COVID-19, cytokines, inflammation, and spices: How are they related?

Abstract

Background

Cytokine storm is the exaggerated immune response often observed in viral infections. It is also intimately linked with the progression of COVID-19 disease as well as associated complications and mortality. Therefore, targeting the cytokine storm might help in reducing COVID-19-associated health complications. The number of COVID-19 associated deaths (as of January 15, 2021; https://www.worldometers.info/coronavirus/) in the USA is high (1199/million) as compared to countries like India (110/million). Although the reason behind this is not clear, spices may have some role in explaining this difference. Spices and herbs are used in different traditional medicines, especially in countries such as India to treat various chronic diseases due to their potent antioxidant and anti-inflammatory properties.

Aim

To evaluate the literature available on the anti-inflammatory properties of spices which might prove beneficial in the prevention and treatment of COVID-19 associated cytokine storm.

Method

A detailed literature search has been conducted on PubMed for collecting information pertaining to the COVID-19; the history, origin, key structural features, and mechanism of infection of SARS-CoV-2; the repurposed drugs in use for the management of COVID-19, and the anti-inflammatory role of spices to combat COVID-19 associated cytokine storm.

Key findings

The literature search resulted in numerous in vitro, in vivo and clinical trials that have reported the potency of spices to exert anti-inflammatory effects by regulating crucial molecular targets for inflammation.

Significance

As spices are derived from Mother Nature and are inexpensive, they are relatively safer to consume. Therefore, their anti-inflammatory property can be exploited to combat the cytokine storm in COVID-19 patients. This review thus focuses on the current knowledge on the role of spices for the treatment of COVID-19 through suppression of inflammation-linked cytokine storm.

Graphical abstract

1. Introduction

The ongoing novel coronavirus pandemic has taken a major toll on human lives worldwide. In December 2019, the first case of the ongoing pandemic of the novel coronavirus disease (COVID-19) was reported [1]. The epicenter of COVID-19 was identified as Wuhan, the capital of Hubei province, China. Initially, the outbreak was declared as a “Global Health Emergency” by the World Health Organization (WHO) on 30^th January 2020 [2]. However, as COVID-19 spread rapidly across the globe affecting thousands of lives worldwide, the WHO finally declared it a Global pandemic on 11^th March 2020 [3].

As per the weekly epidemiological update released by the WHO on 10^th January 2021 at 10:00 CEST, the total number of cases worldwide were reported to be 88,387,352 with 1,919,204 deaths. In India, the total cases were reported to be 10,450,284 with 150,999 deaths [4]. The geographical distribution of the COVID-19 pandemic as per 14-day COVID-19 case notification rate per 100,000 population (as of 13^th January 2021) has been illustrated in Fig. 1 [5].

Fig. 1.

The geographical distribution of the COVID-19 pandemic as per 14-day COVID-19 case notification rate per 100,000 population (as of 13^th January 2021) [5].

The causative pathogen of COVID-19 has been identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is a novel human coronavirus (HCoV) [6]. The SARS-CoV-2 is believed to have a zoonotic origin and bats are considered as their natural reservoir host. The transmission of the virus occurs from human-to-human mostly by direct and indirect contact with cough or sneeze droplets from an infected person and contaminated surfaces, respectively. The incubation period of the virus is approximately 2–14 days. Infected people may present symptoms such as fever, cough, breathlessness, etc. However, some may remain asymptomatic [7,8]. COVID-19 is usually mild; however, infected patients with comorbidities, such as hypertension, diabetes, cancer, immunodeficiency, etc. are more prone to poor prognosis. In such cases, the severity of disease progression might eventually result in pneumonia, acute respiratory distress syndrome (ARDS), and multi-organ failure which may ultimately cause death [7,9].

Although the exact pathophysiological mechanism of COVID-19 is poorly understood; clinical evidence has revealed that COVID-19 infected patients often show an elevated rise in the cytokine levels which is termed as “cytokine storm” or “cytokine release syndrome”. This abnormal level of cytokines is considered to be correlated with severe deterioration of health conditions in the infected patients [10]. Therefore, suppressing elevated inflammatory response produced during COVID-19 may prove crucial in preventing the severity of disease as well as associated health complications [11].

Various studies have reported that naturally occurring spices as well as their isolated active components target the inflammatory pathways and induce anti-inflammatory effects in many chronic diseases [[12], [13], [14]].

A recent study conducted on primary data of 163 countries worldwide in respect of total cases, deaths, and recoveries of COVID-19 revealed a close association of the total number of COVID-19 cases per million population tested and the gram of spice supplied per capita per day. This study further reported that the nation with an increased number of COVID-19 cases per million population corresponds to lower consumption of spices per capita, with some exceptions such as Luxembourg and Iceland [15]. As of 10^th January 2021, the cumulative cases of COVID-19 in United States of America (USA) are 21,761,186 compared to 10,450,284 cases in India. Moreover, the cumulative cases and deaths per 100,000 population in the USA are reported to be 6574.3 and 110.5 (1.68%), respectively, as opposed to 757.3 cumulative cases and 10.9 deaths (1.439%) in India [4]. As of 20^th January 12:07 PM IST, in India, Lakshwadeep (0.00019%), Dadar and Nagar Havelli; Daman and Diu (0.03%), and Mizoram (0.04%) have recorded low number of cases compared to the rest of the states, while Maharashtra recorded the highest number of cases (18.82%) out of the total number of cases (10,596,449). Lakshwadeep has not reported any COVID-19 associated death so far. Further, Dadar and Nagar Havelli; Daman and Diu (0.1%), Mizoram (0.2%), Arunachal Pradesh (0.3%), and Kerala (0.4%) have recorded a low fatality ratio. Interestingly, although Kerala has reported approximately 8% of the total cases, the fatality ratio is quite low (0.4%). This low fatality ratio in Kerala can be attributed to the efficient management of the disease, healthcare system, etc. [16,17]. Moreover, as spices and herbs are rich immunity boosters and are prevalently consumed in India and other Asian countries, it might be associated with faster recovery and lower per million population deaths. This was evinced by a study which reported that the intake of spicy food was associated with a 14% decrease in total mortality and thus suggested their inverse association [15,18]. This review thus focuses on the anti-inflammatory role of spices as potential therapeutic agents to combat the occurrence of “cytokine storm” in COVID-19.

2. Lockdown

The outbreak of COVID-19 was first reported in December in Wuhan and Hubei province. Several places were majorly affected by the COVID-19 which led to the imposition of lockdown. During this lockdown period, several activities such as travel via international flights as well as local transports, mass gatherings at public places such as schools, universities, etc., had been restricted. Moreover, people were not allowed to go outside for any work, except for certain essential activities for a limited period with strict guidelines of social distancing. Despite these enforcements and restrictions, the number of COVID-19 cases had increased significantly throughout the world [19,20]. Initially, India had reported fewer COVID-19 cases because it was able to enforce strict lockdown and social distancing. Moreover, the general public was strongly advised to wear a mask and wash or sanitize hands frequently with soap or sanitizers as a preventive measure throughout the country. The WHO had praised India's early implementation of nationwide lockdown as “tough and timely”. Later, when the restrictions were relaxed, the COVID-19 cases increased drastically [21,22]. Community transfer had been observed in various countries that had not implemented early lockdown. Previous studies reported that travel restrictions and isolation had played a pivotal role in the outbreaks of Ebola, SARS-CoV, and bubonic plague [[23], [24], [25]]. However, the implementation of lockdown alone is not the permanent solution to prevent the further spread of COVID-19 and this raised serious concerns [19].

