UNASSIGNED: The nuclear factor erythroid 2-related factor 2 (Nrf2) is a pivotal transcription factor that controls the expression of numerous cytoprotective genes and regulates cellular defense system against oxidative insults. Thus, activating the Nrf2 pathway is a promising strategy for the treatment of various chronic diseases characterized by oxidative stress.
UNASSIGNED: This review first discusses the biological effects of Nrf2 and the regulatory mechanism of Kelch-like ECH-associated protein 1-Nrf2-antioxidant response element (Keap1-Nrf2-ARE) pathway. Then, Nrf2 activators (2020-present) are summarized based on the mechanism of action. The case studies consist of chemical structures, biological activities, structural optimization, and clinical development.
UNASSIGNED: Extensive efforts have been devoted to developing novel Nrf2 activators with improved potency and drug-like properties. These Nrf2 activators have exhibited beneficial effects in in vitro and in vivo models of oxidative stress-related chronic diseases. However, some specific problems, such as target selectivity and brain blood barrier (BBB) permeability, still need to be addressed in the future.

Introduction: The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is the first line of defense against a plethora of environmental or endogenous deviations in redox metabolism, proteostasis, inflammation, etc. Therefore, pharmacological activation of Nrf2 is a potential therapeutic approach for several diseases related to oxidative stress and inflammation, such as cancer, cardiovascular, and neurodegenerative diseases.Areas covered: The authors first describe the biological function of Nrf2 and the molecular regulatory mechanism of Keap1-Nrf2-ARE ((Kelch-like ECH-Associating protein 1)-Nrf2-(antioxidant response element)). Then, they review recent progress of covalent activators and non-covalent Keap1-Nrf2 protein-protein interaction (PPI) inhibitors from patents and publications in 2017-present, consisting of new chemical molecules, structure optimization of reported activators and progress in preclinical or clinical trials.Expert opinion: Despite significant achievements in the development of Nrf2 activators, the selectivity is the primary consideration. Due to reacting with redox-sensitive cysteines in proteins except for Keap1, electrophilic activators often exhibit off-target effects. For Keap1-Nrf2 PPI inhibitors, how to enhance in vivo efficacy and/or penetrate blood-brain barrier (BBB) to reach central nervous system (CNS) is also challenging. Fragment-based drug discovery (FBDD), carboxylic acid bioisosteric replacement and prodrug approach might be used to circumvent this challenge. Moreover, the possibility of cancer risk caused by Nrf2 activation needs to be considered carefully.

Prostate-specific antigen (PSA) is a serine protease produced by epithelial prostatic cells and its main function is to liquefy seminal coagulum. Currently, PSA is a biomarker for the diagnosis and screening of prostate cancer and it was the first cancer biomarker approved by the FDA. The quantity and serum isoforms of male PSA, allows distinguishing between carcinoma and benign inflammatory disease of the prostate. Initially, it was thought that PSA was produced only by the prostate, and thus, a protein that was expressed exclusively in men. However, several authors report that PSA is a protein that is expressed by multiple non-prostatic tissues not only in men but also in women. Some authors also report that in women, the expression of this protein is highly related to breast and colon cancer and therefore can act as a possible biomarker for early detection, diagnosis and prognosis of these cancers in women. In this review, we will focus on the characteristics of the PSA at a molecular level, its current clinical implications, the expression of this protein in non-prostatic tissues, and its relationship with cancer, especially in women.