Introduction

Since 1918 to the present day, emerging infectious diseases caused by newly evolving viruses like Influenza virus, Ebola virus, Nipah virus, Hanta virus, Zika virus and Coronavirus have imposed serious threat to the public health sector and has burdened the economic growth across the globe. Towards the end of 2019, a new virus identified as severe acute respiratory syndrome coronavirus – 2 (SARS-CoV-2) was reported from Wuhan city, People’s Republic of China, and the World Health Organization (WHO) on 11 February, 2020, declared the disease as Coronavirus disease 2019 (COVID-19). On March 2020, COVID-19 was announced as a global pandemic by WHO, due to its rapid spread across the globe. Fever, dry cough, lethargy, headache, sore throat has been recognized as the most common symptoms associated with COVID-19 along with serious symptoms like shortness of breath, pain in the chest and/or loss of taste, smell, speech or movement.

John Hopkins University and Medicine reported mortality data due to COVID-19, comparing twenty most affected countries worldwide, in which India showed 4.98 percent mortality per 1 lakh population while Peru, Chile, Brazil and US secured the topmost ranks with mortality percentage of 90.87, 60.57, 59.09, 56.77 respectively.¹ As per the WHO Situation Report No. 102 as on January 12, 2022 on COVID 19, India had 35.87 million confirmed cases with a death rate of 1.34 %, the total death being 0.48 million in comparison to the global death rate of 1.74% with 5.49 million deaths out of the 308.45 million confirmed cases of COVID 19.²

The question in this context is, how a country like India with 1.3 billion population is battling against COVID-19 pandemic with a striking difference in the mortality percentage with that of the developed nations. It has been opined that the host pathogen interaction and the tropical environment played a significant role in reducing the susceptibility of a large section of Indian population to COVID-19 along with enhancement of their innate immunity and immune responses against the virus under the hot humid environmental conditions. ³ One probable answer to the low fatality rate of Indians against COVID 19 hitherto not very seriously thought of might be the Indian diet and food habits which is providing some degree of resistance to infection by immunity boosting agents contained in their natural diet as goes the Ayurvedic proverb “When diet is wrong, medicine is of no use; when diet is correct, medicine is of no need”. The Indian diets are however, incomplete without the indulgence of spices and since ages, India is regarded as the “Spice Bowl of the World”. Spices in India are not only used as culinary enhancers with regard to its aroma, color and taste but also, used to cure various ailments and as immunity boosters since time immemorial.

It has been reported that, in countries where there is meagre consumption of dietary spices, occurrence of COVID-19 cases per million population is higher.⁴ Further, a recent study based on molecular docking analysis revealed that spice bioactives have high affinity for binding with the specific targets involved in SARS-CoV-2 infection and transmission.⁵ Thus, this review provides an overview of some recent scientific findings of the most commonly used spices in the regular Indian diet which has the potential bioactive components possessing immunomodulatory effects for boosting up the immune system against the COVID-19 battle.

Innate and Adaptive Immune Response Elicited Against COVID-19 Infection

The host immune system comes into force immediately on account of an acute viral infection by destroying the virus invaded cells or with the action of cellular pro-inflammatory cytokines. ⁶ The elimination of the virus infected cells is achieved through an initial innate immune response via macrophages, natural killer (NK) cells or dendritic cells which is followed by antigen specific adaptive immunity of the host via T and B cells with the release of inflammatory cytokines to inhibit viral replication.^6,7

A recent report helps in understanding the interaction between coronavirus and the host immune system with the secretion of chemokines and cytokines (IL‐1, IL‐6, IL‐8, IL‐21, TNF‐β, and MCP‐1) in large quantities in the SARS-CoV-2 infected cells leading to inflammation in the lung tissue.⁸ Moreover, the host immune response induced against COVID-19 infection is biphasic with initial incubation and non-severe stage followed by a severe stage characterized by inflammation-driven damaging phase.⁹ Incorporation of immune boosters as a strategy to enhance immune responses during the non-severe defense-based protective phase of infection could prevent the disease progression into the severe stage (Fig. 1). However, a patient with acute COVID-19 infection has high levels of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in the lungs which are strong stimulators of HA-synthase-2 (HAS2) in CD31⁺ endothelium, EpCAM+ lung alveolar epithelial cells, and fibroblasts¹⁰ leading to transparent gel like deposition in lungs as revealed by recent autopsies¹¹ and characteristic “ground glass” CT images of the lungs.¹² As such, it is essential to suppress the hyper inflammatory immune response in the severe stage of infection.

Figure 1: Diagrammatic representation of non-severe and severe stages of COVID-19 infection and potential supportive therapy. 9 Click here to view Figure

Indian Dietary Spices as Immunomodulators

Indian traditional foods being a rich source of several functional and medicinal ingredients are often regarded as functional foods. The functional molecules present in Indian foods play a significant role in management of healthy body weight, maintenance of normal blood sugar level and a strong immune system of the body. Moreover, different processing techniques in Indian traditional practices like sprouting, malting and fermentation further enhance the functional properties of such foods.¹³

In respect of the immune response triggered by COVID-19 infection, some of the spices from the regular Indian diet comprise of several bioactive phytochemicals which seems to boost up the immune system of the Indian population in an effective way and thereby, maintaining the fatality percentage at a much lower end in comparison to the other most infected countries of the world. The effectiveness of few such commonly used spices with anti-inflammatory, anti-viral and immunomodulating properties are discussed below:

Turmeric

Turmeric (Curcuma longa) also known as the “Golden Spice” hails from the ginger family, Zingiberaceae, and its use as an inevitable culinary spice dates back to the Vedic culture in India (approximately 4000 years ago). ¹⁴ The bright yellow color of turmeric is due to the presence of turmerone and curcuminoids. Curcuminoids is a mixture of three components (demethoxycurcumin, 5’-methoxycurcumin and dihydrocurcumin) with antioxidant properties. ^{15, 16} In addition to curcuminoids, turmeric possesses other bioactive chemical compounds like sesquiterpenes, diterpenes and triterpenoids. ¹⁷