Some studies also reported that South Korea and Sweden had not implemented stringent lockdown and restrictions on their countries. However, the rate of infections in these countries was observed to be lower than those which had implemented strict lockdown [26,27]. One of the important reasons behind fewer infection and death rates in South Korea was believed to be the rapid testing of COVID-19 [21]. Sweden and Denmark had also followed different strategies rather than stringent lockdown to mitigate the virus spread. The authorities in those countries had appealed for strong awareness and a personal sense of responsibility and further encouraged people to work from home. The patients with comorbidities, such as respiratory ailments, immune deficiency, hypertension, cancer, diabetes, diseases of the heart, liver, and kidneys were found to be more prone to the COVID-19 infection and death. Therefore, people with a high risk of COVID-19 due to comorbidities or age were strongly recommended to follow quarantine and self-isolation to ‘flatten the curve’. Moreover, the kindergartens, nurseries, schools, and colleges remained open during this period while following the norms of social distancing and awareness [9,[27], [28], [29], [30], [31]].

The USA has recorded the highest number of COVID-19 infections and deaths. Currently, India has the 2^nd highest number of COVID-19 cases and the 3^rd highest number of deaths. Brazil is 3^rd and 2^nd in terms of the number of cases and deaths, respectively. European countries (Russia, France, Spain, UK, Italy, and Germany) have also reported a significantly higher number of COVID-19 associated deaths; however, many people recovered and the number of active cases has declined lately [4]. A closer look has uncovered various reasons for the spread of community transfer of COVID-19 in these countries, such as frequent international travels as well as the late and casual implementation of social distancing [21,26]. The implementation of lockdown due to the COVID-19 pandemic has given birth to certain health-related issues, such as obesity, irregular sleeping behavior, anxiety, depression, etc. Moreover, it has also affected the economy very gravely throughout the world [[32], [33], [34]].

3. Human coronaviruses (HCoVs)

3.1. History

The human coronavirus (HCoV) was first characterized in the 1960s [35]. Tyrell and Bynoe from the Common Cold Unit, England, investigated samples from patients with the common cold and isolated a novel flu-like virus in the 1960s. These viruses were labeled as B814 and were reported as ether sensitive in nature. Initially, they were unable to culture B814 by utilizing the available standard culture techniques. However, in 1965, they were successful in growing B814 in organ cultures [[35], [36], [37], [38]]. In 1966, Hamre and Procknow from the University of Chicago isolated and reported the presence of a novel RNA virus associated with respiratory disease. This virus was labeled 229E and it exhibited ether sensitivity like the B814 virus [39].

The B814 and 229E viruses were characterized using electron microscopy by Almeida and Tyrell. These ether sensitive viruses were reportedly indistinguishable from one another as well as the avian infectious bronchitis virus (IBV) [40]. These novel viruses along with other morphologically identical animal viruses such as IBV were grouped into a new genus termed “Coronavirus” (Latin word “corona” meaning “crown”) in 1968. They were named after the characteristic fringe or crown-like rounded projections on their surface (resembling the solar corona) as observed under an electron microscope [35,41]. In 1975, the coronaviruses were clubbed under a novel family of viruses named “Coronaviridae” [42]. Apart from the aforementioned HCoVs, several other strains of HCoVs have been identified; some of these include the HCoV-OC43 (1967), SARS-CoV (2002–2003), HCoV-NL63 (2004), HCoV-HKU1 (2005), Middle East respiratory syndrome (MERS)-CoV (2012), and SARS-CoV-2 (2019) [[43], [44], [45]]. The HCoVs such as 229E, OC43, NL63, and HKU1 are known as endemic CoVs. They are commonly found in the human population and are known to cause mild respiratory infections [46]. However, HCOVs such as SARS-CoV, MERS-CoV, and SARS-CoV-2 are the deadlier viruses that have caused the global outbreak and infected thousands of people worldwide [44].

Towards the latter end of 2002, the emergence of an infectious virus was reported from the Guangdong province, China. This virus was reported to transmit from human-to-human and was later identified as the SARS-CoV in 2002–2003. The infected people mostly presented with symptoms such as fever, cough, myalgia, etc. Other symptoms included headache, dyspnea, hypoxia, vomiting, etc. [[45], [46], [47], [48], [49]]. In some cases, the occurrence of pneumonia and ARDS had also been reported [48].

In 2012, the the first case of MERS-CoV was reported from Saudi Arabia and the outbreak quickly spread across the Arabian Peninsula [50,51]. Several cases were also reported in Asia, Europe, and Africa [52]. The transmission of MERS-CoV reportedly occurs via human-to-human as well as dromedary camel-to-human. However, the cases of camel-to-human infection are comparatively less [53]. Infected people initially exhibit symptoms such as fever, headache, cough, myalgia, etc. However, the disease might progress in severe cases and cause pneumonia, ARDS, septic shock as well as multi-organ failure, which can be fatal. Besides, cases of asymptomatic MERS-CoV infection have also been reported [44].

The recently identified novel coronavirus SARS-CoV-2 belongs to the genera β-coronavirus of the Coronaviridae family [54]. It reportedly shares 96% and 79.6% sequence identity to the bat CoVRaTG13 and SARS-CoV, respectively [8].

3.2. Origin and structural features

The coronaviruses (CoVs) are single, positive-strand RNA viruses. Their genome is approximately 26–32 kilobases in size [44]. They belong to the coronaviridae family of the order nidovirales and are categorized into the genera – alpha (α), beta (β), gamma (γ), and delta (δ) coronavirus [54]. The α- and β-CoVs include both human and animal CoVs. The HCoVs such as 229E, NL63 belong to α-CoV while the OC43, HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2 belong to the β-CoVs. The γ- and δ-CoVs primarily consists of avian coronaviruses [45].

The viral genome of CoV encodes four important structural proteins. They are - the envelope (E), spike (S), membrane (M), and nucleocapsid (N) proteins [54]. The E, S, and M proteins are anchored in the lipid bilayer of the viral envelope [55]. The M protein is approximately 25–30 kDa and gives shape to the virus. The E protein is approximately 8–12 kDa and promotes viral release. Together, the M and E proteins are associated with the viral assembly. Furthermore, they also facilitate the maturation of viral envelopes [56]. The N protein is involved in the formation of the nucleocapsid. It binds with the viral genome and plays an essential role in viral packaging [55]. The S protein (class I fusion protein) is approximately 150 kDa. It is responsible for the characteristic spike-like protrusions on the virus. It comprises S1 and S2 subunits and undergoes cleavage by furin-like protease in the host. The S1 subunit contains a receptor-binding domain (RBD). It binds to the host receptor angiotensin-converting enzyme 2 (ACE2). The S2 subunit of the viral S protein then fuses with the cell membrane of the host, which facilitates viral entry into the host cells [[56], [57], [58]].

3.3. Mechanism of SARS-CoV-2 entry in cells

Till now, the mechanism of SARS-CoV-2 infection is not completely elucidated. Several studies are being conducted globally on SARS-CoV-2 to unravel the mechanism of infection and pathogenesis of the novel coronavirus. The β-CoVs - SARS-CoV and SARS-CoV-2 are substantially identical and are considered to infect humans similarly. The S protein contributes substantially to the attachment and fusion of the virus with the host cell. The RBD of the S1 subunit of the viral S protein binds to the host cell receptor which initiates the viral infection [[56], [57], [58]].

