title: Silymarin Suppresses Cellular Inflammation By Inducing Reparative Stress Signaling.
abstract: 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.
authors.forename: Erica S
authors.initials: ES
authors.lastname: Lovelace
authors.forename: Jessica
authors.initials: J
authors.lastname: Wagoner
authors.affiliation: Center for Ecogenetics and Environmental Health, Department of Environmental and Occupational Health Sciences, University of Washington , Seattle, Washington 98105, United States.
authors.forename: James
authors.initials: J
authors.lastname: MacDonald
authors.affiliation: Center for Ecogenetics and Environmental Health, Department of Environmental and Occupational Health Sciences, University of Washington , Seattle, Washington 98105, United States.
authors.forename: Theo
authors.initials: T
authors.lastname: Bammler
authors.forename: Jacob
authors.initials: J
authors.lastname: Bruckner
authors.affiliation: Malaria Program, Seattle Biomed, Seattle, Washington 98109, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Brownell
authors.affiliation: Center for Ecogenetics and Environmental Health, Department of Environmental and Occupational Health Sciences, University of Washington , Seattle, Washington 98105, United States.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Beyer
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory , Richland, Washington 99352, United States.
authors.forename: Erika M
authors.initials: EM
authors.lastname: Zink
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory , Richland, Washington 99352, United States.
authors.forename: Young-Mo
authors.initials: YM
authors.lastname: Kim
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory , Richland, Washington 99352, United States.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Kyle
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory , Richland, Washington 99352, United States.
authors.forename: Bobbie-Jo M
authors.initials: BJ
authors.lastname: Webb-Robertson
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory , Richland, Washington 99352, United States.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Waters
authors.affiliation: Biological Sciences Division, Pacific Northwest National Laboratory , Richland, Washington 99352, United States.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Metz
authors.affiliation: Center for Ecogenetics and Environmental Health, Department of Environmental and Occupational Health Sciences, University of Washington , Seattle, Washington 98105, United States.
authors.forename: Federico
authors.initials: F
authors.lastname: Farin
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina at Greensboro , Greensboro, North Carolina 27402, United States.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Oberlies
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Polyak
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D002952:Citric Acid Cycle / Q000187:drug effects; D051858:Forkhead Transcription Factors / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D019169:Jurkat Cells; D008099:Liver / Q000378:metabolism; D051379:Mice; D020944:Silybum marianum / Q000737:chemistry*; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II; D015398:Signal Transduction / Q000187:drug effects; D012838:Silymarin / Q000737:chemistry / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D051858:Forkhead Transcription Factors; D016328:NF-kappa B; D012838:Silymarin; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D055372:AMP-Activated Protein Kinases