cases prior to the onset of methanol masers. Amongst the high-velocity emission sources there are two new examples where blueshifted high-velocity outflows dominate the total emission; these substantially increase the previously known meagre population of five such objects and suggest that they may be surprisingly abundant. [source] Chemistry meets proteomics: The use of chemical tagging reactions for MS-based proteomicsPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 20 2006Alexander Leitner Dr. Abstract As proteomics matures from a purely descriptive to a function-oriented discipline of the life sciences, there is strong demand for novel methodologies that increase the depth of information that can be obtained from proteomic studies. MS has long played a central role for protein identification and characterization, often in combination with dedicated chemical modification reactions. Today, chemistry is helping to advance the field of proteomics in numerous ways. In this review, we focus on those methodologies that have a significant impact for the large-scale study of proteins and peptides. This includes approaches that allow the introduction of affinity tags for the enrichment of subclasses of peptides or proteins and strategies for in,vitro stable isotope labeling for quantification purposes, among others. Particular attention is given to the study of PTMs where recent advancements have been promising, but many interesting targets are not yet being addressed. [source] | ||||||||||||||||