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  • Therapeutic potential of peroxisome proliferators--activated receptor-alpha/gamma dual agonist with alleviation of endoplasmic reticulum stress for the treatment of diabetes
  • Han KL; Choi JS; Lee JY; Song J; Joe MK; Jung MH; Hwang JK
  • Diabetes 2008[Mar]; 57 (3): 737-45
  • OBJECTIVE: Peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonists have the potential to be used as therapeutic agents for the treatment of type 2 diabetes. This study evaluated the function of macelignan, a natural compound isolated from Myristica fragrans, as a dual agonist for PPARalpha/gamma and investigated its antidiabetes effects in animal models. RESEARCH DESIGN AND METHODS: GAL4/PPAR chimera transactivation was performed and the expression of PPARalpha/gamma target genes was monitored to examine the ability of macelignan to activate PPARalpha/gamma. Additionally, macelignan was administrated to obese diabetic (db/db) mice to investigate antidiabetes effects and elucidate its molecular mechanisms. RESULTS: Macelignan reduced serum glucose, insulin, triglycerides, free fatty acid levels, and triglycerides levels in the skeletal muscle and liver of db/db mice. Furthermore, macelignan significantly improved glucose and insulin tolerance in these mice, and without altering food intake, their body weights were slightly reduced while weights of troglitazone-treated mice increased. Macelignan increased adiponectin expression in adipose tissue and serum, whereas the expression and serum levels of tumor necrosis factor-alpha and interleukin-6 decreased. Macelignan downregulated inflammatory gene expression in the liver and increased AMP-activated protein kinase activation in the skeletal muscle of db/db mice. Strikingly, macelignan reduced endoplasmic reticulum (ER) stress and c-Jun NH(2)-terminal kinase activation in the liver and adipose tissue of db/db mice and subsequently increased insulin signaling. CONCLUSIONS: Macelignan enhanced insulin sensitivity and improved lipid metabolic disorders by activating PPARalpha/gamma and attenuating ER stress, suggesting that it has potential as an antidiabetes agent for the treatment of type 2 diabetes.
  • |Adaptor Proteins, Signal Transducing/metabolism[MESH]
  • |Adipose Tissue, White/drug effects/metabolism[MESH]
  • |Animals[MESH]
  • |Cell Line[MESH]
  • |Diabetes Mellitus, Type 2/*drug therapy[MESH]
  • |Endoplasmic Reticulum/*drug effects[MESH]
  • |Insulin Receptor Substrate Proteins[MESH]
  • |Lignans/chemistry/*pharmacology/*therapeutic use[MESH]
  • |Liver/drug effects/metabolism[MESH]
  • |Mice[MESH]
  • |Mice, Obese[MESH]
  • |Molecular Structure[MESH]
  • |Myristica/chemistry[MESH]
  • |PPAR alpha/*agonists[MESH]
  • |PPAR gamma/*agonists[MESH]
  • |Stress, Physiological[MESH]
  • |Thapsigargin[MESH]





  • *{{pmid18065517}}
    *<b>[http://www.kidney.de/mlpefetch.php?search=18065517 Therapeutic potential of peroxisome proliferators--activated receptor-alpha/gamma dual agonist with alleviation of endoplasmic reticulum stress for the treatment of diabetes ]</b> Diabetes 2008; 57(3) ; 737-45 Han KL; Choi JS; Lee JY; Song J; Joe MK; Jung MH; Hwang JK

        *18065517*

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    Diabetes

    737 3.57 2008