Studies have reported that SARS-CoV and SARS-CoV-2 utilize the same human ACE2 (hACE2) receptor to attach themselves to the host cells [8]. The ACE2 receptor is significantly expressed in the type II alveolar, oral mucosal, and nasal epithelial cells [[59], [60], [61]]. The respiratory airways, cornea, heart, kidneys, etc., also express the ACE2 receptor [59]. These organs are highly vulnerable and most affected in COVID-19 [62].

A recent study reported that SARS-CoV-2 has a greater affinity to the hACE2 receptor than SARS-CoV. They further stated that structural alterations in the ACE2-binding ridge of SARS-CoV-2 RBD are responsible for the high affinity towards the hACE2 receptor [63]. The enzyme furin cleaves the SARS-CoV-2 S protein at the S1/S2 site and exposes the S2 subunit, which mediates the fusion of viral and host membranes [58,64]. This cleavage is responsible for the pre-activation of the S protein which promotes the subsequent type II transmembrane serine protease (TMPRSS2)-dependent viral entry into host cells [64]. The TMPRSS2 is considered significant for the entry of SARS-CoV-2 in the host cell. A broader expression of TMPRSS2 is reported in the nasal cavity, lungs, colon, gall bladder, kidney, prostate, pancreas, heart, etc. Further, the nasal epithelial cells are enriched with TMPRSS2 as well as the ACE2 receptor [59]. The TMPRSS2 primes the ACE2 receptor-bound viral S protein leading to a conformational change [64,65]. This conformational change activates S protein and facilitates the viral entry into the host cells. Moreover, it also clears the ACE2 receptor [58].

A study reported that TMPRSS2 is expressed specifically in ACE2⁺ cell types. Further, the study also stated that the expression of proteases such as cathepsin B (Cat B) was observed in >70–90% of ACE2⁺ cells. Altogether, the findings implied that SARS-CoV-2 might also utilize alternative pathways for entry [59]. Similar findings were also reported in another in vitro study, which demonstrated that SARS-CoV-2 is dependent on both cathepsin B/L (CatB/L) and TMPRSS2 for priming and entry into the host cell. This study showed that inhibition of any one of these proteases leads to partial inhibition of viral entry, which suggested that in the absence of TMPRSS2, the virus may utilize CatB/L for its entry and vice-versa [66].

Following the entry, SARS-CoV-2 liberates its genomic material (mRNA) in the cytoplasm. It takes over the protein synthesis machinery in the host and translates the mRNA in the nucleus. Besides, it also utilizes the machinery to synthesize viral proteins and subsequently initiates viral replication [58] (Fig. 2 ).

Fig. 2.

Mechanism of SARS-CoV-2 entry in cells. A. Binding of SARS-CoV-2 spike to the host ACE2 receptor. B. Cleavage of SARS-CoV-2 spike by TMPRSS2, membrane fusion, infection, and viral RNA release into the host cell.

Abbreviations: ACE2: Angiotensin converting enzyme-2, NTD: N-terminal domain, RBD: Receptor binding domain, S protein: Spike protein, SARS-CoV-2: Severe Acute Respiratory Coronavirus-2.

4. Cytokine storm in COVID-19

Accumulating pieces of evidence suggest that viral infection instigates an exaggerated or hyperactive immune response in the host leading to a “cytokine storm”. The novel coronavirus infection elicits a similar response in the host. This often involves the interplay of various chemokines, colony-stimulating factors, interferons (IFNs), interleukins (ILs) as well as tumor necrosis factor-α (TNF-α). The cytokine storm is correlated to the severity of the infection and often causes extensive damage or injury. Furthermore, it is also considered as a leading cause of ARDS, and multi-organ failure, which are closely associated with the severity and progression of COVID-19. Moreover, the cytokine storm and associated complications are the major cause of death in COVID-19 patients [10,67,68].

Several studies have investigated the clinical characteristics of the cytokine storm in COVID-19 patients [[69], [70], [71]]. In the extremely severe patients, elevated levels of IL-2 receptor (IL-2R), IL-6 as well as IL-10 were observed. Moreover, a gradual reduction in the absolute count of CD4⁺ T, CD8⁺ T, and B cells was also observed as the severity of the disease progressed. These findings suggested that there is a correlation between immune response and severity of COVID-19 progression [72,73].

A study conducted on forty three COVID-19 patients showed elevated IL-6 levels in severe cases and thus correlated to the severity of the disease [74]. A retrospective multicenter study investigated the deceased and discharged COVID-19 cases. The study reported that elevated IL-6 was observed in the deceased cases. Further, the cause of mortality in the deceased group was primarily due to respiratory failure (53%) [75]. The evaluation of the clinical features in deceased COVID-19 patients showed that a majority of deceased patients were associated with comorbidities, such as hypertension and cardiac anomalies. Further, the majority presented with complications, such as ARDS, respiratory failure, sepsis, acute cardiac injury, and heart failure. Moreover, the concentrations of the IL-2R, IL-6, IL-8, IL-10, and TNF-α were also found to be elevated [76].

A retrospective analysis of COVID-19 patients with pneumonia demonstrated an increased expression of serum IL-6. Furthermore, a decrease in the CD3, CD4, Natural Killer (NK), and CD8 cells were also observed [71]. Cytokine profiling of the peripheral blood samples obtained from severe patients revealed an increase in the levels of IL-6, IL-10, IL-2, and IFN-γ. Besides, it was also observed that the lymphocyte and T cell (especially CD8⁺ T) counts were substantially decreased while the neutrophil count was increased [70]. Another study also showed increased levels of IL-2, IL-7, IL-10, and TNF-α. Further, it reported similar trends for granulocyte colony-stimulating factor (GCSF), C-X-C motif chemokine 10 (CXCL10), monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-1 α [69].

Transcriptomic profiling of cytokines in SARS-CoV-2 infected patients have revealed elevated levels of cytokines MCP-1, CXCL10, MIP-1α, and MIP-1β [77]. Increased expression of CXCL10, IL-6, IL-8, MCP-1, RANTES (regulated on activation, normal T cell expressed and secreted), and TNF-α was also observed in severe COVID-19 patients [78]. The diabetic COVID-19 patients showed substantially increased leukocyte and neutrophil count. Further, elevated level of IL-2R, IL-6, IL-8, and TNF-α were also observed [79].

Altogether, the aforementioned findings indicated a pivotal role of cytokine storm in COVID-19 patients. Therefore, targeting the cytokine storm might help in attenuating the severity of disease progression.

