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J Nat Prod. 2015 Aug 28;78(8):1990-2000. doi: 10.1021/acs.jnatprod.5b00288. Epub 2015 Jul 17.

Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling.

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Center for Ecogenetics and Environmental Health, Department of Environmental and Occupational Health Sciences, University of Washington , Seattle, Washington 98105, United States.
Malaria Program, Seattle Biomed, Seattle, Washington 98109, United States.
Biological Sciences Division, Pacific Northwest National Laboratory , Richland, Washington 99352, United States.
Department of Chemistry and Biochemistry, University of North Carolina at Greensboro , Greensboro, North Carolina 27402, United States.


Silymarin, a characterized extract of the seeds of milk thistle (Silybum marianum), suppresses cellular inflammation. To define how this occurs, transcriptional profiling, metabolomics, and signaling studies were performed in human liver and T cell lines. Cellular stress and metabolic pathways were modulated within 4 h of silymarin treatment: activation of Activating Transcription Factor 4 (ATF-4) and adenosine monophosphate protein kinase (AMPK) and inhibition of mammalian target of rapamycin (mTOR) signaling, the latter being associated with induction of DNA-damage-inducible transcript 4 (DDIT4). Metabolomics analyses revealed silymarin suppression of glycolytic, tricarboxylic acid (TCA) cycle, and amino acid metabolism. Anti-inflammatory effects arose with prolonged (i.e., 24 h) silymarin exposure, with suppression of multiple pro-inflammatory mRNAs and signaling pathways including nuclear factor kappa B (NF-κB) and forkhead box O (FOXO). Studies with murine knock out cells revealed that silymarin inhibition of both mTOR and NF-κB was partially AMPK dependent, whereas silymarin inhibition of mTOR required DDIT4. Other natural products induced similar stress responses, which correlated with their ability to suppress inflammation. Thus, natural products activate stress and repair responses that culminate in an anti-inflammatory cellular phenotype. Natural products like silymarin may be useful as tools to define how metabolic, stress, and repair pathways regulate cellular inflammation.

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