**Abstract**

Regulation of cellular redox homeostasis determines the fate of the cell. Perturbation in redox status is known to elicit multiple cellular pathways. Role of oxidative stress modulation in channelizing the cell towards apoptosis or rescuing the cell by activating pro-survival pathways, depends on the levels of generated oxidative stress. High levels of generated oxidative stress induce cell death pathways whereas mild and low levels are known to elicit the cell survival pathways. Generation of ROS for a short duration of time inducing Redox ticking also triggers the pro-survival pathways inside the cell. Nrf2 is the redox sensitive prosurvival transcription factor which acts as master regulator of redox equilibrium. Nrf2 and its dependent genes including HO-1, GCLC, NQO1 etc. are involved in maintaining the cellular redox homeostasis. Role of Nrf2 as dual edges sword has been highlighted in past decade. The cross talk between the Nrf2 and NF-κB is at the focal point of building the redox response network. The present chapter is aimed at providing the insight on the role of Nrf2 and NF-κB as redox sensitive transcription factors in regulating cellular redox status. Further, the chapter brings in light the therapeutic potential of targeting Nrf2 under multiple clinical settings.

**Keywords:** redox homeostasis, Nrf2, NF-κB, therapeutic potential, cancer, neurodegeneration

### **1. Introduction**

An equilibrium between the oxidants, reactive oxygen species and antioxidants attained by cell is defined as redox status of the cell, In case of any kinds of diseases or pathological conditions which disrupt this equilibrium thus creating an oxidized state, termed as oxidative stress [1]. This redox system essentially works in maintaining cellular homeostasis and cell survival. Reactive oxygen species (ROS) consist of reactive species like superoxide (O2−) and hydroxyl radical (HO), along with nonradical species such as hydrogen peroxide (H2O2). Reactive nitrogen species (RNS) contains nitrogen containing reactive species including nitric oxide (NO) and peroxynitrite (ONOO− ). Agents that contribute to formation of these ROS/RNS may be exogenous sources like Chemicals

(e.g., PCB), irradiation (i.e., UV irradiation, x-ray, gamma-ray) or atmospheric pollutants or they may be endogenous the mitochondria, where O2 − is generated by electron leakage from complex I and III of the electron-transport chain, membrane-associated NAD(P)H oxidase, cytochrome c oxidase, and xanthine oxidase. In case of any oxidative stress experienced by the cell various enzymatic and non- enzymatic antioxidant systems present in the cell are ready to combat. A major class of enzymatic antioxidant systems include multiple isoforms of SOD, (SOD1, SOD2, SOD3) found in the extracellular matrix, cytoplasm, mitochondrial intermembrane space, nucleus, and lysosomes. Another enzymatic system which is responsible for conversion of reduced glutathione (GSH) to oxidized glutathione (GSSG), catalyzed by glutathione peroxidase (GPX) [2]. Non enzymatic systems include chemical antioxidants like glutathione (GSH), α-tocopherol (vitamin E), and ascorbic acid (vitamin C). GSH act as a cosubstrate in the reduction of H2O2 by GPx. It might also react with oxygen-free radical directly, similarly, vitamins E and C also reduce oxygen-free radicals. They act by trapping hydroxyl radicals and other reactive radicals and thus break radical chain reactions and form new less reactive radicals [3]. Reactive oxygen species (ROS) are reported to be involved in different cellular processes ranging from apoptosis and necrosis to cell proliferation and carcinogenesis. Reports confirm the ECS (endocannabinoid system), may play an important role in the regulation of cellular redox homeostasis [4]. Endocannabinoids such as AEA are also known to mediate some of their cellular responses by targeting the non-selective cation channel TRPV1, whose activation has been linked to increased ROS production, AEA has also been reported to target the PPAR family of nuclear receptors, whose activation is known to induce the expression of antioxidant enzymes, including catalase and glutathione peroxidase 3 [5]. Thioredoxins (Trx), function as hydrogen donors to thioredoxin-dependent peroxide reductases. These have a Cys-Gly-Pro-Cys active site, which is indispensable for redox regulatory functions of thioredoxins. Two isoforms of Trx have been observed, these are Trx1 (expressed in the cytoplasm and the nucleus) and Trx2 (expressed in the mitochondria), which are very crucial for cell survival. This implicates its protective role against reactive oxygen species [6].

