are similar to bulk cerium, the oxygen vacancies and increased surface area endow NC with catalytic properties. Studies in cell culture and animal models show that they protect against oxidative stress, mimicking the activity of superoxide dismutase (SOD) and/or catalase, acting as a reactive oxygen species (ROS) scavengers. NC increase the life span of Drosophila melanogaster, reduce inflammation and cell death of transgenic mice and decrease the cellular senescence of rat neurons. Experiments demonstrate the ability of NC to scavenge superoxide in the Ce3+ oxidation state; a reduction of the Ce3+ to Ce4+ ratio leads to loss of SOD mimetics. In PC12 cells (ATCC CRL-1721) derived from a transplantable rat pheochromocytoma, NC promote dopamine secretion and changes in gene expression, and act as reactive oxygen species (ROS) scavengers. The Comt, Maoa, Slc6a3 (known as Dat) and Slc18a2 (known as Vmat2) gene expression is increased upon treatment with NC; in contrast, the expression of Gss and Gpx1 genes is decreased under these conditions. In human lymphoid FaB32 cells, a heparin functionalized NC forms a ternary complex with Fgf2 and Fgfr1 and promotes cell proliferation. This Fgf induced signaling is the paracrine Fgf as Fgf2 is one of five subfamilies that signal via the Fgf receptors (The endocrine subfamily is FGFR-dependent but has a low affinity for the receptor and relies on the Khloto family of transmembrane proteins while the intracrine pathway is FGFR-independent).In the Ce4+ oxidation state NC exhibit significant catalase mimetic activity at physiological hydrogen peroxide concentrations; a reduction of the Ce4+ to Ce3+ ratio leads to loss of catalase mimetics. In addition to superoxide and hydrogen peroxide, NC are also hydroxyl radical (OH) and nitric oxide (NO) scavengers. However, NC can exhibit oxidant behavior and whether NC act as an oxidant or anti-oxidant appears to be pH-dependent. The ability of NC to modulate ROS makes them potentially useful for cancer treatment. NC are indeed cytotoxic to cancer cells and enhance radiation therapy (RT) induced cell death. NC treatment prior to RT reduces RT mediated damage of normal tissue. In a mouse model of macular degeneration, NC have protective effects and induce regression of preexisting pathological manifestations. In diabetic rats, NC reduce ROS to levels comparable to non-diabetic rats; NC pre-treatment of isolated rat pancreatic islet cells leads to improved islet function and increased insulin secretion. In cells, NC are present in the cytoplasm and the nucleus, the periphery of endoplasmic reticulum (ER) and mitochondria. The presence of NC in these organelles is important as the two contribute to ROS formation. Mitochondria represent a major source of ROS production in the normal electron transport chain pathway where premature electron leakage to oxygen can occur. The ER is the site of protein synthesis and folding; ROS formation can occur during the formation of disulfide bonds in proteins. In the human keratinocyte HaCat cell line, the uptake of NC is clathrin-, caveolae- and lipid raft-dependent. Intravenous administration of NC in rats results in its presence in several organs/tissues with liver and spleen having the highest percentage and minimal presence in the brain. Despite the overall lack of toxicity in vivo in animal models, the toxicity of NC in vitro provides conflicting results. These and the therapeutic potential of NC warrant further investigation....(less)