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Author (up) Kim, H.; Higgins, S.; Liles, W.C.; Kain, K.C. file  url
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  Title Endothelial activation and dysregulation in malaria: a potential target for novel therapeutics Type Journal Article
  Year 2011 Publication Current Opinion in Hematology Abbreviated Journal Curr Opin Hematol  
  Volume 18 Issue 3 Pages 177-185  
  Keywords Animals; Antimalarials/therapeutic use; Biomarkers/metabolism; Endothelial Cells/*drug effects/metabolism/*pathology; Humans; Malaria, Cerebral/*drug therapy/metabolism/*pathology; Molecular Targeted Therapy; Nitric Oxide/metabolism  
  Abstract PURPOSE OF REVIEW: Despite parenteral artesunate therapy, the fatality rate of cerebral malaria remains high. Adjunctive therapy targeting the underlying pathophysiology of cerebral malaria may further improve the clinical outcome. Endothelial activation and dysfunction is a central process in the pathogenesis of cerebral malaria. An improved understanding of how endothelium is perturbed in cerebral malaria may yield novel strategies to diagnose and intervene. Here, we discuss recent findings on the key molecular mediators of endothelial activation/dysregulation in cerebral malaria, and innovative endothelial-based experimental approaches to improve detection and treatment. RECENT FINDINGS: Biomarkers of endothelial activation [e.g., angiopoietin (Ang)-1, Ang-2, and a soluble form of the Ang-receptor (soluble Tie-2)] have been shown to be reliable predictors of malarial disease severity and mortality, and may improve clinical triage and management. Moreover, they may represent novel therapeutic targets to improve clinical outcome. Restoring bioavailable nitric oxide by administration of inhaled nitric oxide or its substrate, L-arginine, may rescue endothelial function, decrease Ang-2, and improve disease outcome in cerebral malaria. SUMMARY: Interventions targeting the Ang-Tie-2 axis to promote endothelial quiescence, including agents to improve endothelial nitric oxide, represent potential adjunctive therapies for cerebral malaria.  
  Call Number Serial 1798  
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Author (up) Schenone, M.; Dancik, V.; Wagner, B.K.; Clemons, P.A. file  url
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  Title Target identification and mechanism of action in chemical biology and drug discovery Type Journal Article
  Year 2013 Publication Nature Chemical Biology Abbreviated Journal Nat Chem Biol  
  Volume 9 Issue 4 Pages 232-240  
  Keywords Animals; Biomarkers, Pharmacological/chemistry/*metabolism; *Drug Discovery; *Drug Evaluation, Preclinical; *High-Throughput Screening Assays; Humans; Isotope Labeling; Mass Spectrometry; Molecular Targeted Therapy; Phenotype; RNA Interference; Reverse Genetics; Saccharomyces cerevisiae/drug effects/genetics/metabolism; Small Molecule Libraries/chemistry/*metabolism/pharmacology; Validation Studies as Topic  
  Abstract Target-identification and mechanism-of-action studies have important roles in small-molecule probe and drug discovery. Biological and technological advances have resulted in the increasing use of cell-based assays to discover new biologically active small molecules. Such studies allow small-molecule action to be tested in a more disease-relevant setting at the outset, but they require follow-up studies to determine the precise protein target or targets responsible for the observed phenotype. Target identification can be approached by direct biochemical methods, genetic interactions or computational inference. In many cases, however, combinations of approaches may be required to fully characterize on-target and off-target effects and to understand mechanisms of small-molecule action.  
  Call Number Serial 1592  
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