Oxeiptosis is a novel cell death pathway that was introduced in 2018. As a form of regulated cell death, it operates independently of caspases and is induced by ROS. Distinguished from other cell death pathways such as apoptosis, necroptosis, pyroptosis, and ferroptosis, oxeiptosis features unique damage causes pivotal genes, and signaling pathways (KEAP1/PGAM5/AIFM1). Emerging studies indicate that oxeiptosis plays a significant role in the progression of various diseases and its regulation could serve as a promising therapeutic target. However, the precise molecular mechanisms underlying oxeiptosis remain to be fully elucidated. In this mini-review, we systematically summarize the latest developments in oxeiptosis-related diseases while detailing the molecular mechanisms and regulatory networks of oxeiptosis. These insights offer a foundation for a deeper understanding of oxeiptosis.

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.

Coronavirus disease 2019 (COVID-19) is an infectious disease with approximately 517 million confirmed cases, with the average number of cases revealing that patients recover immediately without hospitalization. However, several other cases found that patients still experience various symptoms after 3-12 weeks, which is known as a long COVID syndrome. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can activate nuclear factor kappa beta (NF-κβ) and unbind the nuclear factor erythroid 2-related factor 2 (Nrf2) with Kelch-like ECH-associated protein 1 (Keap1), causing inhibition of Nrf2, which has an important role in antioxidant response and redox homeostasis. Disrupting the Keap1-Nrf2 pathway enhances Nrf2 activity, and has been identified as a vital approach for the prevention of oxidative stress and inflammation. Hence, natural antioxidants from various sources have been identified as a promising strategy to prevent oxidative stress, which plays a role in reducing the long COVID-19 symptoms. Oxygen-rich natural antioxidant compounds provide an effective Nrf2 activation effect that interact with the conserved amino acid residues in the Keap1-binding pocket, such as Ser602, Ser363, Ser508, and Ser555. In this review, the benefits of various natural antioxidant compounds that can modulate the Nrf2 signaling pathway, which is critical in reducing and curing long COVID-19, are highlighted and discussed.

The recent outcry in the search for direct keap1 inhibitors requires a quicker and more effective drug discovery process which is an inherent property of the Computer Aided Drug Discovery (CADD) to bring drug candidates into the clinic for patient\'s use. This Keap1 (negative regulator of ARE master activator) is emerging as a therapeutic strategy to combat oxidative stress-orchestrated diseases. The advances in computer algorithm and compound databases require that we highlight the functionalities that this technology possesses that can be exploited to target Keap1-Nrf2 PPI. Therefore, in this review, we uncover the in silico approaches that had been exploited towards the identification of keap1 inhibition in the light of appropriate fitting with relevant amino acid residues, we found 3 and 16 other compounds that perfectly fit keap1 kelch pocket/domain. Our goal is to harness the parameters that could orchestrate keap1 surface druggability by utilizing hotspot regions for virtual fragment screening and identification of hotspot residues.

Alzheimer\'s disease (AD) is a progressive neuronal/cognitional dysfunction, leading to disability and death. Despite advances in revealing the pathophysiological mechanisms behind AD, no effective treatment has yet been provided. It urges the need for finding novel multi-target agents in combating the complex dysregulated mechanisms in AD. Amongst the dysregulated pathophysiological pathways in AD, oxidative stress seems to play a critical role in the pathogenesis progression of AD, with a dominant role of nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein-1 (Keap1)/antioxidant responsive elements (ARE) pathway. In the present study, a comprehensive review was conducted using the existing electronic databases, including PubMed, Medline, Web of Science, and Scopus, as well as related articles in the field. Nrf2/Keap1/ARE has shown to be the upstream orchestrate of oxidative pathways, which also ameliorates various inflammatory and apoptotic pathways. So, developing multi-target agents with higher efficacy and lower side effects could pave the road in the prevention/management of AD. The plant kingdom is now a great source of natural secondary metabolites in targeting Nrf2/Keap1/ARE. Among natural entities, phenolic compounds, alkaloids, terpene/terpenoids, carotenoids, sulfur-compounds, as well as some other miscellaneous plant-derived compounds have shown promising future accordingly. Prevailing evidence has shown that activating Nrf2/ARE and downstream antioxidant enzymes, as well as inhibiting Keap1 could play hopeful roles in overcoming AD. The current review highlights the neuroprotective effects of plant secondary metabolites through targeting Nrf2/Keap1/ARE and downstream interconnected mediators in combating AD.

