title: Novel role of resveratrol: suppression of high-mobility group protein box 1 nucleocytoplasmic translocation by the upregulation of sirtuin 1 in sepsis-induced liver injury.
abstract: BACKGROUND
  High-mobility group protein box 1 (HMGB1) is essential in the response to injury during sepsis. We hypothesized that resveratrol (RESV) administration would inhibit nuclear-cytoplasmic HMGB1 translocation in hepatocytes, which is associated with sirtuin 1 (SIRT1) upregulation. We investigated the regulatory role of SIRT1 in HMGB1 nucleocytoplasmic translocation and its effect on sepsis-induced liver injury.
  
  
  METHODS
  Rats were randomly assigned to pretreatment with RESV (60 mg/kg per day), nicotinamide (60 mg/kg per day), or vehicle (olive oil), which was administered by gavage for 3 days directly before cecal ligation and puncture was performed to induce sepsis. Parallel control groups were established. Rats were killed 24 h after surgery, and cytokine production, histology, apoptosis, SIRT1, serum HMGB1, nuclear and cytoplasmic HMGB1/ac-HMGB1, and the interaction between SIRT1 and HMGB1 were evaluated. In vitro evaluations were performed in human liver L02 cells subjected to lipopolysaccharide-induced injury, and siRNA-mediated SIRT1 knockdown experiments were performed.
  
  
  RESULTS
  Sepsis-induced serum aminotransferase activities and proinflammatory chemokine levels were reduced by RESV pretreatment, which also improved liver histological parameters in association with SIRT1 upregulation. Resveratrol inhibited HMGB1 cytoplasmic translocation. Nicotinamide, an SIRT1 inhibitor, reduced the SIRT1-mediated suppression of HMGB1 translocation and aggravated cecal ligation and puncture-induced liver damage. Sirtuin 1 knockdown in vitro confirmed that RESV increased the SIRT1-mediated repression of HMGB1 translocation. In vivo, SIRT1 and HMGB1 physically interacted in the nucleus, and SIRT1 regulated HMGB1 acetylation in response to septic liver injury.
  
  
  CONCLUSIONS
  Resveratrol protects against sepsis-induced liver injury through the SIRT1-mediated HMGB1 nucleocytoplasmic translocation pathway, a new potential therapeutic target in sepsis-induced liver injury.
authors.affiliation: *Department of General Surgery, Second Affiliated Hospital of Dalian Medical University; and †Department of Pharmacology, Dalian Medical University, Dalian, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.forename: Jihong
authors.initials: J
authors.lastname: Yao
authors.forename: Zhenlu
authors.initials: Z
authors.lastname: Li
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Wang
authors.forename: Huirong
authors.initials: H
authors.lastname: Jing
authors.forename: Xinyuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Li
authors.forename: Jinyong
authors.initials: J
authors.lastname: Peng
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Tian
mesh_terms: D000107:Acetylation / Q000187:drug effects; D055371:Acute Lung Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D055785:Gene Knockdown Techniques; D024243:HMGB1 Protein / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods; D018384:Oxidative Stress / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D018805:Sepsis / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D056564:Sirtuin 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology* / Q000627:therapeutic use; D014178:Translocation, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D013267:Stilbenes; D056564:Sirtuin 1; D000077185:Resveratrol