|Fighting Coronavirus with Curcumin||Curcumin|
Breaking News (May 27, 2021)
Clinical trials have demonstrated that curcumin can alleviate the symptoms of mild and severe COVID-19.
Tahmasebi et al. (2021a) Nanocurcumin improves Treg cell responses in patients with mild and severe SARS-CoV2.
Tahmasebi et al. (2021b) Immunomodulatory effects of nanocurcumin on Th17 cell responses in mild and severe COVID-19 patients.
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 . 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 is the major cause of mortality in COVID-19 , SARS  and MERS . 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 . 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 .
GSK-3 Is at the Heart of Inflammation
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 .
The spike glycoprotein on the surface of coronaviruses can also bind to TLR4, and trigger cytokine production . Therefore, inactivation of GSK-3 should attenuate inflammation.
Curcumin is a Potent GSK-3 Inhibitor
Curcumin is well known for its anti-inflammatory property , but how? At the more fundamental level, curcumin has been shown to be a direct and potent GSK-3 inhibitor . 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 , and psychological stress , 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 , consistent with the view that GSK-3 is the central player in inflammation . 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.
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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Author: Frank Lee
Notes (May 24, 2021)
After this article was published on the website, at least 5 papers also support the notion that GSK-3 inhibition could be a promising approach to fighting COVID-19.
b. Souza et al. (2020) Commentary: GSK-3 Inhibition as a Therapeutic Approach Against SARs CoV2.
c. Rudd CE. (2020) Commentary: Does Lithium Deserve a Place in the Treatment Against COVID-19?
d. Liu et al. (2021) Targeting the Coronavirus Nucleocapsid Protein through GSK-3 Inhibition.
Lithium is a well known GSK-3 inhibitor. It has been used for the treatment of COVID-19, with limited beneficial effects. The efficacy of a drug depends on its half-maximal inhibitory concentration (IC50), namely, the concentration required to inhibit half of its targets. The smaller of IC50, the better. The IC50 of lithium for GSK-3 is about 1 mM (Snitow et al., 2021), while the IC50 of curcumin for GSK-3 is only 66.3 nM (Bustanji et al., 2009). 1 mM = 106 nM. Therefore, curcumin is predicted to be far more effective than lithium for the treatment of COVID-19.