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10.1038/aps.2013.97

http://scihub22266oqcxt.onion/10.1038/aps.2013.97
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suck abstract from ncbi


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pmid24077632
      Acta+Pharmacol+Sin 2013 ; 34 (11 ): 1397-402
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  • Benzbromarone, an old uricosuric drug, inhibits human fatty acid binding protein 4 in vitro and lowers the blood glucose level in db/db mice #MMPMID24077632
  • Cai HY ; Wang T ; Zhao JC ; Sun P ; Yan GR ; Ding HP ; Li YX ; Wang HY ; Zhu WL ; Chen KX
  • Acta Pharmacol Sin 2013[Nov]; 34 (11 ): 1397-402 PMID24077632 show ga
  • AIM: Fatty acid-binding protein 4 (FABP4) plays an important role in maintaining glucose and lipid homeostasis. The aim of this study was to find new inhibitors of FABP4 for the treatment of type 2 diabetes. METHODS: Human FABP4 protein was expressed, and its inhibitors were detected in 1,8-ANS displacement assay. The effect of the inhibitor on lipolysis activity was examined in mouse 3T3-L1 preadipocytes. The db/db mice were used to evaluate the anti-diabetic activity of the inhibitor. Molecular docking and site-directed mutagenesis studies were carried out to explore the binding mode between the inhibitor and FABP4. RESULTS: From 232 compounds tested, benzbromarone (BBR), an old uricosuric drug, was discovered to be the best inhibitor of FABP4 with an IC50 value of 14.8 ?mol/L. Furthermore, BBR (25 ?mol/L) significantly inhibited forskolin-stimulated lipolysis in 3T3-L1 cells. Oral administration of BBR (25 or 50 mg/kg, for 4 weeks) dose-dependently reduced the blood glucose level and improved glucose tolerance and insulin resistance in db/db mice. Molecular docking revealed that the residues Ser55, Asp76, and Arg126 of FABP4 formed important interactions with BBR, which was confirmed by site-directed mutagenesis studies. CONCLUSION: BBR is an inhibitor of FABP4 and a potential drug candidate for the treatment of type 2 diabetes and atherosclerosis.
  • |3T3-L1 Cells [MESH]
  • |Animals [MESH]
  • |Benzbromarone/administration & dosage/*pharmacology [MESH]
  • |Blood Glucose/*drug effects [MESH]
  • |Diabetes Mellitus, Type 2/*drug therapy [MESH]
  • |Dose-Response Relationship, Drug [MESH]
  • |Fatty Acid-Binding Proteins/*antagonists & inhibitors [MESH]
  • |Glucose Tolerance Test [MESH]
  • |Humans [MESH]
  • |Inhibitory Concentration 50 [MESH]
  • |Insulin Resistance [MESH]
  • |Male [MESH]
  • |Mice [MESH]
  • |Mice, Inbred C57BL [MESH]
  • |Molecular Docking Simulation [MESH]
  • |Mutagenesis, Site-Directed [MESH]


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