Curcumin, a polyphenolic compound, is the key ingredient of turmeric and its immunomodulatory properties arise from several interactions not only with the immune cells (dendritic cells, macrophages and B and T lymphocytes) but also, with those molecules (cytokines) associated with inflammation.¹⁸ Various studies on curcumin showing immunomodulatory and anti-inflammatory properties are listed in Table 1. Besides, curcumin is reported to have antiviral activity against human immunodeficiency virus, influenza virus, herpes simplex virus, hepatitis B virus and Japanese encephalitis virus through different molecular pathways. ^{34- 40} The potential of curcumin to be developed as a treatment of choice against COVID-19 has also been assessed using molecular docking approach against Main Protease (Mpro) and spike (S) glycoprotein receptor binding domain (RBD) of SARS-CoV-2.⁴¹ The study revealed that curcumin possessed all the optimum physicochemical and pharmacokinetic properties to inhibit Mpro covalently. Furthermore, Ayurvedic medication indicates, intake of turmeric has been used towards treatment for numerous respiration distress like asthma, bronchial hyperactivity and hypersensitivity as well as for runny nostril, cough and sinusitis. ⁴² In India, turmeric mixed with milk is often taken as a remedy against sore throat, fever and cold.

Table 1: Studies associated with curcumin- mediated immunomodulatory and anti-inflammatory effects.³³

Ginger

Ginger belonging to the family Zingiberaceae is a key spice in Indian cuisines which not only acts as a culinary enhancer but possess several nutritional and ethnomedicinal properties. Traditionally, the use of ginger as a medicinal plant against several diseases dates back to more than 2500 years ago. Fresh and dried ginger primarily comprise of gingerols and shogaols as the chief phytochemical components which are responsible for exhibiting a wide range of biological activities like anticancer, antimicrobial, anti-inflammatory, anti-oxidant and anti- allergic activities.⁴³ Moreover, the presence of several active phyto-ingredients in ginger (gingerol, shogaol, paradol, zerumbone) aids in enhancing activity of enzymes as well as its circulation and assimilation throughout the body.⁴⁴

Various studies pertaining to anti- inflammatory properties of ginger are listed in Table 2. Apart from its anti-inflammatory abilities, rhizomes of ginger are rich in metabolites with anti- viral properties. ^{49- 55} An in-vitro study reported that hot water extract of fresh ginger stimulated the secretion of IFN-β in mucosal cells which has anti-viral property against human respiratory syncytial virus (HRSV) by inhibiting viral attachment with the host cell receptors. ⁵² This anti-viral property is therefore comparable in the management of fever, cough and respiratory trouble associated with COVID-19 infection. Further, allicin is another active component of ginger which is reported to contain anti- influenza cytokines against H1N1 virus. ⁵⁶ These properties contribute towards enhancing innate immunity and in this COVID-19 pandemic situation, ginger is an important spice to be included in regular diet in disease prevention and enhancing immunity and strengthening the various biological functions of the body.

Table 2: Studies associated with anti-inflammatory properties of ginger. ⁵⁰

Garlic

Garlic (Allium sativum) is a bulbous spice belonging to the family Amaryllidaceae with characteristic pungent and spicy flavour. Garlic has been considered as an important

medicinal plant since earliest of time through since 6^th century BC. ⁵⁷ The major bioactive component of fresh or crushed garlic is allicin (allyl 2-propenethiosulfinate or diallyl thiosulfinate), a sulfur containing natural compound. In addition to allicin, other sulfur containing phytochemicals of garlic are ajoene, diallyl polysulfides, vinyldithiins, S-allylcysteine, along with  non- sulfur containing compounds like saponins, flavonoids, lectins, polysaccharides (fructan), different enzymes, vitamin A, B and C, minerals and amino-acids.⁵⁸ The interaction of allicin with cellular biomolecules like glutathione and L-cysteine results in the formation of S-allyl-mercapto-glutathione (SAMG) and S-allyl-mercaptocysteine (SAMC) respectively.^{59, 60}

Allicin has a direct impact on pathogens by bringing about unfavorable structural changes in the pathogen’s proteins. ⁶¹ Besides, there exists a plethora of pre-clinical investigations which revealed that garlic and its sulfur containing components possess anti-viral properties against virus associated respiratory infections.^{62- 65} In most of these studies, the proposed mechanism of antiviral action with aqueous garlic extract was found to be by: direct inhibition of viral infection by blocking entry of virus particles through disintegration of viral envelope and cell membrane, enhancing host immune response, inhibiting viral replication by blocking the activity of polymerase enzyme.

Further, regular dietary consumption of raw or crushed garlic has shown great impact in boosting up the immunity levels.^{66, 67} Clinical investigations also revealed that garlic extract supplementation not only modulated inflammation and immunity of obese adults but also, alleviated the severity of cold and flu affected patients by increased production of γδ-T and NK cells, serum antioxidant concentration and decrease in the levels of inflammatory cytokines.^68,69 Thus, as a prophylactic measure, garlic intake in daily meals could definitely enhance the immune system against COVID-19.

Clove

Cloves (Syzygium aromaticum) are dried flower buds with a deep brown color, intense flavour and a burning taste belonging to the family Myrtaceae. In India, clove is used as whole or in ground form in savory as well as sweet dishes. The medicinal property of clove is mainly attributed towards several disease-causing parasites and microbes due to its antiseptic and antimicrobial qualities.⁷⁰

Eugenol is the principle bioactive molecule of clove along with several other natural phenolic compounds such as flavonoids (quercetin and kaempferol), hydroxybenzoic acids, hydroxycinnamic acids and hydroxyphenyl propens.⁷¹ Besides, clove contains caffeic, ellagic, ferulic and salicylic acids belonging to the category of phenolic acids.⁷² Moreover, clove oil is a transparent or pale-yellow essential oil with distinct flavor extracted from buds. Clove oil consists of eugenol, eugenol acetate and β-cariofileno.⁷³

