Importantly, SDG formulations were safely administered to humans intended for 624 weeks with no reported toxicity and secondary lignan metabolites were detectable in biological fluids [37, 38]. protein levels of antioxidant HO-1, GSTM1 and NQO1. Our results identify the potent radioprotective properties from the synthetic biphenolic SDG, preventing DNA damage and enhancing the antioxidant capacity of normal lung cells; thus, rendering SDG a potential radioprotector against radiation exposure. Keywords: antioxidant, DNA damage, flaxseed, ionizing radiation, lignan, phenolic, radioprotection, SDG == 1 . Introduction == Fruits, vegetables, cereals and beverages contain more than 8000 natural compounds that are characterized as polyphenols [1]. Depending on the number of their phenolic rings and other structural characteristics, polyphenols are classified as phenolic acids, flavonoids, stilbenes and lignans [1]. Consumption of polyphenols and the bioavailability of their secondary metabolites has been related to the protection against a variety of pathological conditions including carcinogenesis, cardiovascular diseases, diabetes, osteoporosis and neurodegenerative diseases [1]. The generation of reactive oxygen species (ROS) deregulates the endogenous antioxidant mechanisms in cells, PNRI-299 leading to macromolecule damage, characterized in part by lipid peroxidation, DNA-protein crosslinks, base modifications, adduct formation and DNA single- and double-strand Rabbit Polyclonal to MARK breaks [2, 3]. These modifications initiate complex signal transduction pathways such as those involved in DNA repair, cell cycle arrest and induction of apoptosis [4]. Protection of normal tissue from radiation-induced damage such as that occurring by accidental publicity or as side effect of conventional radiotherapy to treat malignancies [5] is of great importance. Currently, there is an unmet need to develop a safe and effective radioprotecting pharmacological agent [6, 7]. A large number of potential radioprotective agents have been reported, but their high cost, serious side effects and toxicity have limited their clinical usefulness [4, 8]. On the other hand, natural compounds, especially polyphenolics, have been tested as potential radioprotectors, due to their antioxidant, anti-inflammatory, antimicrobial, immunomodulatory and anti-carcinogenic activities as well as their low toxicity profile and high availability. Polyphenolic compounds can act as free radical scavengers and inhibitors of lipid peroxidation. They upregulate pro-survival factors PNRI-299 and cytoprotective antioxidant enzymes, as well as modulate DNA repair [6, 9]. For the past few years, our group has been evaluating the protective effects of dietary flaxseed (FS) supplementation in preclinical murine models of oxidative lung damage such as hyperoxia, acid aspiration injury [10], and ischemia/reperfusion injury. We decided PNRI-299 that the protective effects of FS may be because of in part to its ability to enhance antioxidant enzyme expression in lung tissues [10, 11]. Importantly, dietary FS ameliorated the adverse effects of thoracic radiation when given both prior to publicity [12] as well as post-exposure [13]. In these studies, dietary flaxseed decreased radiation-induced oxidative lung tissue damage, decreased lung inflammation and prevented pulmonary fibrosis. We have further characterized the radioprotective effects of the lignan component (FLC) of wholegrain flaxseed, enriched in the phenolic secoisolariciresinol diglucoside (SDG). The antioxidant and free radical scavenging properties of SDG are well documented [14, 15] which is of paramount importance as the free radical scavenging ability of a compound can be directly related to its radioprotective efficacy. In an early pilot study on lung endothelial cells, SDG exhibited free radical scavenging properties when cells were exposed to gamma-irradiation [12]. Importantly, the entire flaxseed lignan component (FLC) PNRI-299 enriched in SDG, mediated radioprotection [16] and radiation mitigation [17] in mice. We recently chemically synthesized SDG (LGM2605) to allow scalable synthesis intended for evaluation in large scale experiments [18]. We confirmed potent free radical scavenging and antioxidant properties of LGM2605, comparable to the commercially available SDG. We extended our evaluation of synthetic SDG and further confirm DNA radioprotective properties from the synthetic phenolic in cell free systems [19]. However , characterization of the radioprotective properties of SDG in cells or tissues has not yet been evaluated. This study was performed in order to determine the radioprotective ability of the.