5. Molecular pathways linked to inflammation

Inflammation is a vital cellular process or an immune response to injury, tissue damage, or infection in the body which assists in upholding the tissue homeostasis under traumatic or stressed conditions and regulates the host defense mechanism against pathogens [80]. The key molecular mediators of inflammation include inflammatory cytokines such as TNF-α; chemokines; inflammatory enzymes such as cyclooxygenase (cox)-1, and -2; matrix metalloproteinase (MMP)-9, 5-lipooxygenase (5-LOX); transcription factors such as signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-B (NF-κB); ILs, for example, IL-1, -6, and -8. The most important mediator of inflammation is the ubiquitous expression of NF-κB transcription factor which play an essential role in the modulation of a wide array of genes encoding cell adhesion molecules, cytokines, and its receptors which helps in triggering inflammation [14,[81], [82], [83], [84]]. NF-κB is a heterotrimer comprising of three subunits namely p65, p50, and an inhibitory subunit IκBα. It is mainly present in the cytoplasm, and upon activation by different inflammatory stimuli, various carcinogens, radiations (such as UV-light, γ-rays, and x-rays), several free radicals, and cytokines, etc. translocates into the nucleus. After translocation into the nucleus, the activated NF-κB can bind to different promoter regions of several genes and activate around 400 genes which play an important role in inflammation and various other chronic diseases [[85], [86], [87], [88]]. NF-κB activation can regulate the various hallmarks of cancer, such as cancer cell proliferation, survival, angiogenesis, invasion, migration, and metastasis. They also take part in instigating chemoresistance and radiation resistance. The expression of several inflammatory mediators, for instance, cox-2, inducible nitric oxide synthase (iNOS), TNF-α, and ILs are regulated through NF-κB [82,88,89]. TNF-α is the most potent pro-inflammatory cytokine discovered so far. Overexpression of this cytokine can ultimately lead to inflammation and various other chronic diseases, including cancer through the regulation of the NF-κB pathway [88,90,91]. Hence, the TNF-α blockers possess immense potential to control inflammation, and the overall global market for TNF-α blockers was valued at US$ 43.39 billion in 2017 and expected to reach US$ 181.13 billion by 2026 [81,90,92]. The macrophages mainly release a group of cytokines known as interleukins, for example, IL-1β, IL-6, and IL-8 which play crucial roles in inducing an inflammatory response. It is now well evinced that the augmentation of expression of iNOS, cox-2, and abnormal expression of IL-1, IL-6, IL-8 and TNF-α have been observed in case of oxidative stress that ultimately leads to inflammation [14,81,93]. IL-6 is an NF-κB-dependent cytokine that controls the activation of STAT3. STAT3, a transcriptional factor, is activated through Janus-activated kinase (JAK) 1, 2, and 3, which causes tyrosine phosphorylation, homodimerization, nuclear translocation of STAT3 where it binds to the DNA and is responsible for the induction of numerous inflammatory and immune responses. Moreover, several other transcription factors such as nuclear factor erythroid 2–related factor 2 (Nrf2), activator protein-1 (AP-1), nuclear factor of activated T cells (NFAT), and hypoxia-inducible factor-1α (HIF-1α) are also regulated through various inflammatory cytokines which play a pivotal role in controlling the cellular stress responses [14,[93], [94], [95]]. The mitogen-activated protein kinase (MAPK) pathway can act as a molecular target for the prevention and treatment of different inflammatory diseases. The MAPK family consists of mainly three types of stress-activated protein kinase pathways viz. extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), which can regulate the IL-5 level and other cytokines during inflammation [14,96].

6. Available repurposed drugs against COVID-19

The molecular pathogenesis of SARS-CoV-2 is not completely known and studies are being conducted globally to investigate novel drugs and targets. However, at present, there are no available drugs to treat COVID-19. Although, many studies are currently ongoing to develop and test antiviral drugs and vaccines against the causative virus SARS-CoV-2 in preclinical and clinical settings; these vaccines or novel drugs might be unavailable until 2021 [45]. In the absence of novel antiviral drugs, “repurposed drugs” are often prescribed for the treatment of COVID-19 based on the symptoms [97]. Some of the repurposed drugs that are currently used or suggested against SARS-CoV-2 as well as COVID-19 associated cytokine storm and complications are mentioned in Table 1 .

Table 1.

Repurposed drugs against the novel coronavirus (SARS-CoV-2).

Drug	Molecular target/mechanism of action	Company	Reference
Acalabrutinib	Can potentially exert antiviral and anti-inflammatory effects	–	[98]
Amphotericin B	Blocks the interaction of SARS-CoV-2 S-protein with hACE-2 receptor	–	[99]
Anakinra	IL-1 inhibitor; Neutralizes SARS-CoV-2 related hyperinflammation	Swedish Orphan Biovitrum	[97,100]
Arbidol	Inhibit membrane fusion; Prevents the viral entry	–	[101]
Atorvastatin	Attenuates NF-κB activation; Decreases hazard for death	–	[102]
Azithromycin	Mechanism unknown; commonly used as adjunct with hydroxychloroquine	–	[97]
Baricitinib	JAK1 and JAK2 inhibtor, Can potentially inhibit SARS-CoV-2 entry	–	[103]
Bemcentinib	Can potentially reduce viral infection and blocks SARS-CoV-2 spike protein	BerGenBio ASA, Norway	[98]
Bromhexine	Transmembrane protease serine inhibitor	–	[104]
Camostat mesilate	Inhibits serine protease	–	[66,105]
Chloroquine	Changes the pH of endosomes; Prevents viral entry, transport and post-entry events	–	[106]
Cefuroxime	Inhibits the viral RNA-dependent RNA Polymerase	–	[107]
Ciclesonide	Exerts antiviral and anti-inflammatory effects; Treated pneumonia and lung injury	–	[108]
Ciprofloxacin	Binds to SARS-CoV-2 Mpro; Inhibits viral replication	–	[109]
Clarithromycin	Exerts antiviral activity; Inhibits protein synthesis by binding to the 50S ribosomal subunit	–	[110]
Daclatasvir	Inhibits SARS-CoV-2 replication in vitro; Prevents the induction of pro-inflammatory cytokines	–	[111]
Darunavir/cobicistat	HIV protease inhibitor	–	[112]
Dasatinib	Inhibits SARS-CoV-2 3CL protease	–	[99]
Dexamethasone	Reduces inflammation, modulates immune system	–	[113]
Disulfiram	Inhibits 3CL protease	–	[114]
Doxycycline	Decreases pro-inflammatory cytokines like IL-6, TNF-α; Inhibits SARS-CoV-2 papain-like protease, MMPs; Protects against lung injury	–	[115]
Ergotamine	Blocks the interaction of SARS-CoV-2 S-protein with human ACE-2 receptor	–	[99]
Favipiravir	Inhibits the viral RNA-dependent RNA Polymerase	Toyama Chemical, Japan	[116,117]
Galidesivir	Binds to the viral RNA-dependent RNA polymerase	–	[118]
HCQ	Alters the pH of endosomes; prevents viral entry, transport and post-entry events	–	[97]
Imatinib	Suppresses the NF-κB signaling pathway; Stimulates PGE2; Decreases the release of TNF-α, IL-1β and IL-6	–	[119]
Indomethacin	Blocks viral RNA synthesis	–	[120]
Interferron γ/β	Inhibits viral replication (SARS-CoV)	–	[121]
Ivermectin	Inhibits IMPα/β1-mediated nuclear import of viral proteins	–	[122]
Lactoferrin	Exerts immunomodulatory and anti-inflammatory effects; Reduces IL-6 and TNF-α; Inhibits viral entry by binding to the host cell surface HSPGs; Inhibits the SARS-CoV-2 invasion	–	[123]
Lopinavir/Ritonavir	HIV protease inhibitor	–	[97]
Losartan	Blocks AT1R	–	[124]
MEDI3506	Can potentially treat respiratory failure caused by COVID, IL-33 inhibitor	–	[98]
Metformin	May induce activation of AMPK which may casuse phosphorylation of ACE2 receptor, thus interfering with viral entry; Inhibition of mTOR pathway and prevention of immune hyperactivation interference with viral endocytic cycle	–	[125,126]
Methylpred-nisolone	Inhibits inflammatory cascade	–	[127]
Moxifloxacin	Binds to SARS-CoV-2 Mpro; Inhibits viral replication	–	[109]
Nafamostat mesylate	Inhibits TMPRSS2; Prevents viral and host membrane fusion	–	[128]
Niclosamide	Inhibits viral replication (SARS-CoV, MERS-CoV)	–	[129]
Nitazoxanide	Supresses inflammation; Antiviral effects	–	[97,130]
Pirfenidone	Inhibits TNF-α	–	[131]
Povidone-Iodine	Exerts virucidal activity	–	[132]
Remdesivir	Inhibits the viral RNA-dependent RNA polymerase	Gilead Sciences, USA	[133]
Ribavarin	Binds to the viral RNA-dependent RNA polymerase	–	[118]
Rivaroxaban	Inhibits SARS-CoV-2 3CL protease	–	[99]
Sacubitril/Valsartan	Can potentially reduce pro-inflammatory,	–	[134]
	Cytokines and neutrophil count; Increases lymphocyte count; reduces hs-CRP levels
Sarilumab	Blocks IL-6	Regeneron Pharmaceuticals and Sanofi	[97,135]
Saquinavir	Inhibits SARS-CoV-2 3CL protease	–	[99]
Setrobuvir	Binds to the viral RNA-dependent RNA polymerase	–	[107]
Sildenafil	Inhibits SARS-CoV-2 3CL protease	–	[99]
Siltuximab	IL-6 blocker	–	[135]
Sirolimus	Modulates PI3K/Akt/mTOR pathway and inhibits MERS-CoV activity	–	[97]
Sofosbuvir	Binds to the viral RNA-dependent RNA polymerase	–	[118]
Tacrolimus	Inhibits replication of the	–	[136]
(FK506)	SARS-CoV, HCoV-NL63 and HCoV-229E
Tadalafil	Inhibits SARS-CoV-2 3CL protease	–	[99]
Telmisartan	Blocks AT1R	–	[124]
Tenofovir	Binds to the viral RNA-dependent RNA Polymerase	–	[118]
Thymosin α1	Restores T cell exhaustion; Recovers the immune reconstitution via promoting thymus output	–	[137]
Tocilizumab	Inhibits IL-6	Roche and Chugai Pharmaceutical	[97,135]
Vancomycin	Blocks interaction of the SARS-CoV-2 S-protein with hACE-2 receptor	–	[99]
Zilucoplan	C5 inhibitor; can potentially block the severe inflammatory response in COVID-19	–	[98]
α-ketoamides	Binds to SARS-CoV-2 main protease (Mpro)	–	[138]

