title: Friedelane-type triterpenoids as selective anti-inflammatory agents by regulation of differential signaling pathways in LPS-stimulated macrophages.
abstract: A series of 31 pentacyclic triterpenoids isolated from the root barks of Celastrus vulcanicola and Maytenus jelskii were tested for cytotoxicity and inhibitory activity against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. Compounds 18 (C18) and 25 (C25) exhibited significant inhibition of LPS-induced NO release at 50 and 25μM concentrations, respectively, and decreased mRNAs of pro-inflammatory cytokines. At the molecular level, C18 neither inhibited LPS-mediated phosphorylation of mitogen activated protein kinases (MAPKs) nor nuclear translocation of nuclear factor kappa beta (NFκB). Instead, C18 enhanced and prolonged nuclear translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and increased the expression of its target genes including hemeoxigenase 1 (HO1). C25 efficiently inhibited LPS-mediated phosphorylation of JNK, p38 and ERK, without affecting NFκB or Nrf2 signaling pathways. Both compounds reduced LPS-mediated processing of caspase-1 and the cleavage of interleukin 1β (IL1β) proform, reflecting their ability to target the inflammasome. C25 also counteracted LPS effects on iNOS expression and pro-inflammatory cytokines mRNA levels in Bv-2 microglial cells. The anti-inflammatory effect of both compounds was also assessed in human macrophages. Our results suggest that triterpenoids C18 and C25 possess anti-inflammatory effects, which may be therapeutically relevant for diseases linked to inflammation.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (IIBm) (CSIC/UAM), C/ Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), ISCIII, 28029 Madrid, Spain. Electronic address: avillar@iib.uam.es.
authors.forename: Andrea
authors.initials: A
authors.lastname: Villar-Lorenzo
authors.affiliation: Instituto Universitario de Bio-Orgánica Antonio González, Departamento de Química Orgánica, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain; Facultad de Ciencias de la Salud, Universidad Arturo Prat, Casilla 121, Iquique 1110939, Chile. Electronic address: ale_csic@gmail.com.
authors.forename: Alejandro E
authors.initials: AE
authors.lastname: Ardiles
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (IIBm) (CSIC/UAM), C/ Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), ISCIII, 28029 Madrid, Spain. Electronic address: aarroba@iib.uam.es.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Arroba
authors.affiliation: Tumor Immunology Laboratory (IdiPAZ), 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERres), ISCIII, 28029 Madrid, Spain. Electronic address: enheji@gmail.com.
authors.forename: Enrique
authors.initials: E
authors.lastname: Hernández-Jiménez
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (IIBm) (CSIC/UAM), C/ Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), ISCIII, 28029 Madrid, Spain. Electronic address: vpardo@iib.uam.es.
authors.forename: Virginia
authors.initials: V
authors.lastname: Pardo
authors.affiliation: Tumor Immunology Laboratory (IdiPAZ), 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERres), ISCIII, 28029 Madrid, Spain. Electronic address: elopezc@salud.madrid.org.
authors.forename: Eduardo
authors.initials: E
authors.lastname: López-Collazo
authors.affiliation: Instituto Universitario de Bio-Orgánica Antonio González, Departamento de Química Orgánica, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain. Electronic address: ignadiaz@gmail.com.
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Jiménez
authors.affiliation: Instituto Universitario de Bio-Orgánica Antonio González, Departamento de Química Orgánica, Universidad de La Laguna, Avenida Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain. Electronic address: ilopez@ull.es.
authors.forename: Isabel L
authors.initials: IL
authors.lastname: Bazzocchi
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (IIBm) (CSIC/UAM), C/ Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), ISCIII, 28029 Madrid, Spain. Electronic address: aguedagr@iib.uam.es.
authors.forename: Águeda
authors.initials: Á
authors.lastname: González-Rodríguez
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols (IIBm) (CSIC/UAM), C/ Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), ISCIII, 28029 Madrid, Spain. Electronic address: avalverde@iib.uam.es.
authors.forename: Ángela M
authors.initials: ÁM
authors.lastname: Valverde
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D004790:Enzyme Induction; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014315:Triterpenes; C421805:friedelane; D052247:Nitric Oxide Synthase Type II; D020928:Mitogen-Activated Protein Kinases; D020170:Caspase 1
keywords: Antioxidant enzymes; Inflammation; Lipopolysaccharide; Macrophages; Nitric oxide synthase; Triterpenoids