| Betulinic acid inhibits endotoxin-stimulated phosphorylation cascade and pro-inflammatory prostaglandin E(2) production in human peripheral blood mononuclear cells. | |
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MedLine Citation:
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PMID: 21077850 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND AND PURPOSE: Betulinic acid (BA) is a naturally occurring triterpenoid widely distributed throughout the plant kingdom. We previously reported that BA inhibits lipopolysaccharide (LPS)-induced interleukin-6 production through modulation of nuclear factor κB (NF-κB) in human peripheral blood mononuclear cells (hPBMCs). This study attempted to identify other mechanisms through which BA modulates LPS signalling in mononuclear cells. The effects of BA on signalling pathways downstream were focused on in this study. EXPERIMENTAL APPROACH: We determined the ability of BA to interfere with p38 and extracellular regulated kinase (ERK) phosphorylation as well as Akt phosphorylation and nuclear factor-κB activation using LPS-activated hPBMCs as an in vitro model. LPS-induced endotoxin shock in mice was the in vivo model employed. KEY RESULTS: BA inhibited LPS-induced COX-2 protein expression and prostaglandin E(2) production and also attenuated LPS-induced ERK and Akt phosphorylation, but not p38 in hPBMCs. BA abolished LPS-induced IκBα phosphorylation and thus normalized the levels of IκBα in cytosol. BA also inhibited LPS-induced reactive oxygen species formation and lactate dehydrogenase release. Interestingly, BA improved the life span of mice in endotoxin shock and also inhibited PGE(2) production and myeloperoxidase activity in vivo. CONCLUSIONS AND IMPLICATIONS: BA modulates LPS-induced COX-2 expression in hPBMCs by inhibiting ERK and Akt pathways as well as by modulating IκBα phosphorylation. At the same time, no cell toxicity was observed. The effect of the drug was confirmed through in vivo experiments. The study gives an insight into the molecular mechanisms of BA. |
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Authors:
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Vijayan Viji; Antony Helen; Varma R Luxmi |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: British journal of pharmacology Volume: 162 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-02-23 Completed Date: 2011-09-06 Revised Date: 2012-03-01 |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1291-303 Citation Subset: IM |
Copyright Information:
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© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society. |
Affiliation:
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Department of Biochemistry, University of Kerala, Kariavattom Campus, Thiruvananthapuram, Kerala, India. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Disease Models, Animal Electrophoretic Mobility Shift Assay Endotoxins / antagonists & inhibitors*, immunology, metabolism Humans Inflammation / immunology, metabolism Leukocytes, Mononuclear / drug effects*, metabolism Male Mice Mitogen-Activated Protein Kinase 1 / metabolism Mitogen-Activated Protein Kinase 3 / metabolism NF-kappa B / metabolism Peroxidase / metabolism Phosphorylation / drug effects Prostaglandins E / metabolism* Proto-Oncogene Proteins c-akt / metabolism Reactive Oxygen Species / metabolism Sepsis / drug therapy, metabolism Shock, Septic / drug therapy Triterpenes / chemistry, pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Endotoxins; 0/NF-kappa B; 0/Prostaglandins E; 0/Reactive Oxygen Species; 0/Triterpenes; 472-15-1/betulinic acid; EC 1.11.1.7/Peroxidase; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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