Targeting NRF2 in Type 2 diabetes mellitus and depression: Efficacy of natural and synthetic compounds
Introduction
A growing body of literature has explored the bidirectional association between depression and Type 2 diabetes mellitus (T2DM) and the underlying pathophysiological mechanisms that fuel this relationship (Berge and Riise, 2015; Pan et al., 2010; Renn et al., 2011). Both conditions are serious, debilitating, and significantly impair the affected individual's life as well as negatively impact the economy and social functioning. The most intensively researched pathophysiological factor linking these two disorders is stress, especially oxidative stress, which seems to be a common denominator of this association. Table 1 compiles relevant clinical studies that report oxidative stress in patients with depression or Type 2 Diabetes. Increased generation of reactive oxygen species (ROS) and the dampening of the antioxidant defense system may result from other factors such as chronic psychological and physiological stress, inflammation, and insulin resistance. These may, in turn, further propel the disease condition (Réus et al., 2019).
Nuclear factor erythroid 2-related factor 2 (NRF2), a basic leucine zipper transcription factor of the Cap-N-Collar family of proteins, is fundamental for maintaining redox homeostasis in the body. It is considered the master regulator of antioxidative responses and has been implicated in various diseases, including depression and T2DM (Stenvinkel et al., 2020). It is closely associated with the Kelch-like ECH-associated protein 1 (KEAP1), its endogenous cytosolic repressor protein (Itoh et al., 1999). During homeostatic conditions, NRF2 is bound to KEAP1 in the cytosol and is subjected to proteasomal degradation. Following various stress conditions, it dissociates from KEAP1 and translocates into the nucleus, where it forms a heterodimer with the small Maf protein, which then binds to the antioxidant response element (ARE) enhancer sequences of target antioxidant and metabolic genes. NRF2 has been found to influence the expression of a large number of genes that encode proteins responsible for detoxification, redox homeostasis, stress response, and metabolism (Itoh et al., 1997). Fig. 1 provides a brief schematic illustration of the NRF2 signaling pathway. In the mitochondria, NRF2 acts as a sensor of redox imbalance and preserves mitochondrial integrity by associating with the outer mitochondrial membrane. Such a response was absent in NRF2-knockout (KO) mice (Strom et al., 2016).
NRF2 signaling is disrupted in both depression and T2DM, as depicted in Fig. 2 and Fig. 3. The expression levels of both NRF2 and KEAP1 were significantly lower in the post-mortem brains of patients who suffered from major depressive disorder (MDD), schizophrenia, and bipolar disorder (J. Zhang et al., 2018). In patients with prediabetes and T2DM, low blood NRF2 levels were associated with redox imbalance (Jiménez-Osorio et al., 2014). Further, NRF2 expression was significantly lowered in the hippocampus of diabetic db/db mice, accompanied by depressive behavior, hyperglycemia, insulin resistance, neuroinflammation, and ROS overproduction (Zhai et al., 2018). Given the supposable protective role of NRF2 in these disease conditions, several studies have explored the preventative and ameliorative role of several NRF2 activators in the disease progression of depression and T2DM. In this review article, we strive to explore the role of NRF2 in depression and T2DM, and expectantly in their bidirectional association. Efforts are mainly focused on elucidating the possibility of a molecular and physiological link between the transcriptional factor and the two interactive disease conditions. Several natural and synthetic inducers of NRF2 in relation to depression and T2DM have also been discussed.
Section snippets
The involvement of NRF2-downstream targets in depression and T2DM
Around 250 ARE-dependent genes have been reported in the literature, and the relevance of several of these to depression and T2DM are discussed in this section. These genes, which are the downstream targets of NRF2, encode proteins that perform antioxidative and cytoprotective functions. For instance, NRF2 induces the expression of several molecules belonging to the major antioxidant defense systems: i) the glutathione (GSH) system consisting of GSH, glutamate-cysteine ligase (GCL), glutathione
NRF2, stress, and inflammation in depression and T2DM
The involvement of stress and inflammation in various diseases has garnered the attention of researchers. Bidirectional depression and T2DM go hand in hand with inflammatory conditions prevailing in the presence of chronic psychological and physiological stress. Acute as well as chronic stress may be adequate to cause the export of NRF2 from the nucleus to the cytosol and increase overall inflammation, as observed in a rodent model of depression (Djordjevic et al., 2015). Chronic restraint
NRF2 crosstalks with some relevant targets in depression and T2DM
Several signaling pathways and their downstream targets have been identified to be associated with NRF2 signaling. NRF2 is found to interact with a broad category of signaling molecules such as the phosphoinositide 3-kinase (PI3K), serine/threonine kinase/protein kinase B (AKT), glycogen synthase kinase-3 beta (GSK-3β), brain-derived neurotrophic factor (BDNF), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-gamma (PPAR-γ), and nuclear factor kappa B (NF-κB).
Antidepressants
Literature on the modulatory effect of classical antidepressants on NRF2 signaling and the involvement of the latter in antidepressant action is sparse, although there are a few studies that explore the presence of such a dialogue.
Natural and synthetic NRF2-TARGETING compounds in depression and T2DM
Both synthetic and natural compounds have been shown to target NRF2 and exhibit efficacy against depression and T2DM. This section compiles available literature on some compounds that elicit NRF2-mediated protection against depression and T2DM and their associated complications. Table 2 explores the role of some natural bioactive compounds that exert therapeutic potential as NRF2 activators in depression and T2DM and the possible mechanisms via which they thwart disease development.
Targeting NRF2 in the clinical setting: a discussion
Pharmacologically activating NRF2 signaling appears to be beneficial in tackling oxidative damage and inflammation in body tissues afflicted with diseases. Expert reviewers have advocated for NRF2 as a promising target for T2DM and psychiatric illnesses (Bhandari et al., 2021; David et al., 2017). Despite mounting evidence on the involvement of NRF2 in these disorders, it is still elusive whether this particular involvement tilts towards cause or consequence. Most studies have painted NRF2 and
Conclusions and future perspectives
NRF2 stands as an attractive pharmacological target in the prevention or management of chronic diseases as it regulates the expression of various cytoprotective genes that maintain redox balance and prevent central and peripheral inflammation. The pathophysiological factors linking mood disorders and metabolic disorders, including depression and T2DM, are currently being uncovered. The downstream targets genes of NRF2 may play intricate roles in the bidirectional association of depression and
Authors’ contributions
Rhea Subba: Conceptualization, Visualization, Literature search, Writing-original draft, and editing; Mir Hilal Ahmad: Figure designing and editing; Balaram Ghosh: Writing-critical reviewing and editing; Amal Chandra Mondal: Conceptualization, Writing-critical reviewing and editing, Supervision.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
The authors do not have any conflict of interest.
Acknowledgments
The authors acknowledge the Department of Biotechnology (BT/ PR32907/MED/122/227/2019), Ministry of Science and Technology (Govt. of India), DBT-BUILDER-Level III (BT/INF/22/SP45382/2022), Council of Scientific & Industrial Research-Senior Research Fellow (09/263(1172)2019-EMR-I), Indian Council of Medical Research, (45/7//2019/MP/BMS) and School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
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