| Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. | |
| | |
MedLine Citation:
|
PMID: 17822364 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Sepsis is characterized by an inappropriate host immune-inflammatory response and sustained oxidative damage. Nrf2, a bZIP oxidant-responsive transcription factor, regulates a battery of cytoprotective genes including antioxidants and maintains cellular redox homeostasis. Mouse studies have demonstrated a critical role of Nrf2 in improving survival during sepsis. This preclinical ex vivo study using neutrophils and peripheral blood mononuclear cells (PBMCs) as a surrogate cells evaluates the efficacy of CDDO-Im and CDDO-Me [imidazole and methyl ester derivative of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO)] to activate the Nrf2 pathway and protect from lipopolysaccharide (LPS)-induced inflammatory response in humans. CDDO-Im treatment significantly induced Nrf2-dependent antioxidative genes (HO-1, GCLC, GCLM, and NQO1) in PBMCs isolated from six normal subjects. CDDO-Im increased nuclear accumulation of Nrf2 protein. Pretreatment of PBMC by CDDO-Im significantly attenuated LPS-induced cytokine expression. Similar increases in levels of antioxidant genes and suppression of LPS-induced cytokine expression was observed after CDDO-Me pretreatment. CDDO-Im also greatly inhibited LPS, fMLP, TNF-alpha, and TPA-induced ROS generation in neutrophils. In conclusion, these results demonstrate that activation of the Nrf2-dependent antioxidative pathway by CDDO-Im or CDDO-Me protects against the LPS-induced inflammatory response and suggest that they can be potential therapeutic candidates for intervening sepsis syndrome. |
| | |
Authors:
|
Rajesh K Thimmulappa; Ralph J Fuchs; Deepti Malhotra; Catherine Scollick; Kassim Traore; Jay H Bream; Michael A Trush; Karen T Liby; Michael B Sporn; Thomas W Kensler; Shyam Biswal |
Related Documents
:
|
8027674 - Role of endotoxin in mononuclear phagocyte-mediated inflammatory responses. 20848084 - Lipopolysaccharide induces apoptotic insults to human alveolar epithelial a549 cells th... 20458734 - Lipopolysaccharide induces autophagy through birc2 in human umbilical vein endothelial ... 11402054 - Dual role of inflammatory stimuli in activation-induced cell death of mouse microglial ... 18711434 - Orchestrating the orchestrators: chemokines in control of t cell traffic. 8027674 - Role of endotoxin in mononuclear phagocyte-mediated inflammatory responses. |
Publication Detail:
|
Type: Evaluation Studies; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
|
Title: Antioxidants & redox signaling Volume: 9 ISSN: 1523-0864 ISO Abbreviation: Antioxid. Redox Signal. Publication Date: 2007 Nov |
Date Detail:
|
Created Date: 2007-10-22 Completed Date: 2007-12-07 Revised Date: 2011-08-01 |
Medline Journal Info:
|
Nlm Unique ID: 100888899 Medline TA: Antioxid Redox Signal Country: United States |
Other Details:
|
Languages: eng Pagination: 1963-70 Citation Subset: IM |
Affiliation:
|
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Cytokines
/
metabolism* Drug Evaluation, Preclinical Gene Expression Regulation / drug effects Humans Imidazoles / pharmacology* Inflammation / chemically induced, genetics, immunology Leukocytes, Mononuclear / drug effects, immunology* Lipopolysaccharides / toxicity NF-E2-Related Factor 2 / genetics, physiology* Neutrophils / drug effects, immunology* Oleanolic Acid / analogs & derivatives*, pharmacology RNA, Messenger / metabolism Reactive Oxygen Species / metabolism Receptors, Formyl Peptide / metabolism Time Factors Tumor Necrosis Factor-alpha / metabolism |
| Grant Support | |
ID/Acronym/Agency:
|
CA78814/CA/NCI NIH HHS; CA94076/CA/NCI NIH HHS; GM079239/GM/NIGMS NIH HHS; HL081205/HL/NHLBI NIH HHS; P30 ES 03819/ES/NIEHS NIH HHS; P50 CA058184/CA/NCI NIH HHS; R01 GM079239-01A1/GM/NIGMS NIH HHS; R01 HL081205-03/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; 0/Cytokines; 0/Imidazoles; 0/Lipopolysaccharides; 0/NF-E2-Related Factor 2; 0/RNA, Messenger; 0/Reactive Oxygen Species; 0/Receptors, Formyl Peptide; 0/Tumor Necrosis Factor-alpha; 0/methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate; 508-02-1/Oleanolic Acid |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Effect of gender on mitochondrial toxicity of Alzheimer's Abeta peptide.
Next Document: Vascular oxidant stress and inflammation in hyperhomocysteinemia.