Copper(II)-human amylin complex protects pancreatic cells from amylin toxicity.
Copper(II)-human amylin complex protects pancreatic cells from amylin toxicity.
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DOI：
10.1039/c3cp44542a
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发表时间：
2013-08-14
期刊：
影响因子：
--
通讯作者：
Jeremic AM
中科院分区：
文献类型：
--
作者：
Lee EC;Ha E;Singh S;Legesse L;Ahmad S;Karnaukhova E;Donaldson RP;Jeremic AM
人类淀粉酶衍生的低聚物和聚集体被认为在2型糖尿病（T2DM）的发病机制中起重要作用。除了胰淀素引起的细胞损耗外，T2DM常伴有血清铜水平升高。虽然已有研究表明人胰淀素在聚集过程中会在溶液中产生过氧化氢（H2O2），并且在铜（II）离子（Cu2+）的存在下，这一过程会加剧，但对于胰腺β-细胞中Cu2+与胰淀素相互作用的机制及其病理意义知之甚少。因此，本研究探讨了Cu2+和人胰淀素在细胞内和体外催化活性氧（ROS）形成的机制，并考察了Cu2+对胰淀素聚集的调节作用及其对胰岛大鼠胰岛素瘤(RIN-m5F) β-细胞的毒性。我们的研究结果表明，Cu2+与人和大鼠的胰淀素相互作用形成具有低聚集性和氧化性的金属肽复合物。人和非淀粉样变大鼠的胰淀素产生微量的H2O2，在Cu2+的存在下，其积累略有增强。与人和大鼠的淀粉酶形成鲜明对比的是，在还原剂谷胱甘肽和抗坏血酸存在的情况下，Cu2+产生的μM浓度的H2O2超过了淀粉酶的几倍。目前的研究表明，人和大鼠的胰淀素既能产生H2O2，也能淬灭H2O2，并且人胰淀素显著降低Cu2+和谷胱甘肽产生的溶液中H2O2的量，而大鼠胰淀素则不显著。同样，发现人胰淀素也能减少Cu2+和谷胱甘肽引起的羟基自由基形成。此外，Cu2+通过抑制大鼠胰腺胰岛素瘤细胞中促凋亡caspase-3和应激激酶信号通路的激活，减轻了人amylin的毒性作用，部分原因是将人amylin稳定在其天然构象状态。人胰淀素对金属催化ROS的牺牲猝灭和铜的抗聚集和抗凋亡特性表明铜-胰淀素复合物具有新的保护作用。
Human amylin-derived oligomers and aggregates are believed to play an important role in the pathogenesis of type II diabetes mellitus (T2DM). In addition to amylin-evoked cell attrition, T2DM is often accompanied by elevated serum copper levels. Although previous studies have shown that human amylin, in the course of its aggregation, produces hydrogen peroxide (H2O2) in solution, and that this process is exacerbated in the presence of copper(II) ions (Cu2+), very little is known about the mechanism of interaction between Cu2+ and amylin in pancreatic β-cells, including its pathological significance. Hence, in this study we investigated the mechanism by which Cu2+ and human amylin catalyze formation of reactive oxygen species (ROS) in cells and in vitro, and examined the modulatory effect of Cu2+ on amylin aggregation and toxicity in pancreatic rat insulinoma (RIN-m5F) β-cells. Our results indicate that Cu2+ interacts with human and rat amylin to form metalo-peptide complexes with low aggregative and oxidative properties. Human and non-amyloidogenic rat amylin produced minute (nM) amounts of H2O2, the accumulation of which was slightly enhanced in the presence of Cu2+. In a marked contrast to human and rat amylin, and in the presence of the reducing agents glutathione and ascorbate, Cu2+ produced μM concentrations of H2O2 surpassing the amylin effect by several fold. The current study shows that human and rat amylin not only produce but also quench H2O2, and that human but not rat amylin significantly decreases the amount of H2O2 in solution produced by Cu2+ and glutathione. Similarly, human amylin was found to also decrease hydroxyl radical formation elicited by Cu2+ and glutathione. Furthermore, Cu2+ mitigated the toxic effect of human amylin by inhibiting activation of pro-apoptotic caspase-3 and stress-kinase signaling pathways in rat pancreatic insulinoma cells in part by stabilizing human amylin in its native conformational state. This sacrificial quenching of metal-catalyzed ROS by human amylin and copper’s anti-aggregative and anti-apoptotic properties suggest a novel and protective role for the copper–amylin complex.
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影响因子：
2.9
作者：
Eskici, Goezde;Axelsen, Paul H.
通讯作者：
Axelsen, Paul H.
影响因子：
4.8
作者：
Curtain, CC;Ali, F;Barnham, KJ
通讯作者：
Barnham, KJ
DOI：
10.1152/ajpendo.00082.2006
发表时间：
2006-12-01
影响因子：
5.1
作者：
Meier, Juris J.;Kayed, Rakez;Butler, Peter C.
通讯作者：
Butler, Peter C.
影响因子：
3.4
作者：
Lim, Yun-An;Rhein, Virginie;Goetz, Juergen
通讯作者：
Goetz, Juergen
影响因子：
2.9
作者：
Jiang, Dianlu;Men, Lijie;Zhou, Feimeng
通讯作者：
Zhou, Feimeng