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Title: | Involvement of oxidative stress-induced ERK/JNK activation in the Cu2+/pyrrolidine dithiocarbamate complex-triggered mitochondria-regulated apoptosis in pancreatic β-cells |
Authors: | Wu, Chin-Ching Yen, Cheng-Chieh Lee, kuan-I Su, Chin-Chuan Tang, Feng-Cheng Cheng, Kuo-Liang Su, Yi-Chang Chen, Ya-Wen |
Keywords: | Copper (Cu2+);PDTC;Pancreatic β-cell;Oxidative stress;Apoptosis;ERK1/2;JNK |
Date: | 2012-02 |
Issue Date: | 2019-08-15T08:44:16Z (UTC)
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Publisher: | Toxicology Letters |
ISSN: | 0378-4274 |
Abstract: | Oxidative stress was demonstrated to promote the progression of diabetes mellitus (DM). It has been suggested that copper may play a specific role in the progression and pathogenesis of DM. Pyrrolidine dithiocarbamate (PDTC), a widely apply to the medicine, was known to be capable of enhancing copper accumulation. In this study, we investigated the effect of submicromolar-concentration Cu2+/PDTC complex on pancreatic β-cell damage and evaluated the role of oxidative stress in this effect. CuCl2 (0.01–300 μM) did not affect the cell viability in β-cell line RIN-m5F cells. However, combination of CuCl2 (0.5 μM) and PDTC (0.3 μM) markedly reduced RIN-m5F cell viability. Cu2+/PDTC complex could also increase the LPO and decrease the intracellular reduced GSH levels, and display several features of apoptosis signals including: increase in sub-G1 cell population, annexin-V binding, and caspase-3 activity, mitochondrial dysfunctions, and the activation of PARP and caspase cascades, which accompanied with the marked increase the intracellular Cu2+ levels. These apoptotic-related responses of Cu2+/PDTC complex-induced could be effectively prevented by antioxidant N-acetylcysteine (NAC). Furthermore, Cu2+/PDTC complex was capable of increasing the phosphorylations of ERK1/2 and JNK, and its upstream kinase MEK1/2 and MKK4, which could be reversed by NAC. Transfection with ERK2- and JNK-specific si-RNA and specific inhibitors SP600125 and PD98059 could inhibit ERK1/2 and JNK activation and attenuate MMP loss and caspase-3 activity induced by the Cu2+/PDTC complex. Taken together, these results are the first report to demonstrate that the Cu2+/PDTC complex triggers a mitochondria-regulated apoptosis via an oxidative stress-induced ERK/JNK activation-related pathway in pancreatic β-cells. |
URI: | https://ir.csmu.edu.tw:8080/ir/handle/310902500/20319 |
Relation: | Toxicology Letters, Volume 208, Issue 3, 275-285 |
Appears in Collections: | [職業安全衛生學系暨碩士班] 期刊論文
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