Targeting Nrf2/Keap1 signaling pathway by bioactive natural agents: Possible therapeutic strategy to combat liver disease
Graphical abstract
Introduction
The liver is one of the vital organs representing almost 2.5% of the overall body weight in an adult human (Molina and DiMaio, 2012). It maintains homeostasis by regulating the biochemical pathways involving energy metabolism, providing immunity and nutrition to other organs (Godoy et al., 2013). The liver, located at the upper right part of the abdominal cavity, is connected to the hepatic artery and hepatic portal vein and receives about 25% of the cardiac output at rest (Eipel et al., 2010). It filters the blood containing nutrients, toxins, and other substances from the gastrointestinal tract or the duodenum through the hepatic portal vein (Hill and Nassrallah, 2018). Almost half of the body's lymph is produced in the liver, which cleanses the blood through portal veins or the blood from the hepatic arteries (Ohtani and Ohtani, 2008).
The liver holds the name "Nutritional hub" for its majority functions to metabolize carbohydrates, protein, and fat, detoxify toxic elements, and secrete bile juice (Rui, 2014). It helps maintain extra glucose that can be stored as glycogen and released into the bloodstream as ready glucose when needed. The liver can intend to make glucose from glycerol (obtained by breakdown of triglycerides) or dietary sugars like fructose and galactose by the process of gluconeogenesis when the body is deprived of glucose and glycogen (Kumar et al., 2005; Nguyen et al., 2008). The liver also plays a major role in the deamination process to remove the nitrogen-containing amino group (ammonia), which is potentially toxic to the body and serves as a source of some of the proteins involved in blood clotting (Kumar et al., 2004). The removed ammonia is then converted to urea by the liver and is eliminated out of the body (Sukalingam et al., 2018).
The liver resides a major site for burning fatty acids into ketone bodies that are stored in the liver's mitochondrial matrix which can be used by the body at the time of glucose deprivation (Ganesan et al., 2017; Sharmila Banu et al., 2009b). The liver also aids in the production of bile juice using phospholipid and cholesterol that serve as a reservoir of vitamins (Chow et al., 2017; Sharmila Banu et al., 2009a). More importantly, the liver metabolizes alcohol with the NAD-dependent enzyme aldehyde dehydrogenase 2 and alcohol dehydrogenase by nontoxic oxidative degradation of alcohol to acetaldehyde followed by oxidation of acetaldehyde to acetate (Kumar et al., 2007; Muzio et al., 2012; Wang et al., 2020). Disturbances in any of these biochemical reactions cause acute or chronic liver injury leading to the release of inflammatory signals from liver immune cells (e.g., dendritic cells, kupfer cells) with the release of immune mediators, the cytokines/chemokines (Muzio et al., 2012). The prolonged exposure to these inflammatory mediators turns up oxidative stress environment and may trigger apoptotic pathways (Djordjevic et al., 2010; Yu et al., 2009). This kind of proinflammatory cytokine storm leading to chronic liver inflammation has been reported to be commonly diagnosed in alcoholic/nonalcoholic steatohepatitis patients (Severi et al., 2010). They also tend to develop certain immune/metabolic compromises, including high neutrophil count, fever, insulin resistance, and lipid metabolism (Djordjevic et al., 2010; Severi et al., 2010).
Being described as the “laboratory of the body”, the liver plays a chief role in biotransformation and excretion, beside synthesizing hormones, clotting factors, and immune factors (Godoy et al., 2013). Biotransformation helps in the excretion of both exogenous and endogenous substances (Bogdanos et al., 2013). Endogenous substances like reactive oxygen species (ROS) are formed as the natural by-product of cellular activities (Ray et al., 2012). For example, the liver's immune cells, known as Kupfer cells, participate in phagocytosis to destroy the cellular debris or invading bacteria and produces ROS (Bogdanos et al., 2013).
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that is activated under electrophilic or oxidative stress, thereby regulating its downstream antioxidant genes (Jayasuriya et al., 2020; Kobayashi et al., 2006). The activation of Nrf2 is constantly inhibited by its negative regulator Kelch-like ECH-associated protein 1 (Keap1) (Jayasuriya et al., 2020). Under a stress environment, Nrf2 binds to the antioxidant response elements (AREs) and activates downstream targets such as Heme Oxygenase-1 (HO-1), Catalase (CAT), Glutathione Peroxidase (GPx), Superoxide Dismutase (SOD), NADPH-Quinone Oxidoreductase-1 (NQO-1), and Glutamate Cysteine Ligase (GCL) (Lee and Johnson, 2004; Vomhof-Dekrey and Picklo, 2012). Studies have reported the functions of these genes, including catabolizing heme, scavenging superoxide, and proved the Nrf2-mediated gene regulation in enhancing the antioxidant status.
Section snippets
Nrf2-ARE signaling
As a member of cap 'n' collar (CNC) basic leucine zipper protein, Nrf2 binds to ARE of the target by recruiting a small Maf family of transcription factors (Rushmore et al., 1991). Nrf2 level is maintained under the homeostatic condition by Keap1 mediated Cullin3-RING box1 (Cul3-Rbx1) binding, which presents ubiquitination and subsequent proteasomal degradation (Villeneuve et al., 2010). However, its activation under multiple stress environments provides cryoprotection to cells by upregulating
Role of Nrf2 against liver diseases
Numerous scientific reports describe the role of Nrf2 activators that mitigates response against hepatotoxicants. The data presented in this review have been collected from various literature databases, including the scientific Databases of Science Direct, Web of Science, Pubmed, Google, EMBASE, and Scientific Information (SID). The survey included the keywords such as liver, Nrf2, liver diseases, Nrf2 activators, liver diseases and Nrf2 activators, Nrf2 activators against hepatotoxicants, Nrf2
Discussion and future prospects
In this review, we have analyzed the pieces of literature on Nrf2 activators and their mode of action against hepatotoxic agents, to date. Research in the field of Nrf2 is recently increasing, especially in response to phytocompounds. To note, more recent studies on pharmacological activation of Nrf2 have focused on experimental research rather than basic research. It is also evident that many Nrf2 activators are on pre-clinical and clinical research for various chronic diseases including
Conclusion
In conclusion, our analysis has revealed the growing interest and experimental research on pharmacological activation of Nrf2 activation through phytocompounds. Activation of the Nrf2 signaling pathway is an established mechanism for reducing oxidative stress-mediated hepatotoxicity. More extensive studies are essential to identify the underlying mechanisms and establish future therapeutic potentials of these signaling modulators. Further clinical trials are warranted to determine the safety
Declaration of Competing Interest
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.
Acknowledgment
One of the authors, R.J. acknowledges the Council of Scientific and Industrial Research (CSIR), New Delhi, India, for the award of Senior Research Fellowship (File No.: 09/1045(11089)/2020-EMR-I).
Funding
This project is jointly supported by two grants (project code: UIC202007 and UIC202107) from BNU-HKBU United International College and one research grant from Guangdong Education Bureau (Project code: R5201911).
CRediT authorship contribution statement
Ravichandran Jayasuriya: Conceptualization, Data curation, Writing – original draft, Writing – review & editing. Umapathy Dhamodharan: Conceptualization, Writing – review & editing. Daoud Ali: Conceptualization, Writing – review & editing. Kumar Ganesan: Conceptualization, Writing – review & editing. Baojun Xu: Conceptualization, Writing – review & editing, Supervision. Kunka Mohanram Ramkumar: Conceptualization, Writing – review & editing, Supervision.
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