Abbreviations:

ACE2: Angiotensin-converting enzyme-2, Akt: Protein kinase B, AMPK: AMP-activated protein kinase, AT1R: Angiotensin receptor 1, CoV: Coronavirus, COVID-19: Coronavirus disease-19, hACE-2: Human angiotensin-converting enzyme-2, HCoV: Human coronavirus, HCQ: Hydroxy-chloroquine, HIV: Human immunodeficiency virus, hs-CRP: High sensitivity C-reactive protein, HSPGs: Heparan sulfate proteoglycans, IL: Interleukin, IMPα/β1: Importin α/β1, JAK: Janus Kinase, MERS-CoV: Middle East respiratory syndrome coronavirus, MMP: Matrix metalloproteiniases, Mpro: Main protease, mTOR: Mammalian target of rapamycin, NF-κB: Nuclear factor kappa B, PGE₂: Prostaglandin E₂, PI3K: Phosphoinositide 3-kinases, SARS-CoV-2: Severe acute respiratory syndrome coronavirus-2, TNF-α: Tumor necrosis factor-α, 3CL: 3C-like protease.

Among the available repurposed therapeutic drugs currently used against SARS-CoV-2, the most commonly prescribed drugs are antiviral. Several antiviral drugs previously tested against Ebola, human immunodeficiency virus (HIV), Influenza, etc., are currently being investigated to evaluate their efficacy and safety against SARS-CoV-2 [[139], [140], [141]]. These antiviral drugs are used commonly to treat infected patients, alone or in combination [142].

6.1. Arbidol

Arbidol (umifenovir) is an indole-derivative antiviral drug commonly used against influenza. Besides, it also suppresses viruses such as hepatitis B and C, chikungunya, reovirus, Hantaan [143]. Arbidol efficiently inhibits SARS-CoV-2 infection in Vero E6 cells by effectively blocking the entry as well as post-entry stages of the virus [141]. A study conducted molecular dynamics simulation and structure-based studies to analyze the exact target of arbidol on SARS-CoV-2 and determine the associated mechanism. The study revealed that arbidol binds to the S2 domain of S protein on SARS-CoV-2 and thereby interferes with the trimerization, which is essential for the adhesion and fusion with the host cell membrane [101]. Further, SARS-CoV-2 infected hospitalized patients treated with arbidol (0.4 g, three times per day for 9 days) exhibited improvement in the discharge rate as well as a reduction in the mortality rate as compared to the untreated patients [144]. However, a retrospective study stated that umifenovir does not improve the outcome of COVID-19 patients [145].

6.2. Chloroquine and hydroxychloroquine

Chloroquine is a well-known antimalarial drug. It is also used against lupus erythematosus and rheumatoid arthritis (RA). The hydroxylated form of chloroquine i.e., hydroxychloroquine (HCQ) exhibits similar properties [97]. Chloroquine is also reported to possess antiviral activity. Various studies have reported its antiviral activity against HIV-1, hepatitis A virus, and dengue virus. HCQ exerts antiviral activity against HIV-1 [139,146].

Chloroquine inhibits the viral infection by elevating the endosomal pH essential for viral-host cell fusion. It also interrupts the glycosylation of the SARS-CoV receptors [106]. Previously, chloroquine was also reported to exhibit effective antiviral activity against HCoV-OC43 in vivo [147]. It is also reported to be effective against the novel coronavirus infection in Vero E6 cells [106].

An in vitro study demonstrated that HCQ and azithromycin (AZM) exert synergistic effects against SARS-CoV-2 [148]. A retrospective study reported that early treatment of SARS-CoV-2 infected patients with HCQ and AZM resulted in low mortality rates [149]. Further, an open-label non-randomized clinical trial reported that HCQ caused a decline in the viral load in COVID-19 patients. Additionally, it was found that AZM further reinforced its effect but the mechanism by which the two drugs act in combination is unknown [150,151]. WHO has discontinued the HCQ arm for its Solidarity Trial as it induced little or no decrease in mortality [152]. HCQ has been associated with cardiac abnormalities like QT prolongation and AZM might enhance the risk [151].

6.3. Favipiravir

Favipiravir (T705) is an anti-influenza drug, manufactured by Toyama Chemical, Japan. It inhibits the viral RNA-dependent RNA polymerase [117]. An open-label, non-randomized, control study reported that the treatment of infected patients with a combination of favipiravir and IFN-α inhibited the disease progression and results in faster viral clearance as compared to lopinavir/ritonavir. Favipiravir was administered orally for 14 days (1600 mg twice on day 1 followed by 600 mg, twice, daily for the remaining days) while IFN-α was administered via aerosol inhalation (5,000,000 U twice, daily) [116].

