The authors declare that they have no competing interests. The authors wish to thank Dr. Michihito Takahashi for contributing to the histopathological evaluation conducted in this study. This study was conducted under the “Evaluating Risks Associated with Manufactured Nanomaterials” Project (P06041) funded by the New Energy and Industrial Technology Development Organization (NEDO), Japan. “
“Metals play important roles in a wide variety of biological

PF-02341066 chemical structure processes of living systems. Homeostasis of metal ions, maintained through tightly regulated mechanisms of uptake, storage and secretion is therefore critical for life and is maintained within strict limits (Bertini and Cavallaro, 2008). Metal ion transporters participate in maintaining the required levels of the various metal ions in the cellular compartments (Rolfs and Hediger, 1999). Breakdown of metal-ion homeostasis can lead to the metal binding to protein sites different

to those designed for that purpose or replacement of other metals from their natural binding sites (Nelson, 1999). The results have provided evidence that toxic metals can interact with DNA and proteins causing oxidative deterioration of biological macromolecules. Thus the process of Selleck Afatinib breakdown of metal-ion homeostasis has been involved in a plethora of diseases (Halliwell and Gutteridge, 1990, Halliwell and Gutteridge, 2007, Stohs and Bagchi, 1995, Valko et al., 2005, Matés, 2000 and Matés et al., 1999). For example, iron is critical for cell growth, oxygen utilization, various enzymatic activities and responses of immune systems. Despite iron is an abundant trace metal in food, more than 2 billion people worldwide suffer from anemia (Stoltzfus, 2001). Iron deficiency results in impaired production of iron-containing proteins,

the most prominent of which is hemoglobin. Cellular iron deficiency inhibits cell growth, and subsequently leads to cell death. Conversely, abnormal iron uptake has been related to the most common hereditary disease hemochromatosis, ifenprodil leading to tissue damage derived from free radical toxicity (Toyokuni, 1996). In addition, disruption of iron (and copper) homeostasis has been found to play a key role in the etiology of neurological disorders such as Alzheimer’s disease and Parkinson’s disease (Bush and Curtain, 2008). Metals are known to modulate gene expression by interfering with signal transduction pathways that play important roles in cell growth and development (Valko et al., 2006). Deregulation of cell growth and differentiation is a typical characteristic of the cancer phenotype. Actions of metals interfere with deregulation of cell proliferation by activating various transcription factors, controlling cell cycle progression and apoptosis (Evan and Vousden, 2001). The most important involve the nuclear factors NF-κB, AP-1, NFAT and the tumour suppressor protein p53.