An in-vitro study on human dermal fibroblast system revealed that clove essential oil has anti-inflammatory properties due to its major active component eugenol.⁷⁴ Furthermore, an in-vivo study carried out on BALB/c mice showed that clove extract inhibited the production of IL-1 β and IL-6 by macrophages and the results of this study were counter proved under in-vitro conditions.⁷⁵ Another in-vitro study brought out the immunomodulatory property of this spice to verify its therapeutic property wherein, they revealed that macrophages challenged with lipopolysaccharides when incubated with clove at a dose of 100 µg/ well suppressed the synthesis of cytokines (IL-1 β, IL-6 and IL-10).⁷⁶ They proposed a possible mechanism of action which suggested that eugenol could probably suppress the nuclear factor (NF)-κB pathway. Moreover, the anti-viral activity of clove was identified against herpes simplex virus due to another component, eugeniin, which blocked the viral DNA synthesis by inhibiting the viral DNA polymerase. ⁷⁷

Thus, in Indian homes, brewing tea with two to three clove buds along with cinnamon and crushed ginger acts as a natural remedy since ages to clear away symptoms of cold, flu and congestion.

Cinnamon

Cinnamon bark belonging to family Lauraceae is one of the widely used spice across the world as flavoring agent. Apart from its traditional use as a condiment, cinnamon is reported to have anti-inflammatory properties.^78-80 Cinnamon is chemically composed of a variety of resinous compounds like cinnamaldehyde, eugenol, cinnamate, cinnamic acid, and numerous essential oils. ⁸¹

Various assays like carbon clearance test, cyclophosphamide-induced neutropenia, neutrophil adhesion test, effect on serum immunoglobulins, mice lethality test and indirect hemagglutination test were performed to screen the immuno-modulatory property of cinnamon bark which revealed that cinnamon bark at a concentration of 100 mg/kg p.o. reduced the mortality rate by 17% caused by Pasteurella multocida infection, increased the phagocytic index in carbon clearance test, enhanced the ability of neutrophil adhesion, raised serum immunoglobulin levels and antibody titer.⁸² The transcription factor, NF- κB, is involved in the regulation of genes responsible for inflammation and therefore, chronically active in many inflammatory diseases including asthma⁸³ and possibly in the severe phase of COVID-19 infection.  In this context, a study showed that trans-cinnamaldehyde and 2-methoxycinnamaldehyde extracted from cinnamon bark (Cinnamomum cassia Blume) blocked lipopolysaccharide activated DNA binding capacity as well as transcriptional activity of NF- κB.⁸⁴ Thus, these findings substantiate the belief that cinnamon is an immunity boosting spice and especially, in India, ground cinnamon is consumed with honey as a potent immunity booster.

Black Pepper

Black pepper (Piper nigrum) produced from the unripe drupe of the pepper plant belonging to family Piperaceae is not only used as a spice but has a vital position in Indian traditional medicine recommended against fever and chills and broncho- pulmonary disorders (asthma and chronic bronchitis).⁸⁵ The pungent flavour and biting taste of black pepper is derived from its natural component, piperine, an alkaloid, along with several essential oils. Piperine is responsible for all the therapeutic roles which can contribute to general human health including immunomodulatory, anti-inflammatory and anti-microbial activities.

Several reports demonstrate the immunomodulatory and anti-inflammatory properties of piperine of black pepper. Based on an in-vitro study evaluated on fibroblast stimulated with IL-1β revealed that piperine at a dose of 10- 100 µg per ml blocked the expression level of IL-6 which identified piperine as an anti-inflammatory agent.⁸⁶ Results from an in-vivo experiment also showed that piperine when administered on asthma induced Balb/c mice at the dose rate of 4.5- 2.25 mg per kg, suppression in the synthesis rate of TH2 cytokines viz., IL-4, IL-5, IL-13, immunoglobulin E and histamine was observed while, TGF-β gene expression levels were enhanced.⁸⁷  The anti-inflammatory potential of piperine was further supported through an experimental finding on rat lung tissue damage induced by gamma rays which proved decreased levels of TNF-α, IL-6 and IL-1β in the lung tissue.⁸⁸

Thus, based on the therapeutic potential of piperine, incorporation of black pepper as condiment in meals can enhance immune health which is a prerequisite against COVID-19.

Cumin and Black Cumin

Cumin and black cumin (black caraway) are seed spices obtained from Cuminum cyminum and Nigella sativa respectively belonging to the family Apiaceae and Ranunculaceae respectively. The use of these seed spices in Indian curries is due to its rich warm aroma and distinctive flavor. However, they are not without any medicinal value as they are reservoir of essential oils. The major phyto ingredients of cumin are cuminaldehyde, limonene, 1,8-cineole, α- and β-pinene, α- and γ-terpinene, o– and p-cymene, linalool and safranal while, major components found in black cumin are thymoquinone (approximately, 50%), dithymoquinone (nigellone), thymohydroquinone, carvacrol, p-cymene, sesquiterpene longifolene, thymol, 4-terpineol, α-pinene, and t-anethole.^89-90,95

Few recent reports provide experimental evidence regarding the immuno-modulating and anti-inflammatory properties of cumin and black cumin against respiratory and pulmonary diseases (Table 3).

Table 3: Significant immunomodulatory and anti-inflammatory properties of cumin and black cumin

Culinary Spices as Immunity Boosters Against COVID 19: An Overview

The multi- pharmacological role of the bioactive components of various spices used in the everyday Indian diet suggests their pivotal role against SARS-CoV-2 infection. Besides, spices also carry several minerals and micronutrients like zinc, calcium, phosphorous, potassium, sodium and iron as well as vitamins, along with their major phytoactive ingredient⁹⁶ which might synergistically play a significant role during the first phase of SARS-CoV- 2 infection in immunity build up.