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.

Pancreatic cancer (PC) is one of the most fatal diseases with a very high rate of metastasis and low rate of survival. Despite the advances in understanding this devastating disease, PC still accounts for 3% of all cancers and causes almost 7% of death of cancer patients. Recent studies have demonstrated that the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) and its key negative regulator Kelch-like ECH-associated protein 1 (Keap1) are dysregulated in PC and the Keap1-Nrf2 pathway is an emerging target for PC prevention and therapy. Indeed, Nrf2 plays an either tumor-suppressive or promoting function in PC, which depends on the developmental stages of the disease and the cellular context. Several natural-product Nrf2 activators have been developed to prevent pancreatic carcinogenesis, while the Nrf2 inhibitors have been examined for their efficacy in inhibiting PC growth and metastasis and reversing chemoresistance. However, further preclinical and clinical studies for determining the effectiveness and safety of targeting the Keap1-Nrf2 pathway for PC prevention and therapy are warranted. In this review, we comprehensively discuss the dual roles of the Keap1-Nrf2 signaling pathway in PC as well as the current targeting strategies and known activators and inhibitors of Nrf2. We also propose new strategies that may be used to address the current issues and develop more specific and more effective Nrf2 activator/inhibitors for PC prevention and therapy.

Nrf2 is a master transcriptional regulator of antioxidant and cytoprotective pathways. Currently in its third decade, research on Nrf2 has expanded to encompass not only basic but also clinical studies. In the present bibliometric review, we employed the VOSviewer tool to describe the existing Nrf2 literature landscape. As of July 2019, 11,931 papers on Nrf2 were listed in the \"Web of Science\" database, with more than 1000 new papers published each year. As expected, terms related to oxidative stress and antioxidant molecules occur very often in the Nrf2 literature throughout the years. Interestingly, there is also a gradual increase in the occurrence of terms related to diseases or to natural compounds, the most prominent being sulforaphane, curcumin, and resveratrol that modulate the Nrf2 pathway. Going beyond molecular biology/biochemistry and related fields, Nrf2 research has begun to spread into more clinical areas like endocrinology/metabolism, cardiology, and nephrology, likely reflecting an increased interest in clinical applications of Nrf2 pathway activators. China has become the most prolific producer of Nrf2 papers the last five years followed by the USA and Japan, a reverse pattern compared to the past. In conclusion, Nrf2 is the subject of a globally active research field that keeps growing and extends from bench to bedside.

Both melatonin and proteasome inhibitors upregulate antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GP), hemoxygenase 1 (HO-1), and NADPH:quinone oxidoreductase (NQO1). Recent evidence suggests that the antioxidant action of both melatonin and proteasome inhibitors involves the Keap1-ARE (Keap1 antioxidant response element) pathway via the upregulation of Nrf2. Melatonin and proteasome inhibitors suppress the degradation of Nrf2 and also enhance its nuclear translocation. In the nucleus Nrf2, together with a cofactor, stimulates the transcription of antioxidant enzymes and detoxifying enzymes. The ligase (E3) complex (Keap1-Cul3-Rbx1) responsible for ubiquitinating Nrf2, prior to proteasomal degradation, also ubiquitinates IkB kinase and the antiapoptotic factor Bcl-2, and possibly additional proteins. In various systems, NF-κB, which is inhibited by IkBα, is downregulated by proteasome inhibitors as well as by melatonin. Similarly in leukemic cells, Bcl-2 is down-regulated by the proteasome inhibitor, bortezomib, and also by melatonin. Thus melatonin administration modulates the activity of three separate substrates of the Keap1-Cul3-Rbx1 ubiquitin ligase. These facts could be accounted for by the hypothesis that melatonin interacts with the ubiquitin ligase complex or, more likely, by the hypothesis that melatonin acts as a proteasome inhibitor. A recent study documented that melatonin acts as a proteasome inhibitor in cancer cells as well as inhibiting chymotrypsin-like activity in cell-free systems of these cells. Further studies, however, are needed to clarify the interaction of melatonin and the ubiquitin-proteasome system as they relate to oxidative stress.