Oxidative stress. Oxidative stress is either generated through an imbalance in the generation and removal of ROS or from a systemic inability to remove ROS-induced damage in a cell (Xxxxxx et al., 2013). The main free radicals in a cell are ROS and reactive nitric species (RNS), both by-products of aerobic metabolism and mainly produced by the mitochondrial electron transfer chain and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Increased levels of oxidative stress markers have been found in the spinal cord and motor cortex but also serum, CSF and urine of pre- and post-mortem samples of ALS patients (Shaw et al., 1995b; Xxxx et al., 1997; Xxxxxxxx et al., 1997; Xxxxx et al., 1998; Xxxxxxx et al., 2004; Xxxxxxxxx et al., 2008). Oxidative damage to proteins, lipids and DNA were found in post-mortem tissue of SALS, mutant SOD1 related FALS cases and mutant SOD1 mice (Shaw et al., 1995a; Xxxxxxxxxxx et al., 1996; Xxxxxxx et al., 2001; Xxx et al., 2004). The cause of oxidative stress in ALS is unclear but might involve mitochondria, an activation of microglial regulated superoxide production and signalling via NADPH oxidase (Xxxxxx and Xxxxxx, 2007). NADPH oxidase is upregulated in some cases of ALS and in mutant SOD1 transgenic mouse models (Xx et al., 2006; Xxxxxx et al., 2007). Although SOD1 catalyses the conversion of superoxide into hydrogen peroxide and oxygen, the pathogenesis of ALS is not thought to be related to the enzymatic activity of SOD1. This is because modulating SOD1 activity in mutant SOD1 transgenic mice does not influence disease onset or progression (Xxxxxx et al., 1998). Alterations in the redox homeostasis also regulate gene expression of transcriptional factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and hypoxia-inducible factor 1 α (HIF-1α). These transcription factors help maintain homeostasis by regulating gene expression and have a redox regulated cysteine residue in their DNA binding site which could be influenced by the presence of ROS (Xxxxxxx, 2002). A dysregulation of NF-κB and HIF-1α was found in SALS patients (Xxxxxx et al., 2011; Xxxxxxxxx et al., 2011). Thus, oxidative stress probably aggravates other pathophysiological processes that have been observed in ALS such as excitotoxicity, mitochondrial impairment, ER stress, protein aggregation and alterations in astrocytic and microglial signalling (Xxxx et al., 2003; Xxx and Xxxxx, 2004; Xxxxxxxx et al., 2005; Xxxxxxxx et al., 2009; Xxxxx ...
Oxidative stress and Cancer Cancer is a multistep process that involves multiple molecular and cellular carcinogenesis mechanisms [106]. Oxidative stress has long been known as a trigger for tumor development. Cells in every organism are exposed to various oxidizing agents both endogenous and exogenous sources. It is estimated that each human cell is exposed to approximately 105 oxidative attacks a day from hydroxyl radical and other reactive oxygen species [107-109]. As illustrated in Figure 1.3, oxidative stress may cause DNA, RNA, protein, and/or lipid damage, leading to chromosomal instability, genetic mutations, and/or modulation of cell growth that result in cancer [106]. Oxidative DNA damage is a major source of DNA mutations, with over one hundred oxidative adducts having been i entified [110, 111]. It is estimated that on average there are several thousands of DNA alterations per day in each cell caused by both endogenous and exogenous oxidative s ress [112]. The most well-established and abundant oxidative DNA base lesion is 8- hydroxydeoxy guanosine (8-OH-dG) [113].
Oxidative stress and Aging The free-radical theory of aging postulates that the process of aging process is the result of cumulative damage induced by free radical production in aerobic organisms [28]. This theory is based on the fact that the random deleterious effects of free radicals produced during aerobic metabolism accumulate over time, leading damage to DNA, protein, and lipids [130]. Under normal physiological conditions, electrons are constantly leaking from the electron transport chain and interact with oxygen to produce superoxide radicals [131]. The primary site of radical oxygen damage from these superoxide radicals is mitochondrial DNA (mtDNA). As the mtDNA damage accumulates over time, mitochondria are eventually shutting down, causing cells to die, and organisms to age [131]. Such accumulating damage is believed to be crucial in the process of aging process [132, 133]. Disappointing Results from Epidemiological Studies of Anti-oxidants While a considerable body of evidence from basic science and animal studies supports the profound role of oxidative stress in pathogenesis of chronic diseases, outcomes of large, prospective, randomized clinical trials on the association between anti-oxidant supplements and these diseases have remained largely inconclusive. The following sections summarize the largest, most highly publicized trials of antioxidant supplements conducted to date The ATBC (Alpha-Tocopherol Beta-Carotene) [134] trial was one of the first large, randomized clinical trials showing that supplemental α-tocopherol and β-carotene have no preventive effect on the risk of cancer or cardiovascular diseases. The ATBC trial was conducted among 29,133 male smokers in Finland, and found no reduction in CHD morbidity and mortality with vitamin E (50 mg daily) and/or β-carotene (20 mg daily) supplementation. Furthermore, there was a significant 18% increase in the incidence of lung cancer among those with β-carotene supplements. Importantly, the β- carotene dosage of 20 mg/day was substantially higher than that of typical Finnish diet [32]. Unexpected increases in risk of both lung cancer and cardiovascular disease mortality were also observed in the CARET (Beta-Carotene and Retinol Efficacy Trial), a multicenter, randomized, double-blinded, placebo-controlled trial conducted in the United States [135]. In the CARET study, a total of 18,314 current and former smokers, and workers exposed to asbestos were randomized to receive 30 mg of β-carotene and 25,000 IU of...
