Geon Fighting Coronavirus with Curcumin Curcumin

 

Coronaviruses include SARS-CoV, MERS-CoV and SARS-CoV-2 that cause SARS, MERS, and COVID-19, respectively. COVID-19 was first identified in Wuhan, China in December 2019. It is now spreading to more than 80 countries in the world. No one knows when it will end. While all countries are doing their best to prevent epidemic, the spreading rate does not appear to slow down. Since the disease is contagious even in the absence of any symptoms, it is really hard to avoid contact with the viruses. Therefore, we should consider protecting ourselves by increasing resistance to viral infections.

Curcumin is an active component of turmeric used extensively in Indian cooking. Numerous studies have demonstrated its efficacy in fighting a wide variety of diseases (see another article). It can inhibit several viruses such as human immunodeficiency virus (HIV), influenza A virus, noroviruses, herpesviruses and hepatitis viruses [1]. Although curcumin has not been directly tested on COVID-19, this article will show how curcumin could prevent COVID-19 and alleviate its symptoms, including "cytokine storm". The major target of curcumin is an enzyme called glycogen synthase kinase-3 (GSK-3).

Cytokine Storm

Cytokine storm is the major cause of mortality in COVID-19 [2], SARS [3] and MERS [4]. It is a form of "systemic inflammatory response syndrome" that arises from huge amount of pro-inflammatory cytokines, resulting in overwhelming inflammation across the body. In COVID-19, the symptoms initially appear mild, reflecting typical immune response to eradicate the viruses [5]. After a few days, some patients could become seriously ill and died of multiple organ failure. This indicates that the virus replicates faster than the immune system can handle.

Cytokines are a group of small proteins produced mainly in immune cells like macrophages, B lymphocytes and T lymphocytes. GSK-3 plays a pivotal role in the regulation of their production [6].

GSK-3 Is at the Heart of Inflammation

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Figure 1. The structure of coronaviruses. The spike glycoprotein can trigger immune responses. The nucleocapsid (N) protein, which plays crucial roles in viral replication, is a target of GSK-3. [Source: Wikipedia]

The immune response to microbes begins with the detection of foreign substance such as lipopolysaccharides (LPS) in the outer membrane of Gram-negative bacteria. This is achieved by special receptors (e.g., TLR4) on the surface of immune cells. The binding between LPS and TLR4 triggers a series of biochemical processes, leading to the activation of GSK-3 and production of various cytokines, Some cytokines (anti-inflammatory) have inhibitory effects on inflammation while others (pro-inflammatory) stimulate inflammation. It has been found that activation of GSK-3 promotes the production of pro-inflammatory cytokines [6].

The spike glycoprotein on the surface of coronaviruses can also bind to TLR4, and trigger cytokine production [5]. Therefore, inactivation of GSK-3 should attenuate inflammation.

Curcumin is a Potent GSK-3 Inhibitor

Curcumin is well known for its anti-inflammatory property [7], but how? At the more fundamental level, curcumin has been shown to be a direct and potent GSK-3 inhibitor [8]. Since activation of GSK-3 promotes inflammation, the anti-inflammatory property of curcumin could stem from this crucial, but often overlooked, biochemical function. Hence, curcumin can alleviate inflammation simply by inhibiting GSK-3. However, viruses may continue to multiply, is GSK-3 inhibition sufficient to suppress cytokine storm? Strikingly, a GSK-3 inhibitor has been demonstrated to suppress the replication of coronaviruses.

GSK-3 Inhibitor Can Suppress Viral Replication

Numerous studies have shown that the N protein that forms complex with the viral RNA is crucial for the replication of coronaviruses [9,10]. Wu et al. further showed that the N protein is a target of GSK-3 [11,12]. By using a coronavirus, mouse hepatitis virus, they have demonstrated that a GSK-3 inhibitor, kenpaullone, can reduce the viral quantity by 80%. Thus, the coronavirus seems to take advantage of GSK-3 to accelerate replication which, in turn, activates more GSK-3, thereby resulting in a vicious cycle. It is a nightmare for human beings, but a big step in viral evolution.

Vulnerability to COVID-19

GSK-3 is involved not only in infection, but also in a wide range of medical conditions, particularly diabetes [13,14], heart diseases [15], and psychological stress [6], which are associated with hyperactive GSK-3. Individuals with these conditions may aggravate cytokine storms and thus at higher risk for the mortality of COVID-19.

Glucocorticoid Degrades GSK-3

Glucocorticoid is a widely prescribed anti-inflammatory drug. It has been shown to repress the production of inflammatory cytokines. Interestingly, glucocorticoid can induce degradation of GSK-3 [16], consistent with the view that GSK-3 is the central player in inflammation [6]. Glucocorticoid has been used to combat SARS and COVID-19. Due to its serious side effects at high dose. the results were not satisfactory. The World Health Organization does not recommend glucocorticoid for the treatment of COVID-19.

Summary

In summary, activation of GSK-3 stimulates the production of pro-inflammatory cytokines and accelerates replication of coronaviruses. Thus, hyperactive GSK-3 may result in a vicious cycle, leading to cytokine storm. Curcumin can alleviate cytokine storm by inhibiting GSK-3 (Figure 2). While glucocorticoid can also attenuate inflammation by inducing GSK-3 degradation, its serious side effects at high dose may cause more harm than benefit.

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Figure 2. The actions of curcumin, glucocorticoid and GSK-3. Curcumin is a direct and potent GSK-3 inhibitor. Glucocorticoid induces GSK-3 breakdown. GSK-3 stimulates the production of pro-inflammatory cytokines and accelerates replication of coronaviruses.

References

1. Praditya D et al. (2019) Anti-infective Properties of the Golden Spice Curcumin.

2. Huang C et al. (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.

3. Wong CK et al. (2004) Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome.

4. Mahallawi WH et al. (2018) MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile.

5. Li G et al. (2020) Coronavirus infections and immune responses.

6. Jope RS et al. (2017) Stressed and Inflamed, Can GSK3 Be Blamed?

7. Chen CY et al. (2018) The Cancer Prevention, Anti-Inflammatory and Anti-Oxidation of Bioactive Phytochemicals Targeting the TLR4 Signaling Pathway.

8. Bustanji Y et al. (2009) Inhibition of glycogen synthase kinase by curcumin.

9. McBride R et al. (2014) The coronavirus nucleocapsid is a multifunctional protein.

10. Cong Y et al. (2020) Nucleocapsid Protein Recruitment to Replication-Transcription Complexes Plays a Crucial Role in Coronaviral Life Cycle.

11. Wu CH et al. (2009) Glycogen synthase kinase-3 regulates the phosphorylation of severe acute respiratory syndrome coronavirus nucleocapsid protein and viral replication.

12. Wu CH et al. (2014) Nucleocapsid Phosphorylation and RNA Helicase DDX1 Recruitment Enables Coronavirus Transition.

13. MacAulay K and Woodgett JR. (2008) Targeting glycogen synthase kinase-3 (GSK-3) in the treatment of Type 2 diabetes.

14. Nabben M and Neumann D (2016) GSK-3 Inhibitors: Anti-Diabetic Treatment Associated with Cardiac Risk.

15. Lal H et al. (2015) The GSK-3 family as therapeutic target for myocardial disease.

16. Failor KL et al. (2007) Glucocorticoid-induced degradation of glycogen synthase kinase-3 protein.

 

Author: Frank Lee
March 5, 2020