S-Equol Enantioselectively Activates cAMP-Protein Kinase A Signaling and Reduces Alloxan-Induced Cell Death in INS-1 Pancreatic β-Cells
S-Equol Enantioselectively Activates cAMP-Protein Kinase A Signaling and Reduces Alloxan-Induced Cell Death in INS-1 Pancreatic β-Cells
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DOI：
10.3177/jnsv.60.291
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发表时间：
2014-08-01
影响因子：
1.6
通讯作者：
Yamaji, Ryoichi
中科院分区：
文献类型：
--
作者：
Horiuchi, Hiroko;Harada, Naoki;Yamaji, Ryoichi
S等是由异黄酮类大豆苷元通过肠道微生物区系对映体选择性地产生，并被人体吸收。胰腺β细胞死亡的增加与胰岛素分泌缺陷和2型糖尿病风险增加直接相关。在本研究中，我们证明只有S对映体对四氧嘧啶诱导的INS-1胰岛β细胞氧化应激有抑制作用。S-马可剂量依赖性地减少四氧嘧啶诱导的细胞死亡，而R-马则无此作用。相反，不同对映体之间的雌激素活性没有显著差异。S-乙醇的细胞保护作用强于其前体大豆苷元，并可被蛋白质合成抑制剂放线菌亚胺阻断。当细胞与蛋白激酶A(PKA)抑制剂(H89)孵育时，细胞保护作用减弱，但不与雌激素受体抑制剂孵育。S等量对映选择性地升高细胞内cAMP水平。S-Equol，而不是R-Equol，诱导cAMP反应元件结合蛋白在Ser133上的磷酸化，并诱导cAMP反应元件介导的转录，这两种作用在H89存在时都被抑制。综上所述，这些结果表明，S等对映体选择性地增加INS-1细胞的存活可能是通过激活PICA信号来实现的。因此，S-马儿有可能作为抗2型糖尿病药物应用。
S-Equal is enantioselectively produced from the isoflavone daidzein by gut microflora and is absorbed by the body. An increase of pancreatic beta-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 beta-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-Equal increased intracellular cAMP levels in an enantioselective manner. S-Equol, but not R-equol, induced phosphorylation of cAMPresponse 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-equal enantioselectively increases the survival of INS-1 cells presumably through activating PICA signaling. Thus, S-equol might have applications as an anti-type 2 diabetic agent.