Volume 24, Issue 5 (December & January 2021)                   J Arak Uni Med Sci 2021, 24(5): 634-639 | Back to browse issues page

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Samimi F, Azizi R, Jalali Mashayekhi F. Use of Nuclear Factor Erythroid 2-Eelated Factor Activators as A Strategy to Improve the Side Effects of COVID-19. J Arak Uni Med Sci 2021; 24 (5) :634-639
URL: http://jams.arakmu.ac.ir/article-1-6931-en.html
1- Department of Biochemistry and Genetics, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran.
2- Department of Laboratory Sciences, Faculty of Medical Sciences, Khomein University of Medical Sciences, Khomein, Iran.
3- Department of Biochemistry and Genetics, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran. , mashayekhi@arakmu.ac.ir
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Coronavirus disease-19 (COVID-19) is a new member of the coronavirus family causing acute respiratory infection. Patients with COVID-19 have a higher risk of developing oxidative stress during this infection. Moreover, the virus induces ROS production that activates cellular pathways for viral replication. 
Nuclear factor erythroid 2-related factor (Nrf2) is a crucial transcription factor in cellular antioxidant defense by mediating Virus-induced oxidative stress and ROS production. This article suggests that an Nrf2 activator may be beneficial in preventing oxidative stress development in COVID-19 patients. Coronaviruses are a significant group of viruses that cause different illnesses in humans and animals. These illnesses can range from the common cold to more severe diseases such as SARS (Severe acute respiratory syndrome), Middle East Respiratory Syndrome (MERS), and COVID-19. COVID-19 is a new viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 
The main symptoms of COVID-19-infected patients are fever, dry cough, fatigue, and sometimes respiratory problems such as shortness of breath, sore throat, and infection [1]. There is evidence of a link between oxidative stress, viral infection, and replication. Oxidative stress results from an imbalance between the oxidizing system and antioxidant mechanisms that lead to oxidative DNA damage. 
Oxidative stress is involved in many chronic diseases such as diabetes mellitus, cancers, hypertension, heart disease, neurodegenerative diseases, and infectious diseases, particularly RNA viruses. SARS-CoV2, like other RNA viruses such as HIV 1 and hepatitis viruses, and herpes viruses, induce oxidative stress [2] Redox-sensitive proteins in tissues activate or block various downstream molecular signaling pathways caused by oxidative conditions. Some of these redox-sensitive proteins, such as Nrf2, regulate oxidant-sensitive signals. Nrf2 is a transcription factor that plays an essential role in cell defense against oxidative damage. Under normal conditions, Nrf2 is kept in the cytoplasm by Kelch-like-ECH-associated protein 1 (KEAP1), which degrades it by ubiquitination [3]. KEAP1 contains several cysteine residues and negatively regulates Nrf2 activity. 
In response to oxidative stress, modification of cysteine residues of Keap1 causes Nrf2 to dissociate from Keap-1. It travels to the nucleus, where it binds to ARE-containing genes, including NAD(P)H quinone oxidoreductase 1 (NQO1), Heme oxygenase-1 (HO-1), Thioredoxin reductase, glutathione peroxidase, Glutathione (GSH), catalase and superoxide dismutase that play an essential role in antioxidant defense against free harmful radicals. It has been reported that elevated levels of Reactive Oxygen Species (ROS) are associated with a decline in antioxidant defenses and the development of respiratory viral infections [4]. 
The protective role of the Nrf2 signaling pathway has been revealed in respiratory viral infections. Several recent studies indicate that the Nrf2 signaling pathway is suppressed in COVID-19 patient’s lung biopsies; conversely, the application of Nrf2 activators may represent a novel treatment approach for viral infections and inhibit the replication of SARS-CoV2. Several Nrf2 activators have been identified as beneficial effects on viral infection. 
Recent studies have shown that vitamin D supplementation by activating the Nrf2-antioxidant pathway reduces the risk of respiratory infection in patients with COVID-19 [6]. Also, it is reported that thymoquinone (TQ), as a polyphenol compound found in the plant Nigella sativa, reduces the ability of the coronavirus replication in cells, and also this compound may have a protective effect by modulating Nrf2 and inducing HO-1 expression that improved antioxidant response and prevent the COVID-19 infection [6]. 
A study has shown that curcumin, in addition to its antioxidant effects by activating the Nrf2 pathway and induction of Glutathione (GSH) production, inactivates influenza A virus infection and alleviates the impacts of COVID-19 [7]. Many studies have also shown that sulforaphane (SFN), a natural compound derived from broccoli sprouts, suppresses viral replication in respiratory diseases such as influenza A and hepatitis C virus (HCV) and Herpes simplex virus 1 (HSV-1). It has protective effects on conditions considered risk factors for COVID-19, including respiratory diseases, cancer, diabetes, and cardiovascular diseases [3]. 
Quercetin is a flavonoid found in sausages, whole grains, broccoli, onions, apples, and other plants. Quercetin also strengthens antioxidant defenses and scavenges free radicals by activating the Nrf2 messaging pathway. This compound has been used in many studies due to its antiviral properties. Evidence shows that taking quercetin with vitamin C or vitamin D boosts its antiviral effects. Recent studies have suggested that quercetin may be used in treating patients with COVID-19 with severe inflammation due to its anti-inflammatory and antioxidant effects [8]. 
Resveratrol is another antioxidant of interest to researchers and is abundant in grapes and peanuts. One study suggested that resveratrol, an activator of the Nrf2 pathway, enhances the antioxidant path and reduces the severity of COVID-19 disease [9]. Elements such as selenium and zinc also have antioxidant properties and can partially activate the Nrf2 pathway signaling [10]. The present study suggests a conservative approach on the basis of some evidence regarding activation of the Nrf2 signaling pathway for its antiviral and anti-oxidative mechanisms. It means that the use of Nrf2 activators may provide new strategies to prevent virus-induced oxidative stress via Nrf2 induction and a viable way to fight against the COVID-19 virus.

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Type of Study: Short Communication | Subject: Basic Sciences
Received: 2021/06/22 | Accepted: 2021/09/11

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