6.4. Lopinavir/Ritonavir

Lopinavir a protease inhibitor prescribed for the treatment of HIV. The oral bioavailability of lopinavir is considerably poor; therefore it is often prescribed in combination with ritonavir which boosts its exposure. Ritonavir also inhibits the enzymes which metabolize lopinavir and further enhances its antiviral effect [97]. A recent in vitro study reported that lopinavir exhibits antiviral effect against HCoVs such as 229E, SARS-CoV, and MERS-CoV [153]. It is also reported to be effective against SARS-CoV-2 in vitro [154]. However, WHO recently discontinued the lopinavir/ritonavir arm for its WHO-led Solidarity Trial conducted for the treatment of COVID-19 hospitalized patients as the drug exerted little or no decrease in mortality [152].

6.5. Remdesivir

Remdesivir (GS-5734) is a nucleoside analog of adenosine, manufactured by Gilead Sciences. It is a broad-spectrum antiviral drug that inhibits the viral RNA-dependent polymerase and thus, interferes with viral replication [133,140]. It had been previously tested against the Ebola virus [155]. An in vitro study has also demonstrated its antiviral activity against viruses of the Paramyxoviridae, Pneumoviridae as well as Filoviridae families [156]. Remdesivir also shows promising results against SARS-CoV and MERS-CoV infection in human airway epithelial cells [157]. Therefore, various studies are conducted to investigate its efficacy against the novel coronavirus infection in both preclinical and clinical settings. An in vitro study demonstrated that remdesivir was efficacious against novel coronavirus infection [106]. The synergistic inhibitory effect of remdesivir with emetine (a protein synthesis inhibitor) against SARS-CoV-2 was also observed in vitro [154]. Furthermore, remdesivir also induced substantial clinical improvement, when administered during the early stages of SARS-CoV-2 infection, in the rhesus macaque model [158]. A study reported the compassionate use of remdesivir against COVID-19 in SARS-CoV-2 infected patients. 36 out of 53 patients intravenously treated with remdesivir (200 mg of on day 1 followed by 100 mg for 9 days) showed clinical improvement [159].

Antiviral drugs such as oseltamivir, lopinavir, ritonavir, ganciclovir have been used commonly to treat infected patients, alone or in combination or [142]. A cohort study on severe COVID-19 hospitalized patients revealed that the treatment with oseltamivir or ganciclovir lowered the risk of death [160].

6.6. Others

The aforementioned antiviral drugs are some of the most actively prescribed and studied repurposed drugs. However, apart from these, several other drugs are currently being tested in pre-clinical and clinical settings. Some of these drugs are antihelminthic, corticoids, immunomodulators, protease inhibitors, antifibrotic, anti-inflammatory, etc. These drugs have shown effectiveness either in the hospitalized COVID-19 patients or against SARS-CoV-2 in vitro/in vivo/in silico. Moreover, some of these drugs are hypothesized to target COVID-19 associated complications such as hyper inflammation (cytokine storm), pneumonia, ARDS, etc. [97].

Ivermectin and niclosamide are potent antihelminthic drugs [97]. A study demonstrated that ivermectin also shows antiviral activity against SARS-CoV-2 in vitro [122]. Previously, niclosamide had been shown effective against SARS-CoV, MERS-CoV, Ebola virus, rhinovirus, etc. Therefore, these broad-spectrum antihelminthic drugs might be quite promising in inhibiting SARS-CoV-2 [129].

Corticosteroids show anti-inflammatory effects and effectively inhibits the cytokine levels. Therefore, they might be used to combat the cytokine storm in COVID-19 patients. Dexamethasone is a synthetic corticosteroid that has shown promising results against COVID-19. A recent study investigated the short-term treatment with dexamethasone in SARS-CoV-2 patients with hypoxic respiratory failure. The study reported that dexamethasone was well-tolerated and may help in attenuation of the hyper-inflammatory phase [97,113]. Methylprednisolone is an anti-inflammatory and antifibrotic drug that efficiently inhibits the inflammatory response. Further, methylprednisolone might also be associated with an improved outcome as well as lung function in COVID-19 patients [127]. Although these corticosteroids show effective results, their usage for the treatment of COVID-19-associated pneumonia remains controversial. As their continuous administration can suppress the immune system, it is necessary to determine the appropriate dose as well as the rationale for its usage [97,127].

The IL-6 inhibitors tocilizumab, sarilumab, and siltuximab are hypothesized to be effective against COVID-19 patients. These IL-6 inhibitors are also tested against SARS-CoV-2 in both preclinical and clinical studies [97,135]. Early treatment with tocilizumab reportedly improves the clinical outcome and causes a decline in mortality in COVID-19 pneumonia patients [161]. A recent study investigated the effectiveness of tocilizumab for the treatment of mechanically ventilated COVID-19 patients. It was observed that tocilizumab was associated with a low death rate [162]. A study in severe COVID-19 pneumonia patients showed that treatment with sarilumab also exhibited promising results [163].

IL-1 promotes pro-inflammatory cytokines such as IL-6 and contributes significantly to cytokine storm. Anakinra, an IL-1 receptor antagonist, blocks both IL-1α and IL-β. It is therefore believed to be highly effective in combating COVID-19 associated cytokine storm [164]. The Ana-COVID study has shown that it reduces SARS-CoV-2 associated hyper inflammation [100].

Baricitinib is a JAK 1 and JAK 2 inhibitor [103]. A study showed that it improved the respiratory function in COVID-19 patients who failed to respond completely to sarilumab [165]. Further, baricitinib reportedly attenuated pneumonia and decreased the mortality rate in COVID-19 patients [103].

Bromhexine hydrochloride is a mucolytic cough suppressant that also acts as a TMPRSS2 inhibitor. As TMPRSS2 is responsible for the SARS-CoV-2 entry in the host cell, bromhexine might be effective in inhibiting the virus [104,[166], [167]]. Nafamostat mesylate inhibited MERS-CoV infection by acting as a TMPRSS2 inhibitor. A study reported that it also efficiently inhibited the SARS-CoV-2 infection in vitro. Further, it blocked the viral S protein-mediated fusion [128]. Camostat mesylate (also known as camostat mesilate) is a serine protease inhibitor. In vitro studies have shown that camostat mesylate can prevent SARS-CoV-2 infection by inhibiting the TMPRSS2 activity. Therefore, camostat mesylate might be beneficial in the treatment of COVID-19 patients [66,105].

Several studies have shown that the administration of the antidiabetic drug metformin in diabetic COVID-19 patients is associated with a decrease in mortality [[168], [169], [170], [171]]. Currently, a very few studies have been conducted on metformin in association with COVID-19 in vitro and therefore, the exact mechanism of action is unknown. However, a few possible mechanisms of action have been reported [125,126].

Darunavir is a potent HIV protease inhibitor [112]. Cobicistat is an effective booster that enhances the pharmacokinetics of the antiretroviral drugs and is hence often co-administered with darunavir [172]. A pilot study (NCT04252274) showed that darunavir/cobicistat in COVID-19 patients is well-tolerated. However, it did not show any significant improvement as compared to the control group [173]. The aforementioned findings aligned with another in vitro study which showed that darunavir/cobicistat is ineffective against SARS-CoV-2 in vitro [112].

