Keeping in mind the importance of oxidative stress in the regulation/dysregulation of immune system, the use of antioxidants in such diseases has been reasonably proposed. Rheumatoid arthritis (RA) is a classic example of autoimmune disease. Joint inflammation in rheumatoid arthritis (RA) is characterized by invasion of T cells in the synovial space and proliferation of activated macrophages and fibroblasts in the synovial intima [63]. Therefore, in the rheumatic joint there is an increased activity of fibroblasts and leucocytes which produce ROS [64,65]. Very recently, antioxidants have been successfully used as adjuvant therapy in RA [66,67]. Although the results obtained with RA seemed to be very promising, the indiscriminate use of antioxidants in autoimmune disorders is not recommended. In fact, autoimmune lymphoproliferative syndrome (ALPS), MS, type 1 diabetes and multiple autoimmune syndrome, have been linked to decreased Fas functionality [68] and, as discussed previously, antioxidants may up-regulate Fas and FasL in vitro. Increasing evidence provides support that oxidative stress and apoptosis are closely related physiological phenomena and are implicated in diseases including autoimmune diseases. Therefore molecules that target both apoptosis-related signal transduction and oxidative stress, like antioxidants, are likely to result in the improvement of these pathologies.

A novel possible approach to modulate immune system thus preventing autoimmunity or transplant rejection is the activation of cytoprotective and antioxidant enzymes such as HO-1. Heme oxygenase-1, the inducible isoform of HO, is a key protein in the cell stress response and its up-regulation is a common event during pro-inflammatory conditions [11,69-72]. Recent work clearly demonstrated that regulatory T cells overexpress HO-1 and release CO under pro-oxidant conditions. Carbon monoxide may inhibit the proliferation of effector T cells, thus reducing the immune response and prevent autoimmunity and/or graft reaction [73,74]. Dietary antioxidants, in particular polyphenols, has been shown to increase HO-1 expression in different in vitro systems [3,75,76] and the potential use of this natural substances to regulate immune response should be carefully addressed.

Antioxidants, Cancer And Neurodegenerative Disorders

It is well known that the dietary consumption of fruits, vegetables, herbs, or their phytochemical constituents aid in cancer prevention [77-79]. It is believed that the antioxidant properties of such foods protect cells from ROS-mediated DNA damage that can result in mutation and subsequent carcinogenesis. ROS-induced DNA damage can take many forms, ranging from specifically oxidized purine and pyrimidine bases, to DNA lesions such as strand breaks, sister chromatid exchanges (SCEs), and the formation of micronuclei [80]. However, the equation "antioxidant = benefit" is not always true. In vivo experiments demonstrated that retinol increases both the humoral and the cell-mediated immune response and could enhance immune surveillance against tumorigenesis [81-83]. Retinol may influence the immune response by quenching free radicals, which could lower the level of immunosuppressing lipid peroxides, alter arachidonic acid metabolism, etc. [82,84]. In the last few years many studies have been conducted to investigate the effects of vitamins on disease prevention. The first results have been encouraging and a wide number of people are taking antioxidant supplements with the aim to improve their health. These studies, initially, have shown that a high consumption of fruit and vegetables decreases risks of lung cancer in healthy individuals and a combination of β-carotene, vitamin E and selenium reduced stomach cancer mortality in China [85,86]. Conversely, supplemental β-carotene alone or in combination with retinol or vitamin E did not have any effect on cancer risk, or increased the development of lung cancer in smokers [87,88]. In the light of these first contrasting result, and also as a consequence of the wide antioxidant consumption in the general population, various systematic reviews to estimate the association between antioxidant use and disease prevention, in particular for primary cancer incidence and mortality, have been issued. These reviews share the opinion that antioxidant supplementation per se does not prevent cancer. On the contrary, some antioxidant elements seem to be harmful fro health. Recent studies have confirmed the relationship between beta-carotene and an increased incidence of cancer among smokers, but not among non-smokers. Moreover, beta carotene supplementation is associated with increased cancer-related mortality [89]. Vitamin E treatment also appears to be associated with a slightly increased incidence of lung cancer [90]. Other studies report that combination of vitamin A and other antioxidants, significantly increases mortality related to neoplastic diseases [91]. According to these studies, selenium would be the only element displaying beneficial effects, as it has been shown that it reduces total cancer incidence, an apparently sex-related effect, as it is predominant among males, rather than in females [89].