The potential toxic effects of two types of copper(II) oxide (CuO) nanoparticles (NPs) with different specific surface areas, different shapes (rod or spheric), different sizes as raw materials and similar hydrodynamic diameter in suspension were studied on human hepatocarcinoma HepG2 cells. Both CuO NPs were shown to be able to enter into HepG2 cells and induce cellular toxicity by generating reactive oxygen species. CuO NPs increased the abundance of several transcripts coding for pro-inflammatory interleukins and chemokines. Transcriptomic data, siRNA knockdown and DNA binding activities suggested that Nrf2, NF-κB and AP-1 were implicated in the response of HepG2 cells to CuO NPs. CuO NP incubation also induced activation of MAPK pathways, ERKs and JNK/SAPK, playing a major role in the activation of AP-1. In addition, cytotoxicity, inflammatory and antioxidative responses and activation of intracellular transduction pathways induced by rod-shaped CuO NPs were more important than spherical CuO NPs. Measurement of Cu(2+) released in cell culture medium suggested that Cu(2+) cations released from CuO NPs were involved only to a small extent in the toxicity induced by these NPs on HepG2 cells.
The potential toxic effects of copper oxide (CuO) nanoparticles (NPs) were studied on differentiated Caco-2 cell monolayers, a classical in vitro model of human small intestine epithelium. Two types of CuO NPs, with different specific surface area, different sizes as raw material but the same hydrodynamic diameter in suspension, differentially disturbed the monolayer integrity, were cytotoxic and triggered an increase of the abundance of several transcripts coding for pro-inflammatory cytokines and chemokines. Specific surface area was not a major variable explaining the increased toxicity when intestinal epithelium is exposed to rod-shaped CuO NPs, compared with spherical CuO NPs. The results suggest that release of Cu(II) cations and shape of these CuO NPs are likely to be implicated in the toxicity of these CuO NPs.
On the role of copper and the Prion protein in cellular aging In 1961, Prof. L. Hayflick lays the foundations of cellular aging with theory of replicative senescence. It was subsequently shown that stress can trigger a premature senescence, called Stress-induced premature senescence (SIPS). Since then, the list of actors involved in senescence is growing with a little consideration for metals. Copper plays an important role in the living world as it is the catalyst for many biochemical reactions and may be involved in the structure and function of proteins. The importance of copper homeostasis during aging has been demonstrated in a filamentous fungus Podospora anserina. The results of this study provide new evidence suggesting that the link between copper homeostasis and aging can not be restricted to P. anserina, but is conserved. The first part of this work showed that copper is involved in senescence of WI-38 human diploid fibroblasts(HDFs). Using different techniques, we showed for the first time at the cellular level, an accumulation of copper in FDHs during replicative senescence. We also showed that copper could play an active role in establishing the senescent phenotype. Indeed, incubation with an copper-enriched medium generates an oxidative stress,an antioxidant response but also the premature appearance of senescence markers. The latter phenomenon is dependent of the oxidative stress generated by copper and p38MAPK. Another part of this work concerns the role of Prion protein (PrP) in senescence. We have shown that PrP is overexpressed in PBMC from elderly compared with young people, in HDFs in replicative senescence and in premature senescence induced by copper and other oxidative stresses. WI-38 HDFs incubated with copper-enriched medium showed an overexpression of PrP under its normal conformational form (PrPc) which is localized in both cytoplasm and nucleus. We showed that the invalidation of PrP expression by specific siRNAs already induces the appearance of premature senescence. This invalidation seems to increase ROS production and DNA damages. These results suggest that PrP plays a protective role against oxidative stress, DNA damages and senescence. This work highlights the fact that metals such as copper can play a role in the mechanisms of senescence.
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