title: S-equol enantioselectively activates cAMP-protein kinase A signaling and reduces alloxan-induced cell death in INS-1 pancreatic β-cells.
abstract: S-Equol is enantioselectively produced from the isoflavone daidzein by gut microflora and is absorbed by the body. An increase of pancreatic β-cell death is directly associated with defects in insulin secretion and an increased risk of type 2 diabetes mellitus. In the present study, we demonstrate that only the S-enantiomer has suppressive effects against alloxan-induced oxidative stress in INS-1 pancreatic β-cells. S-Equol reduced alloxan-induced cell death in a dose-dependent manner, whereas R-equol had no effects. In contrast, no significant differences were observed between the enantiomers in estrogenic activity. The cytoprotective effects of S-equol were stronger than those of its precursor daidzein and were blocked by the protein synthesis inhibitor cycloheximide. The cytoprotection was diminished when cells were incubated with a protein kinase A (PKA) inhibitor (H89), but not an estrogen receptor inhibitor. S-Equol increased intracellular cAMP levels in an enantioselective manner. S-Equol, but not R-equol, induced phosphorylation of cAMP-response element-binding protein at Ser 133, and induced cAMP-response element-mediated transcription, both of which were diminished in the presence of H89. Taken together, these results show that S-equol enantioselectively increases the survival of INS-1 cells presumably through activating PKA signaling. Thus, S-equol might have applications as an anti-type 2 diabetic agent.
authors.affiliation: Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Horiuchi
authors.forename: Naoki
authors.initials: N
authors.lastname: Harada
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Adachi
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nakano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inui
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Yamaji
mesh_terms: D000496:Alloxan; D000818:Animals; D001419:Bacteria / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D060754:Equol / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D007529:Isoflavones / Q000378:metabolism / Q000494:pharmacology*; D007536:Isomerism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D048789:Phytoestrogens / Q000494:pharmacology; D010936:Plant Extracts / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction
chemical_list: D007328:Insulin; D007529:Isoflavones; D048789:Phytoestrogens; D010936:Plant Extracts; D060754:Equol; C004742:daidzein; D000496:Alloxan; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases