NRF2 and NF-қB interplay in cerebrovascular and neurodegenerative disorders: Molecular mechanisms and possible therapeutic approaches

Abstract

Electrophiles and reactive oxygen species (ROS) play a major role in modulating cellular defense mechanisms as well as physiological functions, and intracellular signaling. However, excessive ROS generation (endogenous and exogenous) can create a state of redox imbalance leading to cellular and tissue damage (Ma and He, 2012) [1]. A growing body of research data strongly suggests that imbalanced ROS and electrophile overproduction are among the major prodromal factors in the onset and progression of several cerebrovascular and neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), stroke, Alzheimer's disease (AD), Parkinson's disease (PD), and aging (Ma and He, 2012; Ramsey et al., 2017; Salminen et al., 2012; Sandberg et al., 2014; Sarlette et al., 2008; Tanji et al., 2013) [1–6]. Cells offset oxidative stress by the action of housekeeping antioxidative enzymes (such as superoxide dismutase, catalase, glutathione peroxidase) as well direct and indirect antioxidants (Dinkova-Kostova and Talalay, 2010) [7]. The DNA sequence responsible for modulating the antioxidative and cytoprotective responses of the cells has been identified as the antioxidant response element (ARE), while the nuclear factor erythroid 2-related factor (NRF2) is the major regulator of the xenobiotic-activated receptor (XAR) responsible for activating the ARE-pathway, thus defined as the NRF2-ARE system (Ma and He, 2012) [1]. In addition, the interplay between the NRF2-ARE system and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB, a protein complex that controls cytokine production and cell survival), has been further investigated in relation to neurodegenerative and neuroinflammatory disorders. On these premises, we provide a review analysis of current understanding of the NRF2-NF-ĸB interplay, their specific role in major CNS disorders, and consequent therapeutic implication for the treatment of neurodegenerative and cerebrovascular diseases.

Antioxidant Defence Systems and Oxidative Stress in Poultry Biology: An Update

“…In general, induction of these programs is associated with upregulation of various protective mechanisms including molecular chaperones, antioxidant and drug-metabolizing enzymes, proteins responsible for the repair and clearance of damaged macromolecules as well as for the maintenance of cell structure, redox and intermediary metabolism [253]. It is clear that Nrf2 and NF-κB have interactive expression and activity to coordinate anti-oxidative and inflammatory responses, but it is not yet known how this interconnection takes place [301]. Thus, stress-associated changes in redox balance and in activities of transcription factors such as Nrf2/Keap1 and NF-κB/ IκB/IKK provide adaptive cell responses to oxidants and a variety of stress stimuli through regulation of gene expression under both physiological and pathological conditions [302].…”

Epigenetic treatment of dermatologic disorders

“…Representing the outermost surface of the body, skin is uniquely vulnerable to a plethora of environmental insults. Exposure to harmful chemicals, xenobiotics, oxidative stress, and solar UV‐radiation is mitigated by various protective mechanisms that rely on signaling networks and the expression of proteins involved in the detoxification of compounds or reactive oxygen species (Dinkova‐Kostova et al, ; Dodson et al, ; Hiebert et al, ; Jadkauskaite et al, ; Raghunath et al, ; Siegenthaler et al, ; Sivandzade, Prasad, Bhalerao, & Cucullo, ; Tonelli, Chio, & Tuveson, ; Vega, Krajisnik, Zhang, & Wondrak, ; Yamamoto, Kensler, & Motohashi, ).…”

“…Not surprisingly, there is great interest in pharmacological modulators of Nrf2 that could be developed into therapeutics for the treatment and prevention of disease (Buendia et al, ; Cuadrado et al, ; Dodson et al, ; Du et al, ; Gacesa et al, ; Kumar, Kim, More, Kim, & Choi, ; Lu, Ji, Jiang, & You, ; Rabbani, Ellison, et al, ; Sivandzade et al, ; Sklirou, Papanagnou, Fokialakis, & Trougakos, ; Sova & Saso, ; Vega, Dodson, Chapman, & Zhang, ; Yamamoto et al, ; Zhang et al, ), including skin disorders (Dodson et al, ; Ferrándiz, Nacher‐Juan, & Alcaraz, ; Gacesa et al, ; Kumar et al, ; Lu et al, ; Penta, Somashekar, & Meeran, ; Rabbani, Ellison, et al, ; Son et al, ; Yamamoto et al, ). Examples of natural products known to induce epigenetic Nrf2‐activating effects are shown in Figure (Bambouskova et al, ; Dodson et al, ; Fazzari et al, ; Fratantonio et al, ; Garaude, ; Gill, Raman, Yost, Garrett, & Vedam‐Mai, ; Gu et al, ; Iranshahy, Iranshahi, Abtahi, & Karimi, ; Irwin, Moos, Faller, Steliou, & Pinkert, ; Kumar et al, ; Li et al, ; Mathers et al, ; Matzinger, Fischhuber, & Heiss, ; Moos, Maneta, et al, ; Moos et al, ; Rigacci & Stefani, ; Rusu, Gheldiu, Mocan, Vlase, & Popa, ; Sivandzade et al, ; Steliou, Boosalis, Perrine, Sangerman, & Faller, ; Steliou, Faller, Pinkert, Irwin, & Moos, ; Tsujita et al, ). Some products are endogenously made, like the prostaglandins and l ‐carnitine as well as butyric, α‐lipoic, fumaric, itaconic, and the nitro‐fatty acids.…”

“…In an attempt to overcome clinical and pharmacological shortfalls, such as efficacy and/or safety issues associated with stochastic off‐target adverse effects that were exposed in clinical trials (Dodson et al, ; Patra, Mukhopadhyay, Sarkar, Mukherjee, & Chawla‐Sarkar, ; Sova & Saso, ), a wide array of synthetic and semisynthetic Nrf2‐modulators were prepared (Deck, Whalen, Hunsaker, Royer, & Jagt, ; Sivandzade et al, ; Sklirou et al, ; Sova & Saso, ). Three notable examples of synthetic Nrf2‐activating compounds that advanced to clinical trials are shown in Figure (Cuadrado et al, ; Gacesa et al, ; Naidu et al, ; Patra et al, ; Rabbani, Ellison, et al, ; Sklirou et al, ; Sova & Saso, ).…”

“…Although mitochondrial dysfunction adversely affects primarily nonregenerative tissue, the neuro- More than 250 genes (of approximately 20,000 protein-coding genes in the human genome (Salzberg, 2018)) are impacted by changes in the expression of the transcription factor nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) (Dodson et al, 2019). Nrf2, a member of the Cap'n'Collar basic-region leucine zipper (CNC-bZIP) transcription factor family (Chatterjee et al, 2018;Chevillard & Blank, 2011;Dodson et al, 2019;Loboda, Damulewicz, Pyza, Jozkowicz, & Dulak, 2016;Raghunath et al, 2018;Siegenthaler et al, 2018;Sivandzade et al, 2019;Tonelli et al, 2018;Yamamoto et al, 2018), binds the nuclear antioxidant response element (ARE) in crosstalk with many other signaling cascades that coordinate a multitude of cellular processes, including redox balance and protective antioxidant phases I-III drug/xenobiotic detoxification responses, protein homeostasis, DNA repair, carbohydrate and lipid metabolism, iron homeostasis, transcriptional regulation, and mitochondrial function (Dodson et al, 2019).…”