title: Identifying panaxynol, a natural activator of nuclear factor erythroid-2 related factor 2 (Nrf2) from American ginseng as a suppressor of inflamed macrophage-induced cardiomyocyte hypertrophy.
abstract: BACKGROUND
  American ginseng is capable of ameliorating cardiac dysfunction and activating Nrf2, a master regulator of antioxidant defense, in the heart. This study was designed to isolate compounds from American ginseng and to determine those responsible for the Nrf2-mediated resolution of inflamed macrophage-induced cardiomyocyte hypertrophy.
  
  
  METHODS
  A standardized crude extract of American ginseng was supplied by the National Research Council of Canada, Institute for National Measurement Standards. A bioassay-based fractionization of American ginseng was performed to identify the putative substances which could activate Nrf2-mediated suppression of pro-inflammatory cytokine expression in macrophages and macrophage-mediated pro-hypertrophic growth in cardiomyocytes.
  
  
  RESULTS
  A hexane fraction of an anti-inflammatory crude extract of American ginseng was found to be most effective in suppressing the inflammatory responses in macrophages. Preparative, reverse-phase HPLC and a comparative analysis by analytical scale LC-UV/MS revealed the hexane fraction contains predominantly C17 polyacetylenes and linolenic acid. Panaxynol, one of the major polyacetylenes, was found to be a potent Nrf2 activator. Panaxynol posttranscriptionally activated Nrf2 by inhibiting Kelch-like ECH-associated protein (Keap) 1-mediated degradation without affecting the binding of Keap1 and Nrf2. Moreover, panaxynol suppressed a selected set of cytokine expression via the activation of Nrf2 while minimally regulating nuclear factor-kappa B (NF-κB)-mediated cytokine expression in macrophages. It also dramatically inhibited the inflamed macrophage-mediated cardiomyocyte death and hypertrophy by activating Nrf2 in macrophages.
  
  
  CONCLUSIONS
  These results demonstrate that American ginseng-derived panaxynol is a specific Nrf2 activator and panaxynol-activated Nrf2 signaling is at least partly responsible for American ginseng-induced health benefit in the heart.
authors.affiliation: Department of Breast and Thyroid Surgery, Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China; Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Qu
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China; Department of Reproductive Medicine, Linyi People׳s Hospital, Linyi, Shandong 276003, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
authors.forename: Yimu
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
authors.forename: Hechu
authors.initials: H
authors.lastname: Li
authors.affiliation: Measurement Science and Standards, National Research Council, Ottawa, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Windust
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, South Carolina College of Pharmacy, Columbia, SC 29208, USA.
authors.forename: Lorne J
authors.initials: LJ
authors.lastname: Hofseth
authors.affiliation: Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
authors.affiliation: Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
authors.forename: Prakash
authors.initials: P
authors.lastname: Nagarkatti
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China.
authors.forename: Xing Li
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China.
authors.forename: Dongqi
authors.initials: D
authors.lastname: Tang
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Janicki
authors.affiliation: Department of Breast and Thyroid Surgery, Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China. Electronic address: txs0509@163.com.
authors.forename: Xingsong
authors.initials: X
authors.lastname: Tian
authors.affiliation: Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208, USA; Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012, China. Electronic address: taixing.cui@uscmed.sc.edu.
authors.forename: Taixing
authors.initials: T
authors.lastname: Cui
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification / Q000494:pharmacology; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D053280:Diynes / Q000302:isolation & purification / Q000494:pharmacology*; D005233:Fatty Alcohols / Q000302:isolation & purification / Q000494:pharmacology*; D005260:Female; D006984:Hypertrophy / Q000188:drug therapy / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D005894:Panax; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D051381:Rats
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D053280:Diynes; D005233:Fatty Alcohols; D051267:NF-E2-Related Factor 2; D010936:Plant Extracts; C018541:falcarinol; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: American ginseng; Cardiomyocytes; Inflammation; Macrophages; Nrf2; Panaxynol