Hyperinflammation is one major aggravating immunological parameter in COVID-19 patients and as such, one possible measure to reduce the mortality in patients is immune suppression at the severe phase of infection .^97,98 In COVID-19 affected patients, IL-6 has been identified as the major inflammatory cytokine during the inflammatory cytokine storm and thus, in this severe phase of infection elevated levels of IL-6 has been reported.^99,100 Another clinical manifestation from SARS-CoV-2 ICU patients, revealed high plasma levels of TNFα , IL2, IL7, IL10, MCP1, GSCF, IP10 and MIP1A.¹⁰¹ In this context, different scientific investigations ^{22,49,75,88,92,93} as discussed under this review, revealed that some of the commonly used spices in traditional Indian everyday meals do carry certain bioactive components and phytochemicals responsible for immuno-modulatory and anti-inflammatory function (Fig. 2). Thus, in India, epigenetic factors like the food habit and the indulgence of spices with high medicinal values could be one possible reason responsible for the low COVID-19 associated fatality amongst the Indian population.

Figure 2: Schematic representation of the major bioactive components of the Indian  culinary spices with potential immunomodulatory and anti-inflammatory properties against the SARS-CoV-2 (COVID-19) infection progression Click here to view Figure

Conclusion

Effective measures in the form of efficient and safe antiviral drug are still not readily available for prophylaxis and treatment against SARS- CoV-2 virus infection. Even with development of a vaccine, viruses tend to change continuously due to phenomena like antigenic drift/ shift which also results in the emergence of novel virus. As such, susceptibility against a viral disease can be significantly reduced by developing innate immunity and enhancement of immune response exploiting various factors like host, pathogen and environment interaction and adopting to food habits and diet comprising of natural bioactive components available in different Indian culinary spices.  These phytoproducts are believed to be one of the major factors to enhance innate immunity and hasten the morbidity and mortality caused by COVID 19 in India. This review highlighted and suggested to open up a new dimension to the research areas for identifying the active principles and explore the mechanism of action of these natural phytoproducts present in the Indian culinary spices in immunity boosting against COVID 19 and other emerging and re-emerging viral infections world over.

Acknowledgements

Declared none.

Authors’ contributions

SD conceived and collected the data and prepared the manuscript. PJ reviewed and approved the manuscript for communication.

Funding Sources

No funding was received for this research.

Conflict of interest

The authors declare no competing interests.

