It has been clearly shown that the cellular oxidant/antioxidant equilibrium is a key factor in determining redox-dependent signal transduction pathways both in vitro and in vivo. Antioxidant nutrients interact with cell receptors (e.g., isofla-vones bind to estrogen receptor alpha and beta) and modulate key enzymes such as phosphatase and kinases. Changes in transcription factor activity leads to changes in mRNA and protein levels as summarized in Fig. 1.3. Furthermore, antioxidants can directly interact with enzymes (e.g., through protein-binding properties), thereby changing their activity.
Molecular and cell biology has changed our understanding of how antiox-idants can mediate their biological properties. A good example is vitamin E—the most important lipid-soluble antioxidant. Since its discovery, studies of the constituent tocopherols and tocotrienols have focused mainly on their antioxidant properties. In 1991, Angelo Azzi's group first described nonantioxidant, cell signaling functions for vitamin E, demonstrating that vitamin E regulates protein kinase C activity in smooth muscle cells (3). At the transcriptional level, vitamin E modulates the expression of the hepatic «-tocopherol transfer protein (TTP) (4) as well as the expression collagenase gene (5) and «-tropomyosin gene (6). Recently, a tocopherol-dependent transcription factor (tocopherol associated protein, TAP) has been discovered (7). In cultured cells, it has been demonstrated that vitamin E inhibits inflammation, cell adhesion, platelet aggregation, and smooth muscle cell proliferation (8). Many of these cellular functions of vitamin E seem to be independent of its antioxidant properties. Thus, antioxidants do not act only as scavengers of reactive oxygen and nitrogen species, thereby
preventing oxidative damage towards lipids, protein, and DNA, they are also cell signaling molecules. Both the free-radical scavenging as well as the cell signaling activity of antioxidants may contribute to their potential beneficial effects in preventing atherogenesis, carcinogenesis, and neurodegneration (Fig. 1.4).
Various transcription factors such as NF-kB, AP-1, Nrf-1, and SP-1 are regulated by the cellular redox status. NF-kB controls the expression of different genes involved in inflammatory and proliferative responses. A spectrum of key genes known to be involved in the development of atherosclerosis have been shown to be regulated by NF-kB, including those encoding for cytokines, chemoattractants, and cell adhesion proteins (8). Several lines of evidence including the inhibition caused by various antioxidants, suggest that NF-kB is subject to redox regulation. Owing to its pivotal role in inflammation and atherogenesis, a significant effort has focused on identifying nutrients that regulate NF-kB activity. In this scenario, flavonoids may play an important role, either by directly affecting key steps in the activation pathway of NF-kB, or by modulating the intracellular redox status, which is, in turn, one of the major determinants of NF-kB activation. Consistent experimental data is accumulating, which suggests that the anti-inflammatory properties of flavonoids are in part due to their ability to down-regulate NF-kB (9).
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