Current Pharmaceutical Design, 2010, 16, 877-883 877 1381-6128/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd. The Hormetic Role of Dietary Antioxidants in Free Radical-Related Diseases V. Calabrese 1, *, C. Cornelius 1 , A. Trovato-Salinaro 1 , M.T. Cambria 1 , M.S. Locascio 1 , L. Di Rienzo 2 , D.F. Condorelli 1 , C. Mancuso 3 , A. De Lorenzo 2 and E. J. Calabrese 4 1 Department of Chemistry, University of Catania, Catania, Italy; 2 Human Nutrition Unit, Department of Neuroscience, University of Rome Tor Vergata, Rome, Italy; 3 Institute of Pharmacology, Catholic University School of Medicine, Roma, Italy; 4 Environmental Health Sciences Division, School of Public Health, University of Massachusetts, Amherst, Massachusetts, USA Abstract: Regular consumption of cruciferous vegetables or spices is associated with a reduced incidence of cancer and reduction of markers for neurodegenerative damage. Furthermore, greater health benefit may be obtained from raw as opposed to cooked vegetables. Nutritional interventions, by increasing dietary intake of fruits and vegetables, can retard and even reverse age-related declines in brain function and cognitive performance. The mechanisms through which such dietary supplementation may diminish free radical-related diseases is related to their ability to reduce the formation of reactive oxygen and nitrogen species, along with the up-regulation of vitagenes, such as members of the heat shock protein (Hsp) family, heme oxygenase-1 and Hsp70. The most prominent dietary factor that increases the risk of many different chronic diseases is excessive calorie intake. Reducing energy consumption by controlled caloric restriction or intermittent fasting increases lifespan and protects various tissues against diseases, in part, by hormetic mechanisms that increase cellular stress resistance. This biphasic dose-response relationship (i.e., hormesis) displays low-dose stimulation and a high-dose inhibition. Despite the current interest in hormesis by the toxicology community, quantitatively similar U-shaped dose responses have long been recognized by researchers to be involved with factors affecting memory, learning, and the occurrence of oxidative stress- mediated degenerative responses. Dietary polyphenols also act hormetically, displaying cytoprotective effects at low doses. However, excessive nutritional supplementation (i.e., high doses) can have negative consequences through the generation of more reactive and harmful intermediates with pathological consequences. Keywords: Antioxidants, free radicals, vitagenes, hormesis. INTRODUCTION Natural antioxidants, such as flavonoids, carotenoids and vitamins, are bioactive molecules derived from plants that exert beneficial effects on health. Epidemiological studies indicate that regular consumption of cruciferous vegetables, such as broccoli, Brussels sprouts, cabbage, cauliflower, kale, swede, turnip, or spices such as curcumin or ferulic acid are associated with a reduced incidence of cancer and reduction of markers for neurodegenerative damage. Further-more, greater health benefit may be obtained from the consumption of raw as opposed to cooked vegetables. Growing interest has been focused on the therapeutic role of antioxidants found in medicinal and dietary plants that might prevent oxidative damage [1,2]. Despite the efforts of innumerable researchers worldwide to ameliorate the outcomes of cancer, it continues to be a significant burden on mankind. In the United States alone, cancer accounts for one out of every four deaths [3]. In 2006 it was estimated that between 550,000 - 600,000 Americans would die from cancer, more than 1500 people a day. Accumulated scientific evidence suggests that one-third of these deaths were related to nutrition, physical inactivity and obesity. Such factors are likely to have a particularly important effect for certain individual types of cancers [4]. Increasing evidence indicates that nutritional factors can have protective effects against various cancers associated with common western dietary patterns. Such Western dietary patterns with their higher intakes of red and processed meats, desserts and fried foods have been associated with higher risks of a variety of tumors, including colon, breast, and prostate. On the other hand, a more prudent dietary pattern (i.e., oriental diet), with its higher intake of fruits, vegetables, whole grains and cereals contributing to increased levels of antioxidants, essential minerals such as selenium, dietary fibers etc has often been associated via epide- miological studies with a markedly lower risk of several cancer *Address correspondence to this author at the Department of Chemistry, Biochemistry and Molecular Biology Section, University of Catania, Via Andrea Doria, 95100 Catania, Italy; Tel: 0039-095-7384067; Fax: 0039-095-580138; E-mail: calabres@unict.it types as well as neurodegenerative responses [5-7]. Thus, a key factor differentiating the oriental diet from some commonly followed Western dietary patterns is the presence of dietary phytochemicals [8]. Dietary antioxidants protect against colo- rectal [9], lung [10], and possibly prostate cancer [11] in humans, in part related to decreasing the accumulation of oxidized macromolecules [12-17]. Feeding experiments in animals have also indicated that broccoli can protect against liver cancer [18]. Cruciferous vegetables uniquely contain substantial quantities of glucosinolates [19], which are primarily responsible for their putative cancer chemopreventive effects. DIETARY ANTIOXIDANTS AND HORMESIS The concept of hormesis has emerged as a significant dose- response model in toxicology and pharmacology [20-23]. The enhanced recognition of hormesis has occurred principally because traditional dose-response models such as the threshold model have not been able to account for the occurrence of non-random biological activity below well-established thresholds of response [24-26]. These biphasic dose-response relationships, referred to here as hormesis, display low-dose stimulation and a high-dose inhibition. Despite the current interest in hormesis by the toxi- cology community, quantitatively similar U-shaped dose responses have long been recognized in pharmacology and associated with memory, learning, and performance, as well as with nutritional antioxidant responses and oxidative stress-mediated degenerative reactions. Several lines of in vitro evidence have implicated ROS in the pathogenesis of neuronal death [27] and different markers of oxidative stress are found in post-mortem examinations of brains from patients with many neurodegenerative disorders [28]. DNA oxidation, protein oxidation, and lipid peroxidation have been reported in brain regions containing neurofibrillary tangles and senile plaques from Alzheimer’s disease (AD) patients [29,30]. Dopaminergic neurons in the substantia nigra of brains of patients with Parkinson’s disease (PD) also exhibit hallmarks of oxidative stress [31]. The oxidative stress hypothesis for neurodegeneration postulates that cumulative oxidative damage over time may explain