Cellular Redox Homeostasis is determined by the ability of a cell to maintain the balance between the magnitude of generated oxidative stress and the rate of its detoxification [7] Maintaining the redox balance is important for proper function and responses of cells. Any disturbance in the redox homeostasis induces oxidative stress mediated signaling cascade that could lead to cell death or induce adaptive survival responses. Outcome of perturbation in the redox balance depends on the magnitude of oxidative stress induced inside the cell [8]. The intracellular "redox homeostasis" or "redox buffering" capacity is maintained primarily by glutathione (GSH oxidized / reduced) and thioredoxin (TRX oxidized/reduced) redox couples. GSH/GSSG ratio represents the major cellular redox buffer and it is therefore used as an indicator of the redox environment of the cell. GSH, Trx and glutaredoxin rectifies the thiol modifications due to oxidative stress. GSH reductase and Trx reductase reduces the GSSG and oxidized Trx at the expense of NADPH. The reducing nature of GSH and Trx is pivotal for the clearance of peroxides by peroxidase and peroxiredoxin [9]. Basal levels of reactive oxygen species (ROS) are endogenously produced in the mitochondria due to partial reduction of oxygen, inflammatory reactions and enzyme linked reactions viz. NAPH oxidase, Xanthine oxidase, cytochrome c oxidase [10]. Induction of mild oxidative stress activates redox sensitive pro-survival pathways like Nrf2 that protects against the oxidative damage. High oxidative stress leads to induction of apoptosis. Owing to their high reactivity, high levels of generated ROS react with the molecule including proteins, carbohydrates, lipids and DNA in the vicinity non-specifically (**Figure 1**).

*Perturbation of Cellular Redox Status: Role of Nrf2, a Master Regulator of Cellular Redox DOI: http://dx.doi.org/10.5772/intechopen.102319*

#### **Figure 1.**

*Cellular redox homeostasis: Electron transport chain in mitochondria, endoplasmic reticulum and oxidases enzymes like NADPH oxidases and xanthine oxidase induces the generation of superoxide and peroxide radicals. The increase in hydrogen peroxide elevates the redox balance towards oxidative stress. Spatial-temporal regulation of the generated oxidative stress determines the cellular fate in term of apoptosis or cytoprotection. Activation & expression of transcription factors leading to the replenishment of antioxidant and cytoprotective machinery of the cell leads to restoration of redox balance.*

This further results in impaired functioning of key cellular components directing the cell towards apoptosis [11]. However, generation of low levels of ROS acts as secondary messenger and activates numerous redox-sensitive pro-survival signaling pathways [12]. Spatio-temporal generation and regulation of ROS underlines their potential to contribute as secondary messenger from cell surface to the nucleus [13]. Scavenging of endogenous ROS can impair normal cellular response like production of cytokines and growth factors by T cells. Redox state of many proteins plays an important role during immune responses [14]. Critical cysteine residues present on proteins act as redox sensors and are prone to oxidation into sulfenic acids or disulphide formation or glutathionylation resulting in the modulation host immune responses [15]. The effect of oxidative stress on functions of these proteins depends on the concentration, duration and location of ROS generated inside the cell. A number of transcription factors and families have been identified which work in events of redox homeostasis or signaling, namely AhR, AP1, β-catenin, Egr-1, FOXO, HIF-1α, p53, NF-κB, Nrf2, Sp1, TTF. The present chapter is aimed at narrating the role of Nrf2 and NF-κB in redox environment and their redox regulation. Nrf2 being the master regulator is further detailed as putative target with therapeutic potential under multiple clinical settings.
