title: Lipopolysaccharides-Induced Inflammatory Response in White Blood Cells Is Associated with Alterations in Senescence Mediators: Modulation by Metformin.
abstract: BACKGROUND
  Sirtuin (SirT), a family of conserved histone deacetylases and transferases, has been proposed to function in inflammatory, cancer, and metabolic diseases. However, it is unclear how SirT modulates these processes. In this study, the effect of metformin on senescence and antisenescence mediators (SirT1-7, p53, and p16(INK4a)) mRNA expression in white blood cells (WBCs) following lipopolysaccharides (LPS)-induced inflammation in mice was examined.
  
  
  METHODS
  C57BL/6 mice were treated with metformin in their drinking water (2 mg/mL) for 1 week followed by intraperitoneal injection of LPS from Escherichia coli serotype 0111:B4 at 2 mg/kg. Blood was collected at the basal level and 1, 2, and 3 hr after LPS injection. SirT1-7, p53, and p16(INK4a) mRNA expression in WBCs was measured by real-time quantitative polymerase chain reaction (RT-qPCR).
  
  
  RESULTS
  SirT7 at 2 hr, SirT1 at 3 hr, and p16(INK4a) at 1 hr were inhibited significantly in WBCs following LPS injection. There were no significant changes in other SirT nor p53 mRNA expression in WBCs after LPS injection. Metformin inhibited SirT2 expression in WBCs significantly (P<0.05) and did not induce any significant changes in other SirT forms and p53, whereas it induced p16(INK4a) mRNA expression in WBCs (P<0.05) at the basal levels. Additionally, metformin treatment significantly inhibited SirT7, SirT1, and p16(INK4a) mRNA expression in WBCs at 1, 2, and 3 hr, whereas p53 was inhibited significantly at 2 hr after LPS injection.
  
  
  CONCLUSIONS
  SirT7 and SirT1 are stress responsive proteins that may mediate inflammation. The data suggest that metformin may exert its potential antisenescence and anti-inflammatory effects by targeting SirT7 and SirT1 pathways. SirT7 inhibition may allow the healing process and prevention of tissue damage by enabling cells to survive through inhibition of cytokines and inflammatory mediators under severe stress conditions.
authors: King Abdullah International Medical Research Center (KAIMRC) and King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Department of Basic Medical Sciences, National Guard Health Affairs, Riyadh, Kingdom of Saudi Arabia.
authors: Ahmad
authors: A
authors: Aljada
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016922:Cellular Senescence / Q000187:drug effects*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000097:blood / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D018836:Inflammation Mediators / Q000097:blood; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000097:blood; D060888:Real-Time Polymerase Chain Reaction; D037761:Sirtuins / Q000097:blood / Q000235:genetics; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000097:blood / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C440499:lipopolysaccharide, Escherichia coli O111 B4; D008687:Metformin; D037761:Sirtuins