title: Novel aminobenzyl-acetamidine derivative modulate the differential regulation of NOSs in LPS induced inflammatory response: role of PI3K/Akt pathway.
abstract: BACKGROUND
  Previous reports suggest that NO may contribute to the pathophysiology of septic shock. Recently, we have synthesized and characterized a series of benzyl- and dibenzyl derivative of N-(3-aminobenzyl)acetamidine, a potent and selective inhibitor of iNOS, in vitro assay. We evaluated the molecular mechanisms by which these compounds are involved in the regulation of NOSs expression.
  
  
  METHODS
  H9c2 cells were stimulated with lipopolysaccharide (LPS) in the presence or absence of acetamidine-derivative. The NOSs mRNA and protein, and activation of signaling pathways (Akt and NF-κB) were assayed.
  
  
  RESULTS
  The induction of endotoxic shock in H9c2 with LPS caused an increase of inducible NOS and a down-regulation of constitutive NOS. The molecular mechanism involved in the modulation of NOSs expression in H9c2 cells upon LPS stimulation resulted in the modification of the redox state responsible for NF-kB nuclear translocation via NIK -IKKα/β-IkBα, simultaneously to the inactivation of the PI3K/Akt pathway. The compounds acted as an anti-inflammatory modulator.
  
  
  CONCLUSIONS
  These results suggest that LPS regulates the opposite NOS expression in H9c2 cells by modifying the redox state of these cells responsible for the NF-kB nuclear translocation via NIK-IKKα/β-IkBα, simultaneous to the inactivation of the PI3K/Akt pathway. The new molecule acts as an anti-inflammatory modulator in LPS-induced inflammation in H9c2 cells by the restoration of eNOS and nNOS expressions, mechanistically involving the PI3K/Akt pathway.
  
  
  CONCLUSIONS
  This study delineates the underlying mechanisms of opposite NOSs expression in H9c2 cells stimulated with LPS.
authors.affiliation: Department of Medicine and Aging Science, University G. d'Annunzio, Chieti, Italy. antoniapatruno@unich.it
authors.forename: Antonia
authors.initials: A
authors.lastname: Patruno
authors.forename: Sara
authors.initials: S
authors.lastname: Franceschelli
authors.forename: Mirko
authors.initials: M
authors.lastname: Pesce
authors.forename: Cristina
authors.initials: C
authors.lastname: Maccallini
authors.forename: Marialuigia
authors.initials: M
authors.lastname: Fantacuzzi
authors.forename: Lorenza
authors.initials: L
authors.lastname: Speranza
authors.forename: Alessio
authors.initials: A
authors.lastname: Ferrone
authors.forename: Maria Anna
authors.initials: MA
authors.lastname: De Lutiis
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ricciotti
authors.forename: Rosa
authors.initials: R
authors.lastname: Amoroso
authors.forename: Mario
authors.initials: M
authors.lastname: Felaco
mesh_terms: D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D032386:Myoblasts, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000578:Amidines; D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009573:Nitrites; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D052247:Nitric Oxide Synthase Type II; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; C023731:acetamidine