News and Publications

Reactive Oxygen Species, Antioxidants, and Cell Fate

Flavonoids are a family of plant-derived, polyphenolic compounds that are widely distributed in fruits and vegetables and therefore regularly consumed in the human diet. A number of physiologic benefits have been attributed to flavonoid consumption, including protection from cardiovascular disease and cancer, but the precise mechanisms underlying these activities remain to be determined. Flavonoids are best known for their activities as potent antioxidants and scavengers of free radicals. However, our recent data suggest that flavonoids can protect cells from oxidative damage by multiple mechanisms, most of which are independent of the antioxidant activity. During the past year, we characterized the different activities of flavonoids and determined the molecular mechanisms that underlie these activities.

In conjunction with A. Hanneken, Department of Molecular and Experimental Medicine, we examined the ability of flavonoids to protect cells derived from the eye from death induced by oxidative stress. Oxidative stress, which can be defined as an imbalance between the production and removal of reactive oxygen species, is implicated in the cell death that occurs in several different eye diseases, including age-related macular degeneration, diabetic retinopathy, and glaucoma. Furthermore, because certain flavonoids are also antiangiogenic, they could be particularly beneficial for the treatment of eye diseases that involve the abnormal growth of blood vessels. We identified a number of flavonoids that can protect different types of eye-derived cells from death induced by oxidative stress, and we are characterizing the mechanisms of action.

Flavonoids can also protect brain-derived nerve cells from death induced by oxidative stress. This finding is important because oxidative stress is implicated in the pathophysiology of a number of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and even in the decline of neuronal function during normal aging. The mechanisms underlying this protection vary among the different flavonoids and are quite complex. For example, we found that flavonoids can upregulate several different endogenous defense systems in cells, and thus the effects of the flavonoids can persist long after the compounds have been metabolized by the cell. We are characterizing the mechanisms and structural features that underlie the upregulation of these different defense systems. Our long-term goal is to design flavonoids that can target multiple antioxidant defense systems.

Certain flavonoids not only protect nerve cells from death but also promote nerve cell differentiation. We recently characterized the pathways involved in the promotion of differentiation and found that they are distinct from those involved in neuroprotection. These results suggest that the consumption of specific flavonoids in the diet could have multiple, beneficial effects on nerve cells after injury, in pathologic conditions, or in normal aging.

In contrast to the generally positive effects of flavonoids on nerve cells, some of the same flavonoids can block the proliferation of fibroblasts and endothelial cells that is induced by growth factors such as fibroblast growth factor 2, a member of a large family of proteins that have mitogenic and morphogenic effects on a wide variety of cell types. The inhibitory effects of flavonoids on proliferation induced by fibroblast growth factor 2 appear to be mediated through their action on a specific signaling pathway that we showed previously was required for proliferation induced by this growth factor. We are determining whether this inhibition is due to a direct effect of the flavonoids on this signaling pathway or due to the inhibition of upstream activators of the pathway. We are also trying to determine the structural characteristics of the flavonoids that are responsible for these effects. Thus, the ability of certain flavonoids to inhibit cell proliferation induced by growth factors may underlie the beneficial effects of the flavonoids in cardiovascular disease and cancer.

Publications

Ding, L., Donate, F., Parry, G.C., Guan, X., Maher, P., Levin, E.G. Inhibition of cell migration and angiogenesis by the amino-terminal fragment of 24kD basic fibroblast growth factor. J. Biol. Chem. 277:31056, 2002.

Moftah, M.Z., Downie, S.A., Bronstein, N.B., Mezentseva, N., Pu, J., Maher, P.A., Newman, S.A. Ectodermal FGFs induce perinodular inhibition of limb chondrogenesis in vitro and in vivo via FGF receptor 2. Dev. Biol. 249:270, 2002.

Soucek, T., Cumming, R., Dargusch, R., Maher, P., Schubert, D. The regulation of glucose metabolism by Hif-1 mediates a neruoprotective response to amyloid beta peptide. Neuron, in press.

Stachowiak, E.K., Myers, J., Berezney, R., Maher, P., Stachowiak, M.K. Integrative nuclear FGFR1 signaling as a part of a universal "feed-forward gate" signaling module that controls cell growth and differentiation. J. Cell Biochem., in press.