Indomethacin, a cox inhibitor, has been reported to exhibit antviral effect against canine CoV (CCoV) as well as SARS-CoV. It inhibits viral RNA synthesis in vitro [120]. A recent study has shown that indomethacin is also effective against the SARS-CoV-2 in vitro as well as CCoV in vivo [174].

Doxycycline, an antibacterial drug, reduces the pro-inflammatory cytokines such as IL-6 and TNF-α. This anti-inflammatory property of doxycycline might repress cytokine storm and prove essential in preventing lung damage associated with COVID-19. Further, a computational study revealed that doxycycline might inhibit SARS-CoV-2 papain-like protease and thereby prevent the infection [115,175].

A retrospective study conducted on severe COVID-19 patients showed that the administration of thymosin-α1 supplement substantially decreased the mortality of severe COVID-19 patients. Further, it also induced the reversion of exhausted T cells [137].

Ciclesonide, an inhaled steroid, effectively inhibits SARS-CoV-2 infection by targeting the viral replication-transcription complex in vitro [176]. A study reported three cases where ciclesonide attenuated COVID-19 associated pneumonia [108].

Imatinib is an break point cluster (Bcr)-Abelson (Abl) tyrosine kinase inhibitor and a potent anticancer drug. It also modulates immune response and exerts anti-inflammatory effects. Further, it also exhibits antiviral effects against SARS-CoV and MERS-CoV. Therefore, it is believed that imatinib might also be effective against SARS-CoV-2 and exert an immunomodulatory effect against COVID-19 pneumonia [119,177]. Another drug, lactoferrin, a non-toxic glycoprotein, is found to have immunomodulatory and anti-inflammatory effects. Therefore, it has been proposed as an adjunct for the treatment of COVID-19 [123]. In addition, many other drugs have high potential in the treatment of COVID-19. For example, povidone-iodine also exhibits potent virucidal activity against SARS-CoV-2 [132]. The drug tacrolimus (FK506), which has been previously tested effective in inhibiting the replication of HCoVs such as SARS-CoV, NL63, and 229E, might also inhibit SARS-CoV-2 [136]. Pirfenidone, an antifibrotic drug, and inhibitor of TNF-α, which is used to treat idiopathic pulmonary fibrosis, might also be effective in combating cytokine storm in COVID-19 patients [131]. It also modulates the angiotensin II type 1 receptor/p38 MAPK/renin-angiotensin system (AT1R/p38 MAPK/RAS axis) [178]. Therefore, it has been hypothesized that pirfenidone might be useful in combating COVID-19 associated cytokine storm as well as lung fibrosis [131]. Another drug, sirolimus (rapamycin), a commonly used immunosuppressant and an inhibitor of mammalian target of rapamycin (mTOR) kinase, was also shown to suppress the MERS-CoV infection effectively [97,179]. Therefore, a Phase II clinical study has been initiated to investigate the effect of sirolimus on COVID-19 patients with pneumonia (NCT04341675) [180]. Another clinical trial, the ACCORD study (EudraCT 2020-001736-95), was initiated to investigate the efficacy of drugs such as bemcentinib and nebulized heparin (potential SARS-CoV-2 S protein blocker), MEDI3506 (anti-IL-33 monoclonal antibody), acalabrutinib (BTK inhibitor), and zilucoplan (complement C5 inhibitor) in COVID-19 patients and the results are awaited [98].

Besides, atorvastatin (an inhibitor of β-Hydroxy β-methylglutaryl-CoA or HMG-CoA reductase), chloroquine and clarithromycin (an antibiotic), losartan and telmisartan (AT1R inhibitor), sacubitril/valsartan (an angiotensin receptor-neprilysin inhibitor), IFN-β and IFN-γ, nitazoxanide (a thiazolide) and daclatasvir (anti-hepatitis C virus drug) have also found to have high potential in the management of COVID-19 [102,110,111,121,124,130,134,181]. For example, atorvastatin treatment was reported to reduce the mortality of COVID-19 patients [102]. Another study showed that the administration of chloroquine and clarithromycin improved the symptoms in a COVID-19 patient with pneumonia [110]. Further, losartan and telmisartan, which effectively block the AT1R, might be useful against SARS-CoV-2 [124]. Moreover, sacubitril/valsartan, which inhibits pro-inflammatory cytokines and suppresses the inflammation, was also found to have the potential for the treatment of COVID-19 patients [134,181]. Another study reported that a combination of IFN-β and IFN-γ inhibit SARS-CoV replication synergistically [121]. Further, daclatasvir was shown to inhibit viral replication of SARS-CoV-2 in vitro and suppress the production of pro-inflammatory cytokines [111]. Another study reported that nitazoxanide suppresses SARS-CoV, MERS-CoV, and influenza virus and inhibits inflammation in vitro [130].

Additionally, a number of in silico studies reported the potential of several compounds in the management of COVID-19. For example, an in silico study shows that disulfiram, rivaroxaban, saquinavir, tadalafil, sildenafil, dasatinib inhibit the SARS-CoV-2 3 C-like (3CL) protease enzyme, which is essential for the viral transcription and replication [99,114]. Further, it showed that ergotamine, amphotericin B, and vancomycin block interaction of SARS-CoV-2 S-protein with the ACE2 receptor in silico [99]. Molecular docking and simulation study also revealed that α-ketoamides, ciprofloxacin, and moxifloxacin bind to SARS-CoV-2 main protease (Mpro) in silico, which might be effective in inhibiting the SARS-CoV-2 infection [109,138]. The drugs setrobuvir and cefuroxime effectively bind to the SARS-CoV-2 RdRp in silico and hence can be used for treatment against the virus [107]. Similar findings were observed for ribavirin, sofosbuvir, galidesivir, and tenofovir [118].

Various studies have also suggested that the compounds derived from Mother Nature can also be effective in the treatment against COVID-19. A recent molecular docking study evaluated the binding potential of various phytochemicals to the non-structural protein 15 (Nsp15), which is associated with viral replication. The study reported that ajmalicine, alpha terpinyl acetate, curcumin, gingerol, novobiocin, piperine, rosmarinic acid, silymarin and aranotin, sarsasapogenin, and ursonic acid exhibited binding affinity with the Nsp15 protein. Therefore, these phytochemicals might effectively inhibit viral replication and their efficacy should be evaluated in pre-clinical as well as clinical studies [182]. Another study conducted molecular docking simulations between functional foods and SARS-CoV-2 Mpro. It reported that quercetrin exhibited inhibition against SARS-CoV-2 Mpro in silico [183]. Curcumin also demonstrated a high binding free energy for the enzymes Cat K, COVID-19 Mpro, and SARS-CoV 3CL protease [184].

The natural compounds such as andrographolide, berberine, curcumin, mangiferin, nimbin, piperine, thebaine, and withaferin A exhibited a binding affinity for the ACE2 receptor as well as SARS-CoV-2 S protein. Further, the compounds gallic acid, luteolin, naringenin, quercetin, resveratrol, and zingiberene showed an affinity to only the ACE2 receptor. These compounds might inhibit the attachment of the SARS-CoV-2 virus to the host cell [185] (Fig. 3 ).

Fig. 3.

