Luo Cheng, Li Yan, Yang Liang, Zheng Yan, Long Jiangang, Jia Jinjing, Xiao Shengxiang, Liu Jiankang
Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, People's Republic of China.
Center for Bioinformatics, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, People's Republic of China.
Int J Nanomedicine. 2014 Oct 10;9:4763-72. doi: 10.2147/IJN.S67688. eCollection 2014.
Copper oxide nanoparticles (CuONP) have attracted increasing attention due to their unique properties and have been extensively utilized in industrial and commercial applications. For example, their antimicrobial capability endows CuONP with applications in dressings and textiles against bacterial infections. Along with the wide applications, concerns about the possible effects of CuONP on humans are also increasing. It is crucial to evaluate the safety and impact of CuONP on humans, and especially the skin, prior to their practical application. The potential toxicity of CuONP to skin keratinocytes has been reported recently. However, the underlying mechanism of toxicity in skin cells has remained unclear. In the present work, we explored the possible mechanism of the cytotoxicity of CuONP in HaCaT human keratinocytes and mouse embryonic fibroblasts (MEF). CuONP exposure induced viability loss, migration inhibition, and G2/M phase cycle arrest in both cell types. CuONP significantly induced mitogen-activated protein kinase (extracellular signal-regulated kinase [Erk], p38, and c-Jun N-terminal kinase [JNK]) activation in dose- and time-dependent manners. U0126 (an inhibitor of Erk), but not SB 239063 (an inhibitor of p38) or SP600125 (an inhibitor of JNK), enhanced CuONP-induced viability loss. CuONP also induced decreases in p53 and p-p53 levels in both cell types. Cyclic pifithrin-α, an inhibitor of p53 transcriptional activity, enhanced CuONP-induced viability loss. Nutlin-3α, a p53 stabilizer, prevented CuONP-induced viability loss in HaCaT cells, but not in MEF cells, due to the inherent toxicity of nutlin-3α to MEF. Moreover, the experiments on primary keratinocytes are in accordance with the conclusions acquired from HaCaT and MEF cells. These data demonstrate that the activation of Erk and p53 plays an important role in CuONP-induced cytotoxicity, and agents that preserve Erk or p53 activation may prevent CuONP-induced cytotoxicity.
氧化铜纳米颗粒（CuONP）因其独特性质而受到越来越多的关注，并已广泛应用于工业和商业领域。例如，其抗菌能力使CuONP可用于敷料和纺织品以抵抗细菌感染。随着其广泛应用，人们对CuONP可能对人类产生的影响的担忧也在增加。在CuONP实际应用之前，评估其对人类尤其是皮肤的安全性和影响至关重要。最近有报道称CuONP对皮肤角质形成细胞具有潜在毒性。然而，其在皮肤细胞中的潜在毒性机制仍不清楚。在本研究中，我们探究了CuONP对HaCaT人角质形成细胞和小鼠胚胎成纤维细胞（MEF）产生细胞毒性的可能机制。CuONP暴露导致两种细胞类型的活力丧失、迁移抑制和G2/M期细胞周期阻滞。CuONP以剂量和时间依赖性方式显著诱导丝裂原活化蛋白激酶（细胞外信号调节激酶[Erk]、p38和c-Jun氨基末端激酶[JNK]）活化。U0126（一种Erk抑制剂）而非SB 239063（一种p38抑制剂）或SP600125（一种JNK抑制剂）增强了CuONP诱导的活力丧失。CuONP还导致两种细胞类型中p53和磷酸化p53水平降低。p53转录活性抑制剂环状pifithrin-α增强了CuONP诱导的活力丧失。p53稳定剂Nutlin-3α可防止CuONP诱导的HaCaT细胞活力丧失，但由于Nutlin-3α对MEF细胞具有固有毒性，因此对MEF细胞无效。此外，原代角质形成细胞实验与从HaCaT和MEF细胞获得的结论一致。这些数据表明，Erk和p53的活化在CuONP诱导的细胞毒性中起重要作用，维持Erk或p53活化的药物可能预防CuONP诱导的细胞毒性。
