Folate deficiency triggers an oxidative-nitrosative stress-mediated apoptotic cell death and impedes insulin biosynthesis in RINm5F pancreatic islet β-cells: relevant to the pathogenesis of diabetes.
Folate deficiency triggers an oxidative-nitrosative stress-mediated apoptotic cell death and impedes insulin biosynthesis in RINm5F pancreatic islet β-cells: relevant to the pathogenesis of diabetes.
复制标题
DOI：
10.1371/journal.pone.0077931
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Chen CH
中科院分区：
文献类型：
--
作者：
Hsu HC;Chiou JF;Wang YH;Chen CH;Mau SY;Ho CT;Chang PJ;Liu TZ;Chen CH
叶酸(叶酸)缺乏可能是包括糖尿病在内的多种氧化应激触发的慢性退行性疾病发病的危险因素，然而，支持这一假说的直接证据很少。出于这个原因，我们开始研究FD是否可以触发产生胰岛素的RINm5F胰岛β细胞的凋亡事件。当这些细胞在FD条件下培养时，观察到一种时间依赖性的生长障碍，这些细胞的死亡本质上是通过线粒体依赖的途径进行的。FD除了引起氧化应激外，还可通过依赖于NF-κB的诱导型一氧化氮合酶(INOSB)介导的一氧化氮(NO)的过量产生来触发亚硝化性应激。后者可引起内质网钙(Ca~(2+))储备耗竭，导致细胞内钙超载，并通过激活CHOP表达而引起内质网应激。此外，还发现FD诱导的RINm5F细胞的凋亡与细胞内谷胱甘肽(GSH)的耗竭和Bcl2表达的严重下调有关。同样，我们还证明FD可以严重阻碍RINm5F细胞合成胰岛素，并且它们在葡萄糖刺激下分泌胰岛素的能力受到一定程度的阻碍。更重要的是，我们发现补充叶酸并不能恢复RINm5F细胞重新合成胰岛素的能力。综上所述，我们的数据提供了强有力的证据，支持FD是糖尿病发病的合法危险因素的假设。
It has been postulated that folic acid (folate) deficiency (FD) may be a risk factor for the pathogenesis of a variety of oxidative stress-triggered chronic degenerative diseases including diabetes, however, the direct evidence to lend support to this hypothesis is scanty. For this reason, we set out to study if FD can trigger the apoptotic events in an insulin-producing pancreatic RINm5F islet β cells. When these cells were cultivated under FD condition, a time-dependent growth impediment was observed and the demise of these cells was demonstrated to be apoptotic in nature proceeding through a mitochondria-dependent pathway. In addition to evoke oxidative stress, FD condition could also trigger nitrosative stress through a NF-κB-dependent iNOS-mediated overproduction of nitric oxide (NO). The latter compound could then trigger depletion of endoplasmic reticulum (ER) calcium (Ca2+) store leading to cytosolic Ca2+ overload and caused ER stress as evidence by the activation of CHOP expression. Furthermore, FD-induced apoptosis of RINm5F cells was found to be correlated with a time-dependent depletion of intracellular gluthathione (GSH) and a severe down-regulation of Bcl-2 expression. Along the same vein, we also demonstrated that FD could severely impede RINm5F cells to synthesize insulin and their abilities to secret insulin in response to glucose stimulation were appreciably hampered. Even more importantly, we found that folate replenishment could not restore the ability of RINm5F cells to resynthesize insulin. Taken together, our data provide strong evidence to support the hypothesis that FD is a legitimate risk factor for the pathogenesis of diabetes.
登录
查看更多内容
影响因子：
7.4
作者：
Lenzen, S;Drinkgern, J;Tiedge, M
通讯作者：
Tiedge, M
影响因子：
11.4
作者：
Dlugosz, Paulina J.;Billen, Lieven P.;Andrews, David W.
通讯作者：
Andrews, David W.
影响因子：
4.8
作者：
Setsukinai, K;Urano, Y;Nagano, T
通讯作者：
Nagano, T
影响因子：
4.8
作者：
Chen, Natalie C.;Yang, Fan;Wang, Hong
通讯作者：
Wang, Hong
DOI：
10.1152/ajpendo.00620.2006
发表时间：
2007-06-01
影响因子：
5.1
作者：
Kitiphongspattana, Kajorn;Khan, Tarannum A.;Gaskins, H. Rex
通讯作者：
Gaskins, H. Rex