Reactive oxygen species (ROS) are identified to control the expression and activity of various essential signaling intermediates involved in cellular proliferation, apoptosis, and differentiation. Indeed, ROS represents a double-edged sword in supporting cell survival and death. Many common pathological processes, including various cancer types and neurodegenerative diseases, are inflammation and oxidative stress triggers, or even initiate them. Keap1-Nrf2 is a master antioxidant pathway in cytoprotective mechanisms through Nrf2 target gene expression. Activation of the Nfr2 pathway benefits cells in the early stages and reduces the level of ROS. In contrast, hyperactivation of Keap1-Nrf2 creates a context that supports the survival of both healthy and cancerous cells, defending them against oxidative stress, chemotherapeutic drugs, and radiotherapy. Considering the dual role of Nrf2 in suppressing or expanding cancer cells, determining its inhibitory/stimulatory position and targeting can represent an impressive role in cancer treatment. This review focused on Nrf2 modulators and their roles in sensitizing breast cancer cells to chemo/radiotherapy agents.

Cd ₁ nitrite reductase catalyzes the conversion of nitrite to NO in denitrifying bacteria. Reduction of the substrate occurs at the d ₁ -heme site, which faces on the distal side some residues thought to be essential for substrate binding and catalysis. We report the results obtained by mutating to Ala the two invariant active site histidines, His-327 and His-369, of the enzyme from Pseudomonas aeruginosa . Both mutants have lost nitrite reductase activity but maintain the ability to reduce O ₂ to water. Nitrite reductase activity is impaired because of the accumulation of a catalytically inactive form, possibly because the productive displacement of NO from the ferric d ₁ -heme iron is impaired. Moreover, the two distal His play different roles in catalysis; His-369 is absolutely essential for the stability of the Michaelis complex. The structures of both mutants show ( i ) the new side chain in the active site, ( ii ) a loss of density of Tyr-10, which slipped away with the N-terminal arm, and ( iii ) a large topological change in the whole c-heme domain, which is displaced 20 Å from the position occupied in the wild-type enzyme. We conclude that the two invariant His play a crucial role in the activity and the structural organization of cd ₁ nitrite reductase from P. aeruginosa .