References

1. John Hopkins University & Medicine. Coronavirus Resource Center. https://coronavirus.jhu.edu/data/mortality.   Accessed 3 Sept 2020.
2. WHO Coronavirus (COVID-19) Dashboard. https://www.who.int/india/emergencies/coronavirus-disease-(covid-19)/india-situation-report Accessed 14 January 2022.
3. Samaddar A., Gadepalli R., Nag V.L., Misra S. The enigma of low COVID-19 fatality rate in India. Front Genet. 2020; 11:854.
   CrossRef
4. Elsayed Y., Khan N.A. Immunity-boosting spices and the novel Coronavirus. ACS Chem Neurosci. 2020; 11(12):1696-98.
   CrossRef
5. Natesh J., Mondal P., Penta D., Abdul Salam A.A., Meeran S.M. Culinary spice bioactives as potential therapeutics against SARS-CoV-2: Computational investigation. Comput Biol Med. 2021; 128:104102.
   CrossRef
6. Oldstone MBA.  Anatomy of viral persistence. PLoS Pathog.2009; 5(7): e1000523
   CrossRef
7. McGill J., Heusel J.W., Legge K.L. Innate immune control and regulation of influenza virus infections. J Leukoc Biol. 2009;86(4):803- 812.
   CrossRef
8. Li G., Fan Y., Lai Y., Han T., Li Z., Zhou P., Pan P., Wang W., Hu D., Liu X., Zhang Q., Wu J. Coronavirus infections and immune responses. J Med Virol. 2020; 92(4):424–432.
   CrossRef
9. Shi Y., Wang Y., Shao C., Huang J., Gan J., Huang X., Bucci E., Piacentini M., Ippolito G., Melino G. COVID-19 infection: the perspectives on immune responses. Cell Death Differ. 2020;27(5):1451–54.
   CrossRef
10. Bell T.J., Brand O.J., Morgan D.J., Salek-Ardakani S., Jagger C., Fujimori T. Cholewa L., Tilakaratna V., Ostling J., Thomas M., Day A.J., Snelgrove R.J., Hussell T. Defective lung function following influenza virus is due to prolonged, reversible hyaluronan synthesis. Matrix Biol. 2018; 80:14–28.
    CrossRef
11. Xu Z., Shi L., Wang Y., Zhang J., Huang L., Zhang C., Liu S., Zhao P., Liu H., Zhu L., Tai Y., Bai C., Gao T., Song J., Xia P., Dong J., Zhao J., Wang F.S. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020; 8(4):420-22.
    CrossRef
12. Wang D., Hu B., Hu C., Zhu F., Liu X., Zhang J., Wang B., Xiang H., Cheng Z., Xiong Y., Zhao Y., Li Y., Wang X., Peng Z. Clinical characteristics of 138 hospitalized patients with 2019 novel Coronavirus–infected pneumonia in Wuhan, China. 2020; 323(11):1061–69.
    CrossRef
13. Hotz C., Gibson R.S. Traditional food-processing and preparation practices to enhance the bioavailability of micronutrients in plant-based diets. J Nutr. 2007; 137(4):1097-11001.
    CrossRef
14. Prasad S., Aggarwal B.B. Turmeric, the golden spice from traditional medicine to modern medicine. In: Benzie IFF, Wachtel-Galor S (ed) Herbal medicine: Biomolecular and clinical aspects.2011; Boca Raton (FL): CRC Press/Taylor & Francis, Chapter 13.
    CrossRef
15. Ruby A.J., Kuttan G., Babu K.D., Rajasekharan K.N., Kuttan R. Anti-tumour and antioxidant activity of natural curcuminoids. Cancer Lett. 1995; 94(1):79–83.
    CrossRef
16. Selvam R., Subramanian L., Gayathri R., Angayarkanni N. The anti-oxidant activity of turmeric (Curcuma longa). J Ethnopharmacol. 1995;47(2):59–67.
    CrossRef
17. Abdel-Lateef E., Mahmoud F., Hammam O., El-Ahwany E., El-Wakil E., Kandil S., Abu Taleb H., El-Sayed M., Hassenein H. Bioactive chemical constituents of Curcuma longa rhizomes extract inhibit the growth of human hepatoma cell line (HepG2). Acta Pharm. 2016; 66(3):387-98.
    CrossRef
18. Momtazi-Borojeni A.A., Haftcheshmeh S.M., Esmaeili S.A., Johnston T.P., Abdollahi E., Sahebkar A, Curcumin: A natural modulator of immune cells in systemic lupus erythematosus. Autoimmun Rev. 2018;17(2):125-135.
    CrossRef
19. Liu L., Liu Y.L., Liu G.X., Chen X., Yang K., Yang Y.X., Xie Q., Gan H.K., Huang X.L., Gan H.T. Curcumin ameliorates dextran sulfate sodium-induced experimental colitis by blocking STAT3 signaling pathway. Int Immunopharmacol. 2013;17(2):314-320.
    CrossRef
20. Duncan S.A., Baganizi D.R., Sahu R., Singh S.R., Dennis V.A. SOCS proteins as regulators of inflammatory responses induced by bacterial infections: A review. Front Microbiol. 2017; 8:2431.
    CrossRef
21. Guimaraes M.R., Leite F.R.M., Spolidorio L.C., Kirkwood K.L., Rossa C. Curcumin abrogates LPS-induced pro-inflammatory cytokines in RAW 264.7 macrophages. Evidence for novel mechanisms involving SOCS-1, -3 and p38 MAPK. Arch Oral Biol. 2013;58(10):1309–17.
    CrossRef
22. Castro C. N., Barcala Tabarrozzi A. E., Winnewisser J., Gimeno M. L., Antunica Noguerol M., Liberman A. C., Paz D. A., Dewey R. A., Perone M. J. Curcumin ameliorates autoimmune diabetes. Evidence in accelerated murine models of type 1 diabetes. Clin Exp Immunol.2014; 177(1):149–60.
    CrossRef
23. Cianciulli A., Calvello R., Porro C., Trotta T., Salvatore R., Panaro M.A. PI3k/Akt signalling pathway plays a crucial role in the anti-inflammatory effects of curcumin in LPS-activated microglia. Int Immunopharmacol. 2016; 36:282–90.
    CrossRef
24. Vaure C., Liu Y. A comparative review of toll-like receptor 4 expression and functionality in different animal species. Front Immunol. 2014; 5:316.
    CrossRef
25. Kim D.K., Lillehoj H.S., Lee S.H., Jang S.I., Lillehoj E.P., Bravo D. Dietary Curcuma longa enhances resistance against Eimeria maxima and Eimeria tenella infections in chickens. Poult Sci. 2013; 92(10):2635-43.
    CrossRef
26. Yue G.G., Chan B.C., Hon P.M., Lee M.Y., Fung K.P., Leung P.C., Lau C.B. Evaluation of in vitro anti-proliferative and immunomodulatory activities of compounds isolated from Curcuma longa. Food Chem Toxicol. 2010; 48(8-9):2011–20.
    CrossRef
27. Kim G.Y., Kim K.H., Lee S.H., Yoon M.S., Lee H.J., Moon D.O., Lee C.M., Ahn S.C., Park Y.C., Park Y.M. Curcumin inhibits immunostimulatory function of dendritic cells: MAPKs and translocation of NF-kappa B as potential targets. J Immunol. 2005;174(12):8116–24.
