title: Modified Si-Miao-San extract inhibits inflammatory response and modulates insulin sensitivity in hepatocytes through an IKKβ/IRS-1/Akt-dependent pathway.
abstract: OBJECTIVE
  Modified Si-Miao-San (mSMS) has showed anti-inflammatory potency and has been used in the clinic to treat metabolic disorders such as obesity and diabetes, but whether its anti-inflammatory activity contributes to improving insulin resistance remains to be determined. This study aims to investigate the mechanistic relationship between its anti-inflammatory activity and modulation of insulin sensitivity in free fatty acid-stimulated HepG2 cells.
  
  
  METHODS
  HepG2 cells were stimulated with palmitate (PA) and the effect of mSMS on insulin mediated-glycogen synthesis and triglyceride secretion was observed. The inhibition of mSMS on gene expression of proinflammatory cytokine tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and inhibitor of NF-κB kinase-β (IKKβ) activation was investigated. In addition, the effects of mSMS on insulin signaling transduction along insulin receptor substrates-1 (IRS-1)/Akt pathway were also evaluated. Furthermore, the effect of mSMS on glucose intolerance induced by conditioned-medium derived from activated macrophages was also assessed in normoglycemic mice.
  
  
  RESULTS
  Treatment of hepatocytes with PA reduced insulin sensitivity and mSMS effectively increased insulin-mediated glycogen synthesis and restored insulin inhibition of triglyceride secretion. mSMS suppressed IKKβ activation and down-regulated TNF-α and IL-6 gene over-expression, demonstrating its anti-inflammatory activity in hepatocytes. PA-evoked inflammation impaired insulin signaling cascades and mSMS improved insulin signaling transduction by modification of Ser/Thr phosphorylation of IRS-1 and downstream Akt (T308), thereby improved insulin sensitivity in hepatocytes. mSMS also improved glucose intolerance induced by inflammatory cytokines in normoglycemic mice, which further demonstrated its modulation toward insulin sensitivity in vivo.
  
  
  CONCLUSIONS
  The results suggest that mSMS inhibited inflammatory response and improved insulin sensitivity in hepatocytes via an IKKβ/IRS-1/Akt-dependent pathway.
authors.affiliation: Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, Jiangsu, PR China.
authors.forename: Kang
authors.initials: K
authors.lastname: Liu
authors.forename: Tianjiong
authors.initials: T
authors.lastname: Luo
authors.forename: Zhongai
authors.initials: Z
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Junping
authors.initials: J
authors.lastname: Kou
authors.forename: Baolin
authors.initials: B
authors.lastname: Liu
authors.forename: Fang
authors.initials: F
authors.lastname: Huang
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D031174:Atractylodes; D031742:Coix; D039323:Coptis; D015536:Down-Regulation; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D006003:Glycogen / Q000096:biosynthesis; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008517:Phytotherapy; D010946:Plants, Medicinal; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D004365:Drugs, Chinese Herbal; D018836:Inflammation Mediators; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D015850:Interleukin-6; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D006003:Glycogen; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase