Prevention of SARS-CoV-2 Infection with Antioxidants and Anti-inflammatory Action of Indian Spices: Light at the End of the Tunnel

1. Research Scholar, Department of Biochemistry, Babu Banarasi Das University, Lucknow, Uttar Pradesh, India. 2. Research Scholar, Department of Nutrition, Babu Banarasi Das University, Lucknow, Uttar Pradesh, India. 3. Professor, Department of Biochemistry, Babu Banarasi Das University, Lucknow, Uttar Pradesh, India.

Abstract

Today, we are living in the era of Coronavirus Disease-2019 (COVID-19), a pandemic that has affected almost the whole globe. It has rightly been called as the ‘twenty-first-century plague’ which has garnered considerable attention from researchers, pharma companies, policymakers, and media. Though vaccines are being deployed and people are eagerly receiving vaccination; the duration of conferred immunity, the possibility of re-infection of recovered/vaccinated individuals, the consequence of the new mutation in SARS-CoV-2 and its impact and challenge for the efficacy and degree of protection that a potential vaccine could provide is under question. In the absence of any definite answer, people are turning towards natural remedies and spices. India is known globally as the land of spices. Spices like ginger, garlic, black pepper, cardamom, turmeric, clove, cinnamon, etc., are known for their rich aroma, texture, and immunity boosting ingredients. These are rich sources of antioxidants such as flavonoids and alkaloids. The antioxidants present in them, neutralise the free radicals generated inside the body during viral infections and also prevent cellular damage. These exhibit anti-inflammatory activity and have the potential to combat “cytokine storm” in severe COVID-19 infection. Their potential has been realised by the public and has led to a tremendous increase in global demand and consumption. The present review enlists the active ingredients present in important spices and addresses their antioxidants, anti-inflammatory, and anti-viral action. Traditional Indian spices that are not only a cardinal part of the diet but are affordable, easily available can be viewed as the light at the end of the tunnel to combat the current COVID-19 conditions as a preventive measure.

Clove, Curcumin, Cytokine storm, Garlic, Ginger, Severe acute respiratory syndrome coronavirus 2

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) which is responsible for the global cause of Coronavirus Disease-2019 (COVID-19) has the property to constantly change itself through mutation. Today, with the help of genetic analysis it is possible to identify multiple variants of SARS-CoV-2. Most of the mutations are harmless while some result in forms that spread more quickly, cause more serious illness, or resist drugs. World Health Organisation (WHO) has given Greek alphabet naming scheme for such “variants of concern” and “variants of interest”. These different variants of viruses identified so far are:

1. UK variant (B.1.1.7 or ‘Kent Variant’ is referred to as “alpha”), detected in December 2020;
2. South Africa variant (B.1.351 or “beta”), also detected in December 2020;
3. Brazil variant (P.1 or “gamma”), identified by January 2021;
4. Two more variants (B.1.427 and B.1.429) were first identified in California in February 2021 (1);
5. Another highly transmissible variant (B.1.617) responsible for the second covid wave in India during April 2021 with notable triple-variant (B.1617.1or “kappa” and B.1.617.2 or “delta”) (2). These different variants rendered the virus more transmissible posing greater public health risks.

Presently, there are no proven effective therapies for COVID-19 to prevent infection or stop transmission of disease. Within a month of the onset of the pandemic, the United States (US) Food and Drug Administration (FDA) issued an emergency use authorisation for the use of repurposed approved drugs such as hydroxychloroquine, chloroquine (antimalarial drug), ritonavir, and lopinavir (a combination of antiretroviral drugs), remdesivir (an experimental Ebola drug) and steroids, interferon-beta, several immunomodulators, and anti-inflammatory drugs for the treatment of hospitalised patients with COVID-19. This lead to a surge in clinical trials of many approved drugs and the development of effective vaccines. The efficacy of different vaccines was reported to be different as per clinical trials:

1. Pfizer (91% against B.1.1.7);
2. Moderna (94% against B.1.1.7);
3. Oxford AstraZeneca (74% against B.1.1.7);
4. Johnson and Johnson (Janssen) (72% against B.1.1.7; 64% against B.1.351, P.1 and B.1.617);
5. Sputnik-V (92% against B.1.1.7);
6. Covaxin- India’s 1^st COVID-19 vaccine (78% against B.1.1.7) (3),(4).

Several vaccines are deployed worldwide to ensure fair and equitable vaccination of mass for prevention of disease along with other safety measures as hand sanitisation, wearing of masks, and social distancing to combat this pandemic. However, many questions still remain unanswered about the real safety and efficacy of vaccines, the possibility of re-infection of recovered/vaccinated individuals, the duration of conferred immunity, the consequence of the new mutation in SARS-CoV-2, and its impact and challenge for the efficacy and degree of protection that a potential vaccine could provide. It has been observed that an individual’s immunity plays an important role in combating infection of SARS-CoV-2 by reducing its pathogenic capacity within the host (5).

The SARS-CoV-2 infection starts with its entry into host epithelial cells (lungs, intestine, etc.) via binding of its S (spike) protein with Angiotensin-Converting Enzyme 2 (ACE 2) receptor of host cells. Some of the active ingredients (andrographolide, berberine, curcumin, mangiferin, nimbin, piperine, thebaine, gallic acid, luteolin, naringenin, quercetin, resveratrol, and zingiberene and withaferin A, etc.) present in spices turmeric, garlic, pepper, cinnamon, etc., have been shown to have binding affinity for either the ACE2 receptor or SARS-CoV-2 S protein or both. These compounds might inhibit the attachment of the SARS-CoV-2 virus to the host cell (6) (Table/Fig 1), (Table/Fig 2), (Table/Fig 3). Further, the entry of the virus inside the cell generates a high amount of free radicals (e.g., superoxide anion radical, hydroxyl radical, singlet oxygen, hydrogen peroxide, peroxynitrite radical, hypochlorite, and nitric oxide radical). These are highly reactive and are capable of destroying biologically essential molecules in the nucleus and membranes of cells, such as DNA, proteins, carbohydrates, and lipid (7),(8),(9). The natural antioxidants present in the body e.g., glutathione, vitamin C and E, superoxide dismutase, CYP etc., can donate an electron to a free radical and neutralise it, thus reducing or preventing its destructive potential of cellular damage (10),(11). With the enormous generation of free radicals, the natural antioxidants fall short and leads to oxidative stress. The miraculous treasure of various antioxidants present in spices prevents the cell from oxidative stress and serves as an immunity booster (10). When a virus enters the host cell cytoplasm, it takes over the host’s protein-synthesising machinery and translates its mRNA in the nucleus for the production of viral proteins. This promotes viral replication and the formation of mature viruses and their release. This leads to activation of cells of the immune system like macrophages, monocytes, and agranulocytes triggering the release of various types of chemokines, interferons, interleukins (IL-2, IL-6, IL-8, IL-10, IL-2R, IL-7, etc), colony-stimulating factors, and Tumour Necrosis Factor-α (TNF-α) (8),(9). The condition of hyperactive pro-inflammatory immune response is called “cytokine storm”. This condition is responsible for the high degree of damages to host cells depending upon the severity and progress of viral infection. It also leads to life-threatening conditions like Acute Respiratory Distress Syndrome (ARDS), multiple organ failure, etc., and finally death of the patient. Congregated evidence for the anti-inflammatory action of spices in various pre-clinical and clinical studies is documented that may help in preventing cytokine storm (12). Quercitin, lycorine, myricetin, caffeic acid, scutellarein, silvestrol, and tryptanthrin etc., have also shown antiviral activities in general (13).

Efforts to carry out clinical trials in the more organised way should come in the forefront for developing Indian spices as an efficient and cheap preventive and treatment option against the devastating pandemic. This review addresses the important constituents present in the Indian spices which are anti-oxidant, anti-inflammatory, immunomodulatory, and may protect from ‘cytokine storm’ to act as an effective weapon for prevention of COVID-19.

SPICES THAT BOOST IMMUNITY AGAINST COVID-19

Ginger (Zingiber officinale)

It is well known and belongs to the family Zingiberaceae. It not only adds flavour and taste to the food but also has a wide range of medicinal properties. Since ancient times, ginger tea or ginger extract has been commonly used to treat common colds, flu, and sore throats (17). Gingerol is an antioxidant that strengthens our immune system, has antiviral effects, and aids in the treatment of respiratory problems. It has recently been shown to be beneficial for COVID-19 patients (18), as it binds to many target virus proteins and decreases pathogenicity, according to Rathinavel T et al., (2020) (19). Important enzymes such as alliinase, peroxidase, and myrosinase are also present. Allicin, alliin, and ajoene are sulfur-rich compounds that are among the main ingredients. It is an effective antioxidant agent since it includes compounds like superoxide dismutase and glutathione peroxidase, which play a key role in the body’s defense mechanism against viral infections (20). It has anti-inflammatory effects, functions as an analgesic, decreases blood cholesterol levels, and is helpful to people with heart disease.

Ginger hot water extract is very effective against the Respiratory Syncytial Virus (RSV), avian influenza, norovirus, and Feline calicivirus in studies (FCV). It stops viral plaques from forming in the airway epithelium cells and blocks viral attachment sites (21). The aqueous ginger extract, garlic, and other herbs protect the food from contamination (22).

Garlic (Allium sativum)

Garlic also has a wide spectrum of pharmacological effects, including cardioprotective, antioxidant, anti-inflammatory, anti-viral, anti-cancerous, and immunomodulatory properties, in addition to its food additive quality. Garlic, belongs to the family Amaryllidaceae, has been used as a medicinal herb in Ayurvedic medicine for antimicrobial and antiparasitic purposes since ancient times. A variety of sulfur compounds are present which are the natural odour of garlic, the main one being allicin (diallyl thiosulfinate) (23). Allicin has been shown to play a role in the formation of T-cells and B-cells (24); it also stimulates the immune system’s CD8+ cells and T lymphocyte cells (25) against a variety of viral infections, including influenza A and B, Human Immunodeficiency Virus (HIV), Herpes Simplex Virus-1 (HSV-1), viral pneumonia, and rhinovirus (26). Garlic has been shown to have immunomodulatory effects by regulating the levels of cytokines and chemokines in the body (27), suggesting that it may be a promising candidate for countering the cytokine storm triggered by COVID-19. Garlic contains fructooligosaccharides, which are essential for immunomodulation. Its extract is thought to be anti-inflammatory, anti-atherosclerotic, and blood pressure-controlling (28).

Blackpepper (Piper nigrum)

Black pepper is commonly known as Kali Mirch in India. Also, popular as ‘spice king’ which increases the texture and aroma of food as a spice. In Ayurveda, it can also be prescribed for bronchopulmonary conditions, fever, neurological disorders, and gastrointestinal problems (29). Antioxidant, anti-viral, anti-inflammatory, anti-mutagenic, anti-parasitic, anti-bacterial, anti-asthmatic, anti-carcinogenic, anti-diarrhoeal, anti-ulcer, anti-thyroid, anti-apoptotic, anti-bacterial, anti-depressant, and immunomodulatory effects are some of its properties. It further enhances the therapeutic efficacy of various drugs, vaccines, and dietary supplements (30),(31),(32),(33). Piperine is a key component of black pepper that regulates the development of cytokines in various types of immune cells, including Th1, Th2, Th17, and Treg cells. It can also minimise inflammatory cell aggregation by preventing the expression of GATA3, IL-4, IL-6, IL-1, ROR, IL-17 A, and TNF in bronchoalveolar lavage fluid and increasing INF- and IL-10 secretion. It also promotes the growth of T and B cells, as well as macrophage cells (31),(34),(35). Piperine is also harmful to cells. It reduces histamine release and serum immunoglobulin E, anti-OVA IgE, anti-OVA IgE1, and anti-OVA IgE1. It induces necrosis and inflammatory cell invasion. It also inhibits Th2/Th17 responses and activates mast cells. It inhibits NF-kB, c-Fos, the cAMP response bound element, and factor-2 transcription. It inhibits PKCa/Extracellular signal-Regulated Kinase (ERK) 1/2 and decreases NF-kB/AP-1 activation, as well as PMA-mediated MMP-9 expression. It’s also in control of p-glycoprotein inhibition and the CYP3A44 feature (36),(37),(38),(37).

Cardamom (Elettaria cardamomum)

Cardamoms are dried fruit capsules of the Zingiberaceae family. Its capsules are used to manage cataracts, nausea, gum infections, teeth and gastrointestinal, kidney diseases, asthma, diarrhoea, cardiac problems, for culinary and alternative medicine applications (38).

Antioxidant properties: Cardamom seeds are the storage of large-quality antioxidants, which scavenge free radicals by preventing the oxidation of other materials. Cardamom, according to Nair S et al., has a moderate degree of natural antioxidant properties due to the existence of phenol compounds such as quercetin, kaempferol, and luteolins (39). Natural antioxidants are considered to be safer than synthetic antioxidants (40). The essential oils in cardamom, including phytonutrients and vitamins, serve as antioxidants, scavenging free radicals and preventing cellular aging (40),(41).

Antimicrobial properties: Cardamom’s essential oil has powerful antimicrobial properties against various food microorganisms (42). The growth of Morgenella morganii was significant inhibited by the use of cardamom oil. Antimicrobial effect was also shown by essential oil extracted from cardamon towards Staphylococcus aureus, Escherichia coli, Streptococcus mutans, Salmonella typhi, Candida albicans, Bacillus pulmilus and Listeria monocytogenes (43). Most research focusing on the antibacterial activity of cardamom extracts and their essential oil was performed using the method of disc diffusion (44).

Turmeric (Curcuma longa)

In India, it is popularly called “Haldi”. The active ingredient is a polyphenolic compound known as curcumin, which acts as anti-inflammatory, anti-microbial, and has an immunomodulatory impact on our body (45). It prevents the entry of viruses into the cell, inhibits the encapsulation of viruses and virus proteases, and modulates many cellular signaling pathways (46). It is also effective in the therapy of osteoarthritis and rheumatoid arthritis. Turmeric has been suggested as a useful treatment of choice against COVID-19 (47). The following are the primary effects of curcumin on respiratory disorders.

Curcumin’s effect on pulmonary inflammation: In the inhibition of inflammatory cytokines, curcumin has its key task. Its presence stops essential signals that regulate the expression of various pro-inflammatory cytokine pathways, such as nuclear factor B and MAPKK. It has anti-inflammatory and anti-fibrotic effects. This decreases the expression of chemokines and cytokines that are involved in lung infection, such as INFγ, MCP-1, IL-6, IL-10 (48),(49). It shows inhibitory effects against RSV infection by preventing viral replication, releasing TNF alpha, and down-controlling phosphor-NF-alpha-B (45),(46).

Curcumin’s effect on pulmonary fibrosis: Pathways mediated by the p38MAPK route for curcumin inhibit apoptosis (48).

Curcumin’s impact on pulmonary oedema: The disorder where fluid accumulation takes place in the lungs is pulmonary oedema. In recent research related to SARS-CoV-2 infection has shown that its protein envelope stimulates protein kinase C, thus reducing the function of pulmonary epithelial sodium channels contributing to pulmonary oedema (50). A study by Tian S et al., has shown that the use of curcumin reduces inflammation, leading to a decrease in the influx of fluid in the lungs of the rat (51).

Impact of curcumin on heart problems associated with COVID-19: The binding of the SARS-CoV-2 virus spike protein to the ACE2 respiratory epithelium cell receptor causes respiratory problems. In people with heart issues, these complications are more pronounced. The theory may be that AEC2 in cardio patients is more frequently expressed (52). Curcumin prevents myocardial ischemia-reperfusion damage by reducing c-Jun N-terminal kinase and NF-B nuclear translocation phosphorylation. It also decreases immune cell penetration and the expression of binding molecules and pro-inflammatory mediators in vascular cells (53).

The impact of curcumin on kidney diseases: In COVID-19, the incidence of acute kidney injury is often manifested in patients with co-morbidities. The high incidence may be due to the high expression of ACE2 in the kidneys in patients with diabetes (54) and may be the reason for renal damage. In rat models, curcumin up-regulates AEC2 and ACE2 mRNA that contributes to increased blood flow in the kidneys (55). By reducing inflammation caused by MCP-1, NF- κB, TNF, IL-1β, COX-2, and COX-1, at the stage of priming and activation, curcumin also decreases renal fibrosis. This lowers anti-inflammatory variables as well. It targets MAPK/ERK, TGF-β/smads, and PPAR-pathways in animal models (56).

Clove (Syzygium aromaticum)

It is a dried flower bud, commonly used because of its strong taste and aroma to prepare spicy recipes. Also, eugenol, a bioactive compound present in cloves has been documented to have a broad range of medicinal properties such as analgesic, anti-inflammatory, immunomodulatory and better remedy for respiratory disorders as one of their phytoconstituents (57). Furthermore, clove also has an important antiviral and antipyretic potency.

Cinnamon (Cinnamomum verum)

It is a medicinal plant commonly known as Dalchini. It is used for fever, oedema, cough, and indigestion as a natural immunity booster (58). Besides, due to its volatile bioactive components, cinnamon, the world’s frequently consumed spice, has also been reported to have essential antioxidant, antitumour, and anti-inflammatory potency (59). Cinnamaldehyde, cuminaldehyde, and eugenol are its major chemical constituents. Its bark consists of various beneficial compounds such as benzaldehyde, cinnamaldehyde, terpenes, and cuminaldehyde (60). By increasing immunoglobulin and phagocytic index levels, it enhances immunity, i.e., cell-mediated and humoral immunity (58). It is documented as a cell-mediated immunity regulator because of its NF-kB obstruction property that activates signaling components, PDK1 and NF-kB (35), CD29 and CD43 are also activated by cinnamon, which prevents cell migration and triggers the attachment of one cell to another cell. It decreases nitric oxide production and also regulates CD80 and CD69 levels and specific receptors such as TLR2 and CR3 that assist in pattern recognition. Cinnamon bark extract reduces the amount of IFN-alpha without affecting the level of IL-4 or IL-2. It also inhibits anti-CD3 antibodies induced by IFN-alpha and IL-4 at mRNA and secreted protein levels increase the secretion of IL2 protein at the cellular level, helping to reduce cell death. It inhibits IL-2 mRNA expression, inhibits anti-CD3 activation mediated by p38, JNK, ERK1/2, and STAT4, but does not degrade 1k B or STAT6 (49). This shows the inhibitory effects of cinnamon on cytokine secretion and its role in the signaling molecules of activated T cells. It also leads to a decrease in the process of subG1 and increases the necrotic to apoptotic cell ratio. Its constituents cinnamaldehyde and cinnamophilinhave thromboxane A2, the receptor antagonist. It is anticoagulative and anti-atherosclerotic, preventing unwanted clumping of platelets [61]. SARS-CoV-2 inhibitors from Cinnamon have recently been identified through in silico studies [62].

Star Anise (Illicium verum)

Star anise best known as Chinese star anise, is an aromatic member of the family Schisandraceae. It is of star shape, often reported to have numerous therapeutic applications because of its bioactive compounds, is commonly used as a culinary ingredient. It is one of the essential components of Chinese herbs and is well known for its antiviral effects. As an effective booster of immunity, it helps the body to fight many viral diseases. It is also the source of shikimic acid, the key molecule used in the manufacturing of oseltamivir (Tamiflu^®), an antiviral drug for influenza A and influenza B. It has a wide range of other potentials properties in addition to its antiviral properties, such as antioxidant, antimicrobial, antifungal, etc. It is commonly used as a treatment in cough, asthma, dysentery, and in arthritis [63].

Nutmeg (Myristica fragrans)

Because of its mysterious sweet and spicy taste, Myristica fragrans has been one of the key constituents in Indian cuisine since ancient times and has also been reported to have important medical values. Nutmeg is used as a pain reliever because it has myristcine, myrcene, safrol, camphene, sabinene, linalool, 1,8-cineole, and eugenol as its volatile constituent, and it also has properties to treat stomach disease, respiratory disorders, heart disease, as well as a brain tonic, liver tonic and immunity booster [64].

Conclusion

Nutrition plays a key role in maintaining good health. Spices when added to our food items in a suitable amount, provide taste as well as act as a source of antioxidants to our body to protect from attack of harmful microorganisms. They interfere to different inflammatory factors like cytokines, growth factors (TNF- α interleukin), COX, lipoxygenase, and NOX in the NF-κB pathway.

In ancient and modern India, these spices were commonly used to treat many diseases. Many Indian spices having above mentioned active ingredients have tremendous potential as an immune booster, antioxidants, and anti-inflammatory agents in preventing/alleviating SARS-CoV-2 infection.

DOI and Others

10.7860/JCDR/2021/49530.15245

Date of Submission: Mar 20, 2021
Date of Peer Review: May 18, 2021
Date of Acceptance: Jun 24, 2021
Date of Publishing: Aug 01, 2021

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? NA
• Was informed consent obtained from the subjects involved in the study? NA
• For any images presented appropriate consent has been obtained from the subjects. NA

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