PMID- 27751938 OWN - NLM STAT- MEDLINE DCOM- 20170524 LR - 20170524 IS - 1096-0333 (Electronic) IS - 0041-008X (Linking) VI - 313 DP - 2016 Dec 15 TI - Friedelane-type triterpenoids as selective anti-inflammatory agents by regulation of differential signaling pathways in LPS-stimulated macrophages. PG - 57-67 LID - S0041-008X(16)30305-2 [pii] LID - 10.1016/j.taap.2016.10.004 [doi] AB - 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 25muM 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 (NFkappaB). 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 NFkappaB or Nrf2 signaling pathways. Both compounds reduced LPS-mediated processing of caspase-1 and the cleavage of interleukin 1beta (IL1beta) 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. CI - Copyright A(c) 2016 Elsevier Inc. All rights reserved. FAU - Villar-Lorenzo, Andrea AU - Villar-Lorenzo A AD - Instituto de Investigaciones Biomedicas Alberto Sols (IIBm) (CSIC/UAM), C/ Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), ISCIII, 28029 Madrid, Spain. Electronic address: avillar@iib.uam.es. FAU - Ardiles, Alejandro E AU - Ardiles AE AD - Instituto Universitario de Bio-Organica Antonio Gonzalez, Departamento de Quimica Organica, Universidad de La Laguna, Avenida Astrofisico Francisco Sanchez 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. FAU - Arroba, Ana I AU - Arroba AI AD - Instituto de Investigaciones Biomedicas Alberto Sols (IIBm) (CSIC/UAM), C/ Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), ISCIII, 28029 Madrid, Spain. Electronic address: aarroba@iib.uam.es. FAU - Hernandez-Jimenez, Enrique AU - Hernandez-Jimenez E AD - Tumor Immunology Laboratory (IdiPAZ), 28029 Madrid, Spain; Centro de Investigacion Biomedica en Red de Enfermedades Respiratorias (CIBERres), ISCIII, 28029 Madrid, Spain. Electronic address: enheji@gmail.com. FAU - Pardo, Virginia AU - Pardo V AD - Instituto de Investigaciones Biomedicas Alberto Sols (IIBm) (CSIC/UAM), C/ Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), ISCIII, 28029 Madrid, Spain. Electronic address: vpardo@iib.uam.es. FAU - Lopez-Collazo, Eduardo AU - Lopez-Collazo E AD - Tumor Immunology Laboratory (IdiPAZ), 28029 Madrid, Spain; Centro de Investigacion Biomedica en Red de Enfermedades Respiratorias (CIBERres), ISCIII, 28029 Madrid, Spain. Electronic address: elopezc@salud.madrid.org. FAU - Jimenez, Ignacio A AU - Jimenez IA AD - Instituto Universitario de Bio-Organica Antonio Gonzalez, Departamento de Quimica Organica, Universidad de La Laguna, Avenida Astrofisico Francisco Sanchez 2, 38206 La Laguna, Tenerife, Spain. Electronic address: ignadiaz@gmail.com. FAU - Bazzocchi, Isabel L AU - Bazzocchi IL AD - Instituto Universitario de Bio-Organica Antonio Gonzalez, Departamento de Quimica Organica, Universidad de La Laguna, Avenida Astrofisico Francisco Sanchez 2, 38206 La Laguna, Tenerife, Spain. Electronic address: ilopez@ull.es. FAU - Gonzalez-Rodriguez, Agueda AU - Gonzalez-Rodriguez A AD - Instituto de Investigaciones Biomedicas Alberto Sols (IIBm) (CSIC/UAM), C/ Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), ISCIII, 28029 Madrid, Spain. Electronic address: aguedagr@iib.uam.es. FAU - Valverde, Angela M AU - Valverde AM AD - Instituto de Investigaciones Biomedicas Alberto Sols (IIBm) (CSIC/UAM), C/ Arturo Duperier 4, 28029 Madrid, Spain; Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERdem), ISCIII, 28029 Madrid, Spain. Electronic address: avalverde@iib.uam.es. LA - eng PT - Journal Article DEP - 20161015 PL - United States TA - Toxicol Appl Pharmacol JT - Toxicology and applied pharmacology JID - 0416575 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Interleukin-1beta) RN - 0 (Lipopolysaccharides) RN - 0 (RNA, Messenger) RN - 0 (Triterpenes) RN - 0 (friedelane) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type II) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - EC 3.4.22.36 (Caspase 1) SB - IM MH - Animals MH - Anti-Inflammatory Agents/*pharmacology MH - Caspase 1/metabolism MH - Cell Line MH - Enzyme Induction MH - Interleukin-1beta/metabolism MH - Lipopolysaccharides/*toxicity MH - Macrophages/*drug effects/metabolism MH - Mice MH - Mitogen-Activated Protein Kinases/metabolism MH - Nitric Oxide Synthase Type II/biosynthesis/genetics/metabolism MH - Phosphorylation MH - RNA, Messenger/genetics MH - Signal Transduction/*drug effects MH - Triterpenes/*pharmacology OTO - NOTNLM OT - Antioxidant enzymes OT - Inflammation OT - Lipopolysaccharide OT - Macrophages OT - Nitric oxide synthase OT - Triterpenoids EDAT- 2016/10/19 06:00 MHDA- 2017/05/26 06:00 CRDT- 2016/11/07 06:00 PHST- 2016/05/05 00:00 [received] PHST- 2016/09/24 00:00 [revised] PHST- 2016/10/05 00:00 [accepted] PHST- 2016/10/19 06:00 [pubmed] PHST- 2017/05/26 06:00 [medline] PHST- 2016/11/07 06:00 [entrez] AID - S0041-008X(16)30305-2 [pii] AID - 10.1016/j.taap.2016.10.004 [doi] PST - ppublish SO - Toxicol Appl Pharmacol. 2016 Dec 15;313:57-67. doi: 10.1016/j.taap.2016.10.004. Epub 2016 Oct 15.