sting that fullerenes interfere with the generation of mitochondrial-derived ROS [603]. It is also demonstrated that mitochondrial membrane potential is a critical determinant in human MC FcR-mediated degranulation. While further studies are needed these data suggest that fullerenes inhibit MC through a mechanism involving the mitochondrial membrane potential and suggest a role of the mitochondria in human MC non-IgE mediator release. Nuclear factor-kappa B is involved in the pathophysiology of inflammatory and efforts to target its function through molecular targets in the pathway leading to its activation are underway [646]. This transcription factor induces both TNF- and IL-1 gene expression which can both in turn activate the NF-B pathway inducing an autocrine loop which perpetuates inflammation. Interestingly, some of the drugs for RA were shown to block either the NF-B activation cascade or its action [64,65,67]. For example, gold-containing therapeutics, TNF- inhibitors, and methotrexate, all regularly used for treating arthritis, can effect NF-B function [680]. Several fullerene derivatives, including ALM and TGA, inhibited IC-induced NF-B activation in human MC. Current studies are examining what signaling molecules in the ROS/ TNF/NF-B pathway [49] are affected by fullerene derivatives. Arthritic joint tissues demonstrate a striking predilection for uptake of ALM. Indeed, this strong uptake may provide a partial basis for their efficacy in ameliorating K/BxN arthritis. It was also demonstrated that fullerene derivatives inhibited the onset of arthritis in K/BxN serum transfer arthritis in C57Bl/6 mice. There was a small but not significant improvement in the CIA model. The K/BxN serum transfer model induces a rapid and severe synovitis dependent on neutrophils, MC, and macrophages. A role for MC in this system had also been proposed by studies in mice that lack MC on the basis of mutations affecting the Kit-KitL (stem cell factor) axis (W/Wv,Sl/Sld, and Pretty2) [29,33]. These mice are resistant to disease induction following serum transfer, and susceptibility can be restored by MC engraftment. However, studies in Kit-independent models of MC deficiency have not found an effect on arthritis in this model, suggesting that the phenotype of Kit-mutant mice may reflect the role of stem cell factor on lineages beyond the MC [50]. In the Cre-Master mice employed here, MC deficiency results through a genotoxicity from high levels of Cre recombinase driven by the carboxypeptidase A3 locus, resulting in Trp53-dependent MC depletion. Whereas Cre-Master still exhibit some residual arthritis inhibition by fullerenes, our data suggested that MC are not the only relevant target of fullerenes in this system. Given the differences in 17764671 MC phenotypes and expression between the rodent and human systems [71], further studies are needed to determine whether the effect of fullerenes on MC represents an interesting strategy for intervention in human arthritis. As in other studies using purified and well characterized fullerene derivatives [25,26,724], no liver or kidney toxicity was detected using repeated dosing of concentrations higher than that needed for in vivo efficacy. The in vivo imaging studies also demonstrated a lack of uptake in other organs, which portends well for a favorable toxicity profile in MEDChem Express 55837-20-2 clinical development of ALM. More advanced toxicity studies would be needed to assess these two fullerene derivatives before moving forward wit