The potential of spices in suppressing SARS-CoV-2 cytokine storm-induced lung fibrosis. The binding of SARS-CoV-2 to the ACE2 receptor causes the fusion of the viral and the target host membrane which eventually leads to the release of the viral RNA in the cytoplasm of the host cell. Following its release, the virus utilizes the host machinery to synthesize viral proteins and subsequently initiates viral replication, followed by packaging and assembly of the viral particles. The mature virus thus formed and released ellicit aggravated inflammatory response or cytokine storm in the host, which causes ARDS or lung fibrosis in severe cases. As spices are potent anti-inflammatory agents, they might prove effective in combating the SARS-CoV-2 induced cytokine storm and thus might be beneficial in preventing cytokine storm-induced complications such as ARDS or lung fibrosis.

Abbreviations: ACE2: Angiotensin converting enzyme-2, SARS-CoV-2: Severe Acute Respiratory Coronavirus-2.

7. Anti-inflammatory role of spices

Mother Nature has bestowed us with various promising medicinal plants as well as plant-based products such as fruits, vegetables, herbs, and spices that are abundantly consumed [[186], [187], [188], [189], [190], [191], [192], [193], [194]]. Apart from their high nutritional value, these are also rich in therapeutic properties [189,193,[195], [196], [197], [198], [199], [200]].

Various medicinal plants have been a part of traditional medicine for ages and are consumed due to their health benefits as well as efficacy against a plethora of diseases [[201], [202], [203], [204], [205], [206], [207], [208], [209], [210], [211], [212], [213], [214], [215]].

The leaves of the plants which are utilized for culinary purposes and consumed fresh are known as herbs. Spices, on the other hand, are consumed as dried parts of a plant. It can be a bud, root, seed, bark, berries, or even stigma of a flower [14,186,216]. In addition to their usage in culinary purposes for imparting flavor and taste to food, they are also beneficial to health. Spices and herbs have been used in various traditional medicines since time immemorial. They effectively act against many diseases such as arthritis, asthma, cancer, diabetes, etc. [[217], [218], [219], [220]]. In severe cases of COVID-19, cytokine storm is commonly observed and is majorly responsible for the degradation of health conditions [10]. As spices and herbs exhibit potent anti-inflammatory activities, they could be used to combat the elevated levels in COVID-19 associated cases and boost immunity with minimal or no side-effects [14]. Some of the spices, as well as their anti-inflammatory roles, are mentioned below and in Table 2 (Fig. 4 ).

Table 2.

Anti-inflammatory role of spices.

Spices	Active compound/form of use	Disease	In vitro/in vivo	Model	Mechanism	References
Asafetida (Ferula asafetida L.)	–A	Liver cancer	In vitro	HepG2, SK-Hep1	↓ NF-κB, ↓ TGF-β1, ↑ caspase-3, ↑ TNF-α	[221]
	–B	Breast cancer	In vivo	BALB/c mice	↓ LOX	[222]
	–	Breast cancer	In vivo	SD rats	↓ cyt-P450, ↓ cyt b5, ↑ catalase, ↑ GSH, ↑ GST,	[223]
					↑ SOD, ↓ TBARS, ↑ DT-diaphorase
	–B	–	In vivo	Albino mice	↓ LOX	[224]
Basil (Ocimum sp.)	–C	Asthma	In vivo	Wistar rats	↓ IL-4, ↓ IgE, ↓ PLA2, ↓ TP, ↑ IFN-γ/IL-4 ratio	[225]
	–C	Gastric ulcer	In vivo	Swiss albino	↓ TBARS, ↓ NO, ↓ H2O2, ↑ GSH, ↑ GPx, ↑ GST,	[226]
				CD1 mice	↑ catalase, ↑ GR, ↓ TNF-α, ↓ IL-6, ↑ PGE2, ↑ IL-4
Bay leaves (Laurus nobilis)	–C		In vitro	BMDMs	↓ p-IκB, ↓ p-STAT3, ↓ pro‐IL‐1β, ↓ procaspase‐1,	[227]
					↓ IL‐1β, ↓ caspase‐1, ↓ NLRP3 inflammasome,
					↓ NF‐κB signaling, ↓ mRNA expression of IL‐6,
					TNF‐α, and iNOS
	–C	ALI	In vivo	C57BL/6 mice	↓ MPO activity, ↓ IL‐1β, ↓ IL‐6, ↓ TNF‐α	[227]
	1,8‐Cineole	–	In vitro	BMDMs	↓ IL‐1β, ↓ caspase‐1, ↓ Activation of NF‐κB and	[227]
					STAT3, ↓ mRNA expression of IL‐6, TNF‐α, and
					iNOS
Black cumin (Nigella sativa)	–C	Lung inflammation	In vivo	Wistar rats	↓ TGF-β1, ↓ IFN-γ, ↓ PGE2, ↑ IL-4, ↑ catalase,	[228]
					↑ SOD, ↓ MDA, ↑ thiol
	–A	Low-grade inflammation	In vitro	THP-1 cells	↓ IL-1β, ↓ MCP-1, ↓ gene expression of DNMT3A and HDAC1	[229]
	–C	Diabetes	In vivo	Wistar rats	↓ mRNA expression of VCAM-1 and LOX-1,	[230]
					↑ mRNA expression of eNOS
	–C	–	In vivo	Wistar rats	↓ MDA, ↓ NO, ↓ IL-6, ↑ thiol, ↑ SOD, ↑ catalase,	[231]
					↓ AST, ↓ ALT, ↓ ALP, ↑ serum protein, ↑ albumin
	–A	Allergic asthma	In vivo	Wistar rats	↓ IL-4, ↓ NO	[232]
	TQ	AD	In vivo	SD rats	↓ TLR2, ↓ TLR4, ↓ TNF-α, ↓ MyD88, ↓ IL-1β,	[233]
					↓ IRF-3, ↓ NF-κB
Black Pepper (Piper nigrum)	–C	Asthma	In vivo	BALB/c mice	↓ IL-1β, ↓ TNF-α, ↓ IL-4, ↓ RORγt, ↓IgE,	[234]
					↓ IL-17A
	–C	AR	In vivo	BALB/c mice	↓ E-cadherin, ↑ HO-1, ↑ Nrf2	[235]
	–C	AR	In vivo	BALB/c mice	↓ p-YSTAT3, ↓ IL-6, ↓ TNF-α, ↓ NF-κB p65,	[236]
					↓ IL-1β
	Pipernigramides	Edema	In vitro	RAW 264.7	↓ TNF-α, ↓ IL-1β, ↓ IL-6, ↓ PGE2, ↓ p-IKKβ	[237]
	Pipernigramides	Edema	In vivo	ICR mice	↓ NO, ↓ neutrophil infiltration	[237]
	Piperine	Lung metastasis	In vivo	C57BL/6 mice	↓ tumor nodule formation, ↑ survival rate, ↓ SA,	[238]
					↓ GGT
	Piperine	Bacterial sepsis	In vitro	J774A.1, BMDM	↓ IL-1β, ↓ HMGB1, ↓ p-AMPK	[239]
	Piperine	Bacterial sepsis	In vivo	C57BL/6 mice	↓ IL-1β release	[239]
	Piperine	AP	In vitro	PAC	↓ MPO, ↓ TNF-α, ↓ IL-1β, ↓ IL-6	[240]
	Piperine	AP	In vivo	C57BL/6 mice	↓ p-ERK1/2, ↓ p-p38, ↓ p-JNK	[240]
	Piperine	LN	In vitro	HK-2 cells	