    CrossRef
28. Weissenberger J.,   Priester M.,   Bernreuther C., Rakel S.,   Glatzel M.,   Seifert V., Kogel D. Dietary curcumin attenuates glioma growth in a syngeneic mouse model by inhibition of the JAK1,2/STAT3 signaling pathway. Clin Cancer Res. 2010; 16(23):5781-95.
    CrossRef
29. Zhu H.T., Bian C., Yuan J.C., Chu W.H., Xiang X., Chen F., Wang C.S., Feng H., Lin, J.K. Curcumin attenuates acute inflammatory injury by inhibiting the TLR4/MyD88/NF-κB signaling pathway in experimental traumatic brain injury. J Neuroinflamm. 2014; 11:59.
    CrossRef
30. Moghadamtousi S.Z., Kadir H.A., Hassandarvish P., Tajik H. Abubakar S., Zandi K. A review on antibacterial, antiviral and antifungal activity of curcumin. BioMed Res Int. 2014: Article ID186864.
    CrossRef
31. Bansal S., Chhibber S. Curcumin alone and in combination with augmentin protects against pulmonary inflammation and acute lung injury generated during Klebsiella pneumoniae B5055-induced lung infection in BALB/c mice. J Med Microbiol. 2010; 59:429-37.
    CrossRef
32. Bansal S., Chhibber S. Phytochemical-induced reduction of pulmonary inflammation during Klebsiella pneumoniae lung infection in mice. J Infect Dev Ctries. 2014; 8(7):838-844.
    CrossRef
33. Catanzaro M., Corsini E., Rosini M., Racchi M., Lanni C. Immunomodulators inspired by nature: A review on curcumin and echinacea.  2018; 23:2778.
    CrossRef
34. Li C.J., Zhang L.J., Dezube B.J., Crumpacker C.S., Pardee A.B. Three inhibitors of type 1 human immunodeficiency virus long terminal repeat-directed gene expression and virus replication. Proceedings of the National Academy of Sciences of the United States of America. 1993; 90:1839–42.
    CrossRef
35. Mazumder A., Raghavan K., Weinstein J., Kohn K.W., Pommier Y. Inhibition of human immunodeficiency virus type1 integrase by curcumin. Biochem Pharmacol. 1995; 49:1165-70.
    CrossRef
36. Balasubramanyam K., Varier R., Altaf M., Swaminathan V., Siddappa N.B., Ranga U., Kundu T.K. Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem. 2004; 279(49): 51163–71.
    CrossRef
37. Chen D.Y., Shien J.H., Tiley L., Chiou S.S., Wang S.Y., Chang T.J., Lee Y.J., Chan K.W., Hsu W.L. Curcumin inhibits influenza virus infection and haemagglutination activity. Food Chem. 2010; 119(4):1346-51.
    CrossRef
38. Bourne K.Z., Bourne N., Reising S.F., Stanberry L.R. Plant products as topical microbicide candidates: assessment of in vitro and in vivo activity against herpes simplex virus type 2. Antivir Res. 1999; 42(3): 219-26.
    CrossRef
39. Kim H.J., Yoo H.S., Kim J.C., Park C.S., Choi M.S., Kim M., Choi H., Min J.S., Kim Y.S., Yoon S.W. Ahn J.K. Antiviral effect of Curcuma longa Linn extract against hepatitis B virus replication. J Ethnopharmacol. 2009; 124(2):189-96.
    CrossRef
40. Dutta K., Ghosh D., Basu A. Curcumin protects neuronal cells from japanese encephalitis virus-mediated cell death and also inhibits infective viral particle formation by dysregulation of ubiquitin-proteasome system. J Neuroimmune Pharm. 2009; 4:328-37.
    CrossRef
41. Teli D.M., Shah M.B., Chhabria M.T. In silico Screening of Natural Compounds as Potential Inhibitors of SARS-CoV-2 Main Protease and Spike RBD: Targets for COVID-19. Front Mol Biosci. 2021; 7:599079.
    CrossRef
42. Araujo CAC., Leon L.L. Biological Activities of Curcuma longa Mem Inst Oswaldo Cruz. 2001; 96:723-28.
    CrossRef
43. SemwalB., Semwal D.K., Combrinck S., Viljoen A.M. Gingerols and shogaols: Important nutraceutical principles from ginger. Phytochemistry. 2015; 117: 554-68.
    CrossRef
44. Dissanayake KGC., Waliwita WALC., Liyanage R.P. A Review on medicinal uses of Zingiber officinale (Ginger). International Journal of Health Sciences and Research. 2020; 10:6.
45. Luettig J., Rosenthal R., Lee I.M., Krug S.M., Schulzke J.D. The ginger component 6-shogaol prevents TNF-alpha-induced barrier loss via inhibition of PI3K/Akt and NF-kappa B signaling. Mol Nutr Food Res. 2016; 60:2576–86.
    CrossRef
46. Zhang G., Nitteranon V., Chan L.Y., Parkin K.L. (2013) Glutathione conjugation attenuates biological activities of 6-dehydroshogaol from ginger. Food Chem. 2013; 140(1-2):1–8.
    CrossRef
47. Abolaji A.O., Ojo M., Afolabi T.T., Arowoogun M.D. Darlinton Nwawolor, Ebenezer O.F. Protective properties of 6-gingerol-rich fraction from Zingiber offcinale (ginger) on chlorpyrifos-induced oxidative damage and inflammation in the brain, ovary and uterus of rats. Chem Biol Interact. 2017; 270:15-23.
48. Hsiang C., Lo H., Huang H., Li C., Wu S., Ho T. Ginger extract and zingerone ameliorated trinitrobenzene sulphonic acid-induced colitis in mice via modulation of nuclear factor-kappa B activity and interleukin-1 beta signalling pathway. Food Chem. 2013; 136(1):170-77.
    CrossRef
49. Ueno N., Hasebe T., Kaneko A., Yamamoto M., Fujiya M., Kohgo Y., Kono T., Wang C.Z., Yuan C.S., Bissonnette M., Chang E.B., Musch M.W.TU-100 (Daikenchuto) and ginger ameliorate anti-CD3 antibody induced T cell-mediated murine enteritis: microbe-independent effects involving Akt and Nf-kappa b suppression. PLoS ONE. 2014; 9(5): e97456.
    CrossRef
50. Mao Q.Q., Xu X.Y., Cao S.Y., Gan R.Y., Corke H., Beta T., Li H. B. Bioactive Compounds and Bioactivities of Ginger (Zingiber officinaleRoscoe).  2019; 8(6): 185.
    CrossRef
51. Kaushik S., Jangra G., Kundu V., Yadav JP., Kaushik S. Anti-viral activity of Zingiber officinale (Ginger) ingredients against the Chikungunya virus. Virus Dis. 2020; 31(3):270-76.
    CrossRef
