Inhibiting NADPH Oxidases to Target Vascular and Other Pathologies: An Update on Recent Experimental and Clinical Studies

Abstract

Reactive oxygen species (ROS) can be beneficial or harmful in health and disease. While low levels of ROS serve as signaling molecules to regulate vascular tone and the growth and proliferation of endothelial cells, elevated levels of ROS contribute to numerous pathologies, such as endothelial dysfunctions, colon cancer, and fibrosis. ROS and their cellular sources have been extensively studied as potential targets for clinical intervention. Whereas various ROS sources are important for different pathologies, four NADPH oxidases (NOX1, NOX2, NOX4, and NOX5) play a prominent role in homeostasis and disease. NOX1-generated ROS have been implicated in hypertension, suggesting that inhibition of NOX1 may be a promising therapeutic approach. NOX2 and NOX4 oxidases are of specific interest due to their role in producing extra- and intracellular hydrogen peroxide (H2O2). NOX4-released hydrogen peroxide activates NOX2, which in turn stimulates the release of mitochondrial ROS resulting in ROS-induced ROS release (RIRR) signaling. Increased ROS production from NOX5 contributes to atherosclerosis. This review aims to summarize recent findings on NOX enzymes and clinical trials inhibiting NADPH oxidases to target pathologies including diabetes, idiopathic pulmonary fibrosis (IPF), and primary biliary cholangitis (PBC).

Cancer Metabolism: The Role of ROS in DNA Damage and Induction of Apoptosis in Cancer Cells

“…In addition, the generation of ROS also pends on the regulation of NADPH oxidases (NOXs), nitric oxide synthase (NOS) xanthine oxidase. Among them, NOXs are the main regulatory enzymes of ROS re tion [47]. Research studies have shown that NOX1 expression significantly increase regulation of O2 − and maintains the proliferative phenotype of colon cancer cells [48 In addition, there are both tumor cells and a variety of normal cells in the tumor m environment, in which stromal cell cancer-associated fibroblast-derived H2O2 lead extracellular oxidative stress and promotes tumor growth and invasion [50].…”

High Throughput Confined Migration Microfluidic Device for Drug Screening

“…[ 51 ] Several NOXs, and their regulatory subunits, show markedly increased expression in many types of human tumors or cancer cell lines cultured at different stages of tumorigenesis. [ 52 ] We have revealed that the NOX inhibitor DPI could significantly suppress cancer cell‐confined migration. Previous work demonstrated that DPI could induce senescence of breast cancer and colon cancer cells.…”

Bioinformatics Analysis of the Cross-talk Between Idiopathic Pulmonary Fibrosis and Hashimoto's Thyroiditis on the Hub Genes and Key Pathways

“…Additionally, IPF patients have altered CD8 expression, which destroys the trachea and soft tissues [31] and is correlated with the severity and extent of the disease [25], as well as a bad prognosis [32]. CYBB is involved in the initiation of pulmonary fibrosis, and its upregulation leads to elevated levels of mitochondrial and NADPH oxidase reactive oxygen species in IPF [2,33]. The upregulation of CYBB expression in HT patients may be related to the activation of phagocytosis induction after oxidative stress stimulation [30,34].…”