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The highly reactive superoxide radicals forms when dioxides interact with air, a process that can be achieved in all living organisms and can then be further purposed depending on its context and the process through which it is metabolized.[1][2] This reaction can occur endogenously through various metabolic pathways and can result in the formation of different reactive oxygen species (ROS), such as hydrogen peroxide (HO), hypochlorite (ClO), peroxynitrite (ONOO), and hydroxyl radical (OH).[3][4][5][1] Historically considered dangerous, free radicals were given the responsibility as the perpetrators of numerous pathophysiological states, such as cardiovascular disease, inflammation, hereditary diseases, aging, and many other diseases.[6] Even though it is known that these diseases thrive under the overproduction of free radicals, superoxides also have a pivotal role in maintaining physiological states. These include defense functions like antibacterial properties and phagocytosis, as well as their ability to act as signaling molecules.[6] Superoxides are also included as part of the process of cell death and cellular disfunction, given their ability to react with distinct biomolecules, such as proteins, lipids, and DNA.[7] These superoxide molecules can be produced in various cell sites, including the cytosol, endoplasmic reticulum, peroxisomes, and mitochondria, the latter generating and compartmentalizing almost 90% of the reactive oxygen species, mainly through coenzyme Q.[8] Given its active part in many of the body’s reactions, intricate regulation is achieved by the enzyme superoxide dismutases (SODs), which catalyzes the deactivation of superoxide and maintains the physiological concentration of superoxides.[3] Due to the complexity and importance of superoxide radicals in various metabolic processes, they play a role in various diseases, including inflammation-driven diseases, atherosclerosis, cancer, and other pathologies that pose a burden to modern-day society.

There are numerous pathological mechanisms in which superoxides play a pivotal role. Oxidative stress has been shown to be one of the major driving factors in cancer and angiogenesis.[10] One of the most studied phenomena is the reperfusion injury, in which the reintroduction of oxygen in tissues can exacerbate its damage, mainly due to the generation of oxygen radicals.[12] Mitochondrial ROS produced during reperfusion injures the mitochondria, disrupting ATP production and dysregulating calcium levels, and increasing mitochondrial membrane permeability.[26] Zinc, known to have antioxidant action, is important in attenuating reperfusion injury in cardiomyocytes by alleviating mitochondrial ROS generation.[27] Its deficiency is associated with oxidative stress in numerous cell types.[27] Also, there has been increasing evidence in recent times that points to the importance of superoxides in carcinogenesis. Research has proven that cancer cells have increased superoxide generation and that this increased concentration may lead to malignant transformation.[10] The reversal of malignant phenotypes is achievable by reducing cellular levels of superoxide; this occurs by the expression of superoxide dismutases that have shown efficacy in reducing tumor growth, metastasis, and other malignant features.[10] Supporting these findings is the fact that some cancer cells lose mitochondrial SODs, with a net increase in the intracellular concentration of superoxide.[5] Interestingly enough, hydrogen peroxide plays an ambivalent role in carcinogenesis. At submicromolar levels, it promotes carcinogenesis, whereas, at micromolar levels, it provides anti-tumoral activities.[10] There is also proof that the overstimulation of NMDA glutamate receptors in neurons leads to an increased amount of superoxide, mediated by intracellular calcium.[28] This specific NMDA receptor stimulation ends in excitotoxic neuronal death, comparable to other calcium-mediated signaling pathways that do not provoke neuronal death.[28]

The reversal of malignant phenotypes is achievable by reducing cellular levels of superoxide; this occurs by the expression of superoxide dismutases that have shown efficacy in reducing tumor growth, metastasis, and other malignant features.[10] Supporting these findings is the fact that some cancer cells lose mitochondrial SODs, with a net increase in the intracellular concentration of superoxide.[5] Interestingly enough, hydrogen peroxide plays an ambivalent role in carcinogenesis. At submicromolar levels, it promotes carcinogenesis, whereas, at micromolar levels, it provides anti-tumoral activities.[10] There is also proof that the overstimulation of NMDA glutamate receptors in neurons leads to an increased amount of superoxide, mediated by intracellular calcium.[28] This specific NMDA receptor stimulation ends in excitotoxic neuronal death, comparable to other calcium-mediated signaling pathways that do not provoke neuronal death.[28] ROS has also been implicated in disrupting the blood-brain barrier, resulting in the entry of toxic substances into the central nervous system and disruption of neuronal homeostasis.[29] The exposure of cells or tissues to peroxynitrite can reduce myocardial contractility, disrupt platelet aggregation, and induce cytotoxicity.[30] Oxidative alterations of endothelial cells and lipoproteins have been implicated in atherogenesis, mediated by the catalysis of transition metal ions such as iron and copper by superoxide.[11]