**3. Oxidative Stress**

Oxidative stress is an enclosed physiological pathway regulated by the antioxidant mechanisms. Improper regulation of oxidative stress is correlated with several recurrent pathological or physiological conditions [14]. Oxidative stress can be defined as an imbalance between the generation of harmful free radicals and their removal by the antioxidant defense system. Highly reactive unstable free radicals are composed of many compounds. However, the most common are ROS (superoxide, hydroxile, alcoxile, peroxile, hydrogen peroxide) and reactive nitrogen species (RNS) (nitric oxide, nitrogen dioxide, peroxinitrile); collectively called reactive oxygen and nitrogen species (RONS) [24]. Free radicals are very reactive atoms or molecules that have one or more unpaired electrons in their outer shell and can be formed by the interaction of oxygen with specific molecules [25]. These radicals are produced by the loss or acceptance of an electron in cells, therefore behaving as the oxidants or reductants [26]. The endogenous sources of RONS consist of: nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, myeloperoxidase (MPO), lipoxygenase, and angiotensin II [27]. External sources of RONS are air pollution, tobacco, alcohol, drugs, industrial solvents, etc., which are metabolized to free radicals in the body [28].

NADPH oxidase is a common source of the superoxide anion (O2−) formed by the reduction of one electron of the molecular oxygen by electrons supplied by the NADPH during cellular respiration. Most O2− is catalyzed by superoxide dismutase (SOD) to hydrogen peroxide (H2O2) [29]. H2O2 is not a free radical because it has no unpaired electrons, but via the Fenton or Haber-Weiss reaction, it is able to form very reactive hydroxyl radicals (OH−). Hydroxyl radicals are highly reactive and react especially with phospholipids in cell membranes and proteins [30].

Too much RONS can cause irreversible damage to the biological molecules, proteins, carbohydrates, lipids, RNA and DNA, leading to the spread of many pathological problems and oxidative tissue damage [31]. Antioxidant systems suitable with enzymatic (e.g., SOD, catalase (CAT) and glutathione peroxidase (GPX)) and non-enzymatic (e.g., uric acid, bilirubin, vitamin E, vitamin C, glutathione (GSH), ascorbic acid, and α-tocopherol) processes, both act to reduce the oxidation potential of RONS through direct and indirect mechanisms. Direct antioxidants activate redox reactions and trap and inactivate RONS in a process that is sacrificed and must be regenerated [32]. On the other hand, indirect antioxidants may or may not be redox-active and apply their antioxidant effects via the up-regulation of cytoprotective proteins [32].

The ROS involve many physiological functions. The intracellular concentration of ROS increases transiently in response to a stimulus such as cytokines, growth factors, or other hormones; this pattern is common in many physiological conditions, where the release of ROS is quickly controlled by the antioxidant regulatory mechanisms. If stable or unbalanced, increased oxidative stress may suppress antioxidant capabilities, and the ROS can cause damage [14]. The ROS release is involved in major cellular signaling pathways and allows the transmission of extracellular stimuli and changes in cell physiology by modulating the transcription of some genes or by post-transcriptional modulation. To date, "redox-responsive" signaling pathways have been implicated in important functions such as nitric oxide (NO) generation, vascular tone regulation and neurotransmission, cell adhesion, immune responses, and hypoxia and apoptosis [11,33].