52. Chang JS., Wang KC., Yeh CF., Shieh DE., Chiang LC. Fresh ginger (Zingiber officinale) has anti-viral activity against human respiratory syncytial virus in human respiratory tract cell lines. J Ethnopharmacol. 2013; 145(1):146-51.
    CrossRef
53. El-Wahab AA., El-Adawi H., El-Demellawy M. In-vitro study of the antiviral activity of Zingiber officinale. Planta Med. 2009; 75- PF7.
    CrossRef
54. Abdel-Moneim A., Morsy BM., Mahmoud AM., Abo-Seif MA., Zanaty MI. Beneficial therapeutic effects of Nigella sativa and/or Zingiber officinale in HCV patients in Egypt. Excli J. 2013; 12:943-55.
55. Imanishi N., Andoh T., Mantani N., Sakai S., Terasawa K., Shimada Y., Sato M., Katada Y., Ueda K. Ochiai H. Macrophage mediated inhibitory effect of Zingiber officinale Rosc, a traditional oriental herbal medicine, on the growth of influenza A/Aichi/2/68 Am J Chin Med 2006; 34(1):157-169.
    CrossRef
56. Sahoo M., Jena L., Rath SN., Kumar S. Identification of Suitable Inhibitor against Influenza A (H1N1) neuraminidase protein by molecular docking. Genomics Inform 2016;14(3):96-103.
    CrossRef
57. Dannesteter J. AVESTA: VENDIDAD: Fargard 20: The origins of medicine. Translated from Sacred Books of the East, American Edition, New York, 2003. The Christian Literature Company, 1898, online, Available at avesta.org.
58. Rouf R., Uddin S. J., Sarker D. K., Islam M. T., Ali E. S., Shilpi J. A., Nahar L., Tiralongo E., Sarker S. D. Anti-viral potential of garlic (Allium sativum) and it’s organosulfur compounds: A systematic update of pre-clinical and clinical data. Trends Food Sci Technol. 2020; https://doi.org/10.1016/j.tifs.2020.08.006.
    CrossRef
59. El-Saber Batiha G., Magdy Beshbishy A., G Wasef L., Elewa Y.H.A., A Al-Sagan A., Abd El-Hack M.E., Taha A.E., M Abd-Elhakim Y., Prasad Devkota H. Chemical constituents and pharmacological activities of garlic (Allium sativum ): A review. Nutrients. 2020; 12(3):872.
    CrossRef
60. Trio P.Z., You S., He X., He J., Sakao K., Hou, D.X. Chemopreventive functions and molecular mechanisms of garlic organosulfur compounds. Food Funct. 2014; 5(5):833-44.
    CrossRef
61. Borlinghaus J., Albrecht F., Gruhlke MCH., Nwachukwu ID., Slusarenko AJ. Allicin: chemistry and biological properties. 2014; 19:12591-618.
    CrossRef
62. Rasool A., Khan M.U., Ali M.A., Anjum A.A., Ahmed I., Aslam A., Mustafa G., Masood S., Ali, M.A., Nawaz M. Anti-avian influenza virus H9N2 activity of aqueous extracts of Zingiber officinalis (Ginger) and Allium sativum (Garlic) in chick embryos. Pak J Pharm Sci. 2017; 30(4):1341-44.
63. Mohajer Shojai T., Ghalyanchi Langeroudi A., Karimi V., Barin A., Sadri N. The effect of Allium sativum (Garlic) extract on infectious bronchitis virus in specific pathogen free embryonic egg. Avicenna J Phytomedicine. 2016; 6(4):458-67.
64. Chavan RD., Shinde P., Girkar K., Madage R., Chowdhary A. Assessment of anti influenza activity and hemagglutination inhibition of Plumbago indica and Allium sativum Pharmacogn Res. 2016; 8(2):105-11.
    CrossRef
65. Weber N.D., Andersen D.O., North J.A., Murray B.K., Lawson L.D., Hughes, B.G. In vitro virucidal effects of Allium sativum (garlic) extract and compounds. Planta Med. 1992; 58(5):417-23.
    CrossRef
66. Abdullah T. A strategic call to utilize Echinacea-garlic in flu-cold seasons. J Natl Med Assoc. 2000; 92(1):48-51.
67. Charron C.S., Dawson H.D., Albaugh G.P., Solverson P.M., Vinyard B.T., Solano-Aguilar G.I., Molokin A., Novotny J.A. A single meal containing raw, crushed garlic influences expression of immunity and cancer related genes in whole blood of humans. J Nutr. 2015; 145(11):2448-55.
    CrossRef
68. Xu C., Mathews A.E., Rodrigues C., Eudy B.J., Rowe C.A., O’Donoughue A., Percival S.S. Aged garlic extract supplementation modifies inflammation and immunity of adults with obesity: A randomized, double-blind, placebo-controlled 1 clinical trial. Clin Nutr ESPEN. 2018; 24:148-55.
    CrossRef
69. Nantz M.P., Rowe C.A., Muller C.E., Creasy R.A., Stanilka J.M., Percival S.S. Supplementation with aged garlic extract improves both NK and γδ-T cell function and reduces the severity of cold and flu symptoms: a randomized, double-blind, placebo-controlled nutrition intervention. Clin Nutr. 2012; 31(3):337-44.
    CrossRef
70. El-Saber Batiha G., Alkazmi LM., Wasef LG., Beshbishy AM., Nadwa E.H., Rashwan E.K. Syzygium aromaticum (Myrtaceae): Traditional uses, bioactive chemical constituents, pharmacological and toxicological activities. Biomolecules. 2020; 10(2): 202.
    CrossRef
71. Neveu V., Perez-Jiménez J., Vos F., Crespy V., du Chaffaut L., Mennen L., Knox C., Eisner R., Cruz J., Wishart D., Scalbert A. Phenol-Explorer: An online comprehensive database on polyphenol contents in foods. Database 2010: bap024
    CrossRef
72. Cortés-Rojas D.F., de Souza C.R., Oliveira W.P. Clove (Syzygium aromaticum): A precious spice. Asian Pac J Trop Med. 2014; 4(2):90-96.
    CrossRef
73. Jirovetz L., Buchbauer G., Stoilova I., Stoyanova A., Krastanov A., Schmidt E. Chemical Composition and Antioxidant properties of clove leaf essential oil. J Agric Food Chem. 2006; 54(17):6303-07.
    CrossRef
74. Han X., Parker T.L. Anti-inflammatory activity of clove (Eugenia caryophyllata) essential oil in human dermal fibroblasts. Pharm Biol. 2017; 55(1):1619-22.
    CrossRef
75. Rodrigues T.G., Fernandes A .Jr., Sousa J.P., Bastos J.K., Sforcin J.M. In vitro and in vivo effects of clove on pro-inflammatory cytokines production by macrophages. Nat Prod Res. 2009; 23(4):319-26.
    CrossRef
76. Bachiega T.F., de Sousa J.P., Bastos J.K., Sforcin J.M. Clove and eugenol in noncytotoxic concentrations exert immunomodulatory/ anti-inflammatory action on cytokine production by murine macrophages. J Pharm Pharmacol. 2012; 64(4):610-16.
    CrossRef
