Reactive oxygen species (ROS) are cellular signals generated ubiquitously by all mammalian cells, but their relative unbalance triggers also diseases through intracellular damage to DNA, RNA, proteins, and lipids. NADPH oxidases (NOX) are the only known enzyme family with the sole function to produce ROS. The NOX physiological functions concern host defence, cellular signaling, regulation of gene expression, and cell differentiation. On the other hand, increased NOX activity contributes to a wide range of pathological processes, including cardiovascular diseases, neurodegeneration, organ failure, and cancer. Therefore targeting these enzymatic ROS sources by natural compounds, without affecting the physiological redox state, may be an important tool. This review summarizes the current state of knowledge of the role of NOX enzymes in physiology and pathology and provides an overview of the currently available NADPH oxidase inhibitors derived from natural extracts such as polyphenols. 1. ROS Involvement in Cell Pathophysiology Oxidative stress is a molecular deregulation in reactive oxygen species (ROS) metabolism involved in the pathogenesis of several diseases. Oxidative stress is no longer considered as a simple imbalance between the production and scavenging of ROS, but as a dysfunction of enzymes involved in ROS production [1]. Reactive oxygen species such as superoxide, hydrogen peroxide, and peroxynitrite are generated by all mammalian cells and have been recognized for many decades as causing cell damage by oxidation and nitration of macromolecules, such as DNA, RNA, proteins, and lipids. Moreover, ROS can also promote cell signaling pathways modulated by growth factors and transcription factors, therefore regulating cell proliferation, differentiation, and apoptosis [2], which are important processes for proper cell functioning [3]. At physiological concentrations they facilitate the signal transduction derived from receptor tyrosine kinases and transcriptional factors such as NF-E2-related factor-2 (Nrf-2) leading to antioxidant gene expression [4]. The instability of an unpaired electron in its valence shell causes the high reactivity of superoxide. Superoxide has been implicated in numerous pathological processes, including cancer, cardiovascular disease (e.g., atherosclerosis and stroke), and acute and chronic diseases due to microbial infections. Superoxide can directly or indirectly damage DNA through oxidation [5], directly inactivate cellular antioxidants enzymes such as catalase and glutathione peroxidase [6], and activate
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