Molecular insights of NADPH oxidases and its pathological consequences

Abstract

Reactive oxygen species (ROS), formed by the partial reduction of oxygen, were for a long time considered to be a byproduct of cellular metabolism. Since, increase in cellular levels of ROS results in oxidative stress leading to damage of nucleic acids, proteins, and lipids resulting in numerous pathological conditions; ROS was considered a bane for aerobic species. Hence, the discovery of NADPH oxidases (NOX), an enzyme family that specifically generates ROS as its prime product came as a surprise to redox biologists. NOX family proteins participate in various cellular functions including cell proliferation and differentiation, regulation of genes and protein expression, apoptosis, and host defence immunological response. Balanced expression and activation of NOX with subsequent production of ROS are critically important to regulate various genes and proteins to maintain homeostasis of the cell. However, dysregulation of NOX activation leading to enhanced ROS levels is associated with various pathophysiologies including diabetes, cardiovascular diseases, neurodegenerative diseases, ageing, atherosclerosis, and cancer. Although our current knowledge on NOX signifies its importance in the normal functioning of various cellular pathways; yet the choice of ROS producing enzymes which can tip the scale from homeostasis toward damage, as mediators of biological functions remain an oddity. Though the role of NOX in maintaining normal cellular functions is now deemed essential, yet its dysregulation leading to catastrophic events cannot be denied. Hence, this review focuses on the involvement of NOX enzymes in various pathological conditions imploring them as possible targets for therapies. Significance of the study The NOXs are multi‐subunit enzymes that generate ROS as a prime product. NOX generated ROS are usually regulated by various molecular factors and play a vital role in different physiological processes. The dysregulation of NOX activity is associated with pathological consequences. Recently, the dynamic proximity of NOX enzymes with different molecular signatures of pathologies has been studied extensively. It is essential to identify the precise role of NOX machinery in its niche during the progression of pathology. Although inhibition of NOX could be a promising approach for therapeutic interventions, it is critical to expand the current understanding of NOX's dynamicity and shed light on their molecular partners and regulators.

Inhibition of Lipopolysaccharide-Induced Inflammatory and Oxidative Responses by Trans-cinnamaldehyde in C2C12 Myoblasts

“…For Nrf-2 to act as a transcription factor, it must be liberated from Kelch-like ECH-associated protein 1, a negative regulator of Nrf2, in the cytoplasm and phosphorylated before translocation to the nucleus 61 , 62 . Unlike HO-1, NOXs are key enzymes involved in the production of ROS as important regulators of redox homeostasis 63 , 64 . NOX consists of seven members, of which NOX2 acts as a major contributor of ROS generation during skeletal muscle contraction 65 , 66 .…”

NADPH Oxidases: Redox Regulators of Stem Cell Fate and Function

“…They are involved in many processes, including host defense, proliferation, regulation of gene expression, wound healing, and cell differentiation during embryogenesis. However, in case of uncontrolled increased activation or downregulation, pathological events occur [ 6 ], such as several degenerative and inflammatory diseases and the development and progression of cancer [ 7 ].…”

Transforming Growth Factor-β and Oxidative Stress in Cancer: A Crosstalk in Driving Tumor Transformation

“…ROS derived from NOX can act by modulating various metabolic events, in particular gene expression, proliferation, cell migration, and angiogenesis [ 30 ]. In cancer cells, it has been demonstrated that oxidative stress leading to tumor initiation or progression may result from overproduction of ROS by members of NOX [ 31 ]. Among the different NOX isoforms, NOX 2 and 4 when deregulated have been associated with cancer; particularly, NOX4 overexpression has been shown in different types of cancers, such as renal and pancreatic cancers, and in glioblastoma and invasive breast cancers [ 31 ].…”

“…In cancer cells, it has been demonstrated that oxidative stress leading to tumor initiation or progression may result from overproduction of ROS by members of NOX [ 31 ]. Among the different NOX isoforms, NOX 2 and 4 when deregulated have been associated with cancer; particularly, NOX4 overexpression has been shown in different types of cancers, such as renal and pancreatic cancers, and in glioblastoma and invasive breast cancers [ 31 ]. However, conflicting evidence also suggests a role for NOX4 as a tumor suppressor: it has been shown that genetic deletion of NOX4 enhances cancerogen-induced formation of solid tumors [ 32 ]; moreover, NOX4 has been demonstrated to inhibit hepatocyte proliferation and liver cancer progression [ 33 ].…”