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WE SHOULD ALL KNOW ABOUT NRF2 PATHWAY


Cells in homeostasis may produce free radicals as a result of physiological reactions (cellular respiration, for example). O2 is the normal stable form of oxygen, however when involved in some reactions in the body O2– is formed. Oxidative stress occurs in cells when the production of reactive oxygen species (ROS), such as such as hydroxyl radical (HO), perhydroxyl radical (HOO-), superoxide anion (O2–) and reactive nitrogen species (RNS) including nitric oxide (NO), exceeds the antioxidant capacity of a cell. These free radicals are chemically unstable, and highly reactive as they are trying to find a way to lose their extra electron, and the only way to do that is to transfer it to another molecule or compound.


The main damage to cells results from the ROS-induced alteration of macromolecules such as polyunsaturated fatty acids in membrane lipids, proteins and DNA structure.


This is where antioxidants step in, it’s their function to mop up these highly reactive species making sure they don’t interact with any of the important molecules in a cell. The nature develops an effective defense mechanism. To make sure levels of cellular stress do not get too high, the body produces enzymes such as superoxide dismutase (SOD, catalase (CAT) or glutathione reductase. These enzymes break down the superoxide anion radical O2– into H2O and O2. The SOD is considered to be 100 times more effective than the Vitamin E as far as antioxidative effect is concerned.


The production of these endogenous antioxidant enzymes occurs constantly in the body, however, when antioxidant function in the body becomes overwhelmed by free radicals, a specific pathway is activated called the Nrf2 pathway.

The Nrf2 pathway (for Nuclear Related Factor 2) is the system the body turns on when it wants to make its “in-house antioxidants”. Nrf2 is a transcription factor which is a major regulator of cell antioxidant responses. Transcription factors are a class of protein which bind to DNA and induce the expression of particular genes, in the case of Nrf2, the pathway stimulates the production of potent antioxidants as shown in the table below.

In normal situation, Nrf2 exists in the cytosol of a cell, or the region outside of the nucleus where it cannot interact with DNA. It is held here by another protein called Keap1, which prevents it moving into the nucleus.


Schematic diagram showing the behavior/activity của Nrf2 under stressful and homeostatic conditions. ARE antioxidant responsive element.

Keap1 contains several sensors for reactive oxygen species. If these receptors are activated then Nrf2 is released, and can pass into the nucleus. Once within the nucleus Nrf2 binds to a region of DNA known as an “Antioxidant Response Element” or ARE. These ARE elements are closely associated with the genes coding for SOD and the GSTs (and many other genes) as discussed above. When Nrf2 binds it induces the production of active proteins from these genes. Both of these proteins exhibit potent antioxidant capacity and can rapidly clear oxidative stress.


The important role for Nrf2 has been shown by several studies with a particular focus on animal models. Mice which have been genetically engineered to lack Nrf2 protein are considerably more sensitive to chemical carcinogens, and also chemical toxins leading to increased inflammation in the lung and brain, all major markers of oxidative stress.


The Nrf2 pathway can be affected as well by some toxins iVient in the diets of the Swine and Poultry. Recently, a lot of toxicological studies on mycotoxins have suggested that blockage of Nrf2 pathway might serve as a potential molecular mechanism of observed toxicity of mycotoxins in animals.


Several studies have shown that the presence of Alflatoxin B1 in the diet can cause changes in intracellular antioxidant mechanisms affecting the Nrf2 pathway and limiting the intracellular production of SOD, GPx and CAT expression.


Studies in 2010 and 2018 confirmed that dietary contamination by the T-2 toxin (from fusarium) downregulated the expression of the Nrf2 transcription factor. This T-2 toxin is recognized for cytotoxic effect induces cell apoptosis through mitochondrial structural disorganization, increase of ROS, and DNA damage.


Researchers demonstrated that Ochratoxin A has a direct effect on the depressing effect on the decreased expression of Nrf2 in cells derived from pig’s kidney. The authors postulated that downregulation of Nrf2 might be partially responsible for nephrotoxicity of that mycotoxins. A similar effect was observed in porcine renal proximal tubular cells.


Similar conclusions have been established in the induction of apoptosis and oxidative stress by Ochratoxin in chicken kidneys and liver through the downregulation of Nrf2/Keap1.


Many other mycotoxins like, Deoxynivalenol, Nivalenol, Fumonisin, Zearalenone are responsible for penetrating the cells and triggering production of Reactive Oxygen species, either directly or indirectly through the downregulation of Nrf2 pathway. That will affect lipid membranes and DNA fragmentation, especially hepatocytes. But mycotoxins can lead to oxidative stress toxicity to placental cells or even embryonic cells that partly explained the problems of reproduction often observed in cases of mycotoxins contamination.

Given the fact that mycotoxins are heavily present in Asia, it is critical to pay a special attention on the cell oxidative stress (intra-cellular level of ROS). Some solutions exist on the market to stimulate the Nrf2 pathway by acting directly on the Keap1 complex and therefore releasing the Nrf2 on its way to the nucleus. That proactive mode of action ensures an augmented endogenous production of Superoxide dismutase ensuring cell protection and enabling an optimal level of growth and production of the animals, despite the constant environmental challenges they are facing.


If you want more information on the Nrf2 pathway and the way to enhance it, please do not hesitate to come back to me with your questions.


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