title: Selective inhibition of 12-lipoxygenase protects islets and beta cells from inflammatory cytokine-mediated beta cell dysfunction.
abstract: OBJECTIVE
  Islet inflammation leads to loss of functional pancreatic beta cell mass. Increasing evidence suggests that activation of 12-lipoxygenase leads to inflammatory beta cell loss. This study evaluates new specific small-molecule inhibitors of 12-lipoxygenase for protecting rodent and human beta cells from inflammatory damage.
  
  
  METHODS
  Mouse beta cell lines and mouse and human islets were treated with inflammatory cytokines IL-1β, TNFα and IFNγ in the absence or presence of novel selective 12-lipoxygenase inhibitors. Glucose-stimulated insulin secretion (GSIS), gene expression, cell survival and 12-S-hydroxyeicosatetraenoic acid (12-S-HETE) levels were evaluated using established methods. Pharmacokinetic analysis was performed with the lead inhibitor in CD1 mice.
  
  
  RESULTS
  Inflammatory cytokines led to the loss of human beta cell function, elevated cell death, increased inflammatory gene expression and upregulation of 12-lipoxygenase expression and activity (measured by 12-S-HETE generation). Two 12-lipoxygenase inhibitors, Compounds 5 and 9, produced a concentration-dependent reduction of stimulated 12-S-HETE levels. GSIS was preserved in the presence of the 12-lipoxygenase inhibitors. 12-Lipoxygenase inhibition preserved survival of primary mouse and human islets. When administered orally, Compound 5 reduced plasma 12-S-HETE in CD1 mice. Compounds 5 and 9 preserved the function and survival of human donor islets exposed to inflammatory cytokines.
  
  
  CONCLUSIONS
  Selective inhibition of 12-lipoxygenase activity confers protection to beta cells during exposure to inflammatory cytokines. These concept validation studies identify 12-lipoxygenase as a promising target in the prevention of loss of functional beta cells in diabetes.
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, 700 W. Olney Road, Norfolk, VA, 23507, USA, TaylorD@evms.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Taylor-Fishwick
authors.forename: Jessica
authors.initials: J
authors.lastname: Weaver
authors.forename: Lindsey
authors.initials: L
authors.lastname: Glenn
authors.forename: Norine
authors.initials: N
authors.lastname: Kuhn
authors.forename: Ganesha
authors.initials: G
authors.lastname: Rai
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.forename: Angela
authors.initials: A
authors.lastname: Dudda
authors.forename: Dieter
authors.initials: D
authors.lastname: Schmoll
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Holman
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Nadler
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase