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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Nagarkatti, P. S. Tomar, S. Nagarkatti, M. |
| Description | Author Affiliation: Tomar S ( Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA.) |
| Abstract | BACKGROUND AND PURPOSE: Acute liver failure (ALF) is a severe and potentially lethal clinical syndrome. 3,3'-Diindolylmethane (DIM) is a natural plant-derived compound with anti-cancer activities. Recently, DIM has also been shown to have anti-inflammatory properties. Here, we tested the hypothesis that DIM would suppress endotoxin-induced ALF. EXPERIMENTAL APPROACH: We investigated the therapeutic potential of DIM in a mouse model of D-galactosamine/Lipopolysaccharide (GalN/LPS)-induced ALF. The efficacy of DIM treatment was assessed by survival, liver histopathology, serum levels of alanine transaminase, pro-inflammatory cytokines and number of activated liver macrophages. Effects of DIM on the expression of two miRNAs, 106a and 20b, and their predicted target gene were measured by qRT-PCR and Western blotting. Effects of DIM on the release of TNF- from RAW264.7 macrophages transfected with mimics of these miRNAs and activated by LPS was assessed by elisa. KEY RESULTS: DIM treatment protected mice from ALF symptoms and reduced the number of activated liver macrophages. DIM increased expression of miR-106a and miR-20b in liver mononuclear cells and decreased expression of their predicted target gene IL-1 receptor-associated kinase 4 (IRAK4), involved in signalling from Toll-like receptor 4 (TLR4). In vitro transfection of RAW264.7 cells using miRNA mimics of miR-106a and 20b decreased expression of IRAK4 and of TNF- secretion, following LPS stimulation. CONCLUSIONS AND IMPLICATIONS: DIM attenuated GalN/LPS-induced ALF by regulating the expression of unique miRNAs that target key molecules in the TLR4 inflammatory pathway. DIM may represent a potential novel hepatoprotective agent. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 8 |
| Volume Number | 172 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2015-04-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Indoles Therapeutic Use Liver Failure, Acute Drug Therapy Protective Agents Alanine Transaminase Blood Animals Caspase 3 Metabolism Cell Line Chemokine CCL2 Galactosamine Pharmacology Interleukin-1 Receptor-Associated Kinases Interleukin-6 Leukocytes, Mononuclear Drug Effects Lipopolysaccharides Liver Pathology Chemically Induced Macrophage Activation Mice, Inbred C57BL MicroRNAs Signal Transduction Toll-Like Receptors Tumor Necrosis Factor-alpha |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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