77. Kurokawa M., Hozumi T., Basnet P., Nakano M., Kadota S., Namba T., Kawana T., Shiraki K. Purification and characterization of eugeniin as an antiherpesvirus compound from Geum japonicum and Syzygium aromaticum. J Pharmacol Exp Ther. 1998; 284(2):728-35.
78. Chao LK., Hua KF., Hsu HY., Cheng SS., Liu JY., Chang ST. Study on the Anti-inflammatory activity of essential oil from leaves of Cinnamomum osmophloeum. J Agr Food Chem. 2005; 53(18):7274-7278.
    CrossRef
79. Tung YT., Chua MT., Wang SY., Chang ST. Anti-inflammation activities of essential oil and its constituents from indigenous cinnamon (Cinnamomum osmophloeum) twigs. Bioresour Technol. 2008; 99(9):3908–3913.
    CrossRef
80. Tung YT., Yen PL., Lin CY., Chang ST. Anti-inflammatory activities of essential oils and their constituents from different provenances of indigenous cinnamon (Cinnamomum osmophloeum) leaves. Pharm Biol. 2010; 48(10):1130-1136.
    CrossRef
81. Senanayake UM., Lee TH., Wills RBH.Volatile constituents of cinnamon (Cinnamomum zeylanicum) oils. J Agr Food Chem. 1978; 26(4):822-824.
    CrossRef
82. Niphade SR., Mohammed A., Gowda KC., Emmanuel T., Deshmukh P. Immunomodulatory activity of Cinnamomum zeylanicum Pharm Biol. 2009; 47(12):1168-73.
    CrossRef
83. Monaco C., Andreakos E.,   Kiriakidis S.,   Mauri C.,   Bicknell C., Foxwell B., Cheshire N., Paleolog E., Feldmann M. Canonical pathway of nuclear factor κB activation selectively regulates proinflammatory and prothrombotic responses in human atherosclerosis. Proceedings of the National Academy of Sciences of the United States of America. 2004; 101(15): 5634-9.
    CrossRef
84. Reddy A.M., Seo J.H., Ryu S.Y., Kim Y.S., Kim Y.S., Min K.R., Kim Y. Cinnamaldehyde and 2-methoxycinnamaldehyde as NF-kappaB inhibitors from Cinnamomum cassia. Planta Med. 2004; 70(9):823-27.
    CrossRef
85. Salehi B., Zakaria Z.A., Gyawali R., Ibrahim S.A., Rajkovic J., Shinwari Z.K., Khan T., Sharifi-Rad J., Ozleyen A., Turkdonmez E., Valussi M., Tumer T.B., Monzote Fidalgo L., Martorel, M., Setzer, W.N.  Piper species: A comprehensive review on their phytochemistry, biological activities and applications. 2019; 24(7):1364.
    CrossRef
86. Bang J.S., Oh D.H., Choi H.M., Sur B.J., Lim S.J., Kim J.Y., Yang H.I., Yoo M.C., Hahm D.H. Kim K.S. Anti-inflammatory and antiarthritic effects of piperine in human interleukin 1beta-stimulated fibroblast-like synoviocytes and in rat arthritis models. Arthritis Res Ther. 2009; 11(2): R49.
    CrossRef
87. Kim SH., Lee YC. Piperine inhibits eosinophil infiltration and airway hyperresponsiveness by suppressing T cell activity and Th2 cytokine production in the ovalbumin-induced asthma model. J Pharm Pharmacol. 2009; 61(3):353-9.
    CrossRef
88. Elkady A., Tawfik S.S. Anti-inflammatory role of piperine against rat lung tissue damage induced by gamma-rays. Int J Radiat Res. 2018; 16(1):75–84.
89. Johri R.K. Cuminum cyminum and Carum carvi: An update. Pharmacogn Rev. 2011; 5(9):63-72.
    CrossRef
90. Ali B.H., Blunden G. Pharmacological and toxicological properties of Nigella sativa. Phytother Res. 2003; 17(4): 299–305.
    CrossRef
91. Chauhan P.S., Satti N.K., Suri K.A., Amina M., Bani S. Stimulatory effects of Cuminum cyminumand flavonoid glycoside on cyclosporine-A and restraint stress induced immune-suppression in swiss albino mice. Chem Biol Interac. 2010; 185(1):66–72.
    CrossRef
92. Wei J., Zhang X., Bi Y., Miao R., Zhang Z,. Su H. Anti-inflammatory effects of cumin essential oil by blocking JNK, ERK, and NF-κb signaling pathways in LPS-stimulated RAW 264.7 cells. Evid Based Complement Alternat Medn. 2015: 474509.
    CrossRef
93. Taka E., Mazzio E.A., Goodman C.B., Redmon N., Flores-Rozas H., Reams R., Darling-Reed S. Soliman K.F. Anti-inflammatory effects of thymoquinone in activated bv-2 microglial cells. J Neuroimmunol. 2015; 286:5-12.
94. Kanter M., Akpolat M. Aktas C. Protective effects of the volatile oil of Nigella sativa seeds on beta-cell damage in streptozotocin-induced diabetic rats: a light and electron microscopic study. J Mol Histol. 2009; 40(5-6):379-85.
    CrossRef
95. Boskabady MH., Javan H., Sajady M., Rakhshandeh H. The possible prophylactic effect of Nigella sativa seed extract in asthmatic patients. Fund Clin Pharmacol. 2007; 21:559-66.
    CrossRef
96. Omotayo Arike, O., Adepoju Thomas O., Keshinro Oluremi O. Evaluation of micronutrient potentials of seven commonly consumed indigenous spices from Nigeria. Am J Food Nutr. 2013; 3(3):122-6.
    CrossRef
97. Xu Z., Shi L., Wang Y., Zhang J., Huang L., Zhang C., Liu S., Zhao P., Liu H., Zhu L., Tai Y., Bai C., Gao T., Song J., Xia P., Dong J., Zhao J., Wang F.S. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020; 8(4):420-22.
    CrossRef
98. Mehta P., McAuley DF., Brown M., Sanchez E., Tattersall R.S., Manson J.J., HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. 2020; 395(10229):1033-1034.
    CrossRef
99. Wan S., Yi Q., Fan S., Lv J., Zhang X., Guo L., Lang C., Xiao Q., Xiao K., Yi Z., Qiang M., Xiang J., Zhang B., Chen Y. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP). 2020; medRxiv doi:10.1101/2020.02.10.20021832
    CrossRef
100. Wong C.K., Lam C.W., Wu A.K., Ip W.K., Lee N.L., Chan I.H., Lit L.C., Hui D.S., Chan M.H., Chung S.S., Sung J.J. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. 2004; 136(1):95–103.
     CrossRef
101. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., Zhang L., Fan G., Xu J., Gu X., Cheng Z., Yu T., Xia J., Wei Y., Wu W., Xie X., Yin W., Li H., Liu M., Xiao Y., Gao H., Guo L., Xie J., Wang G., Jiang R., Gao Z., Jin Q., Wang J., Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223):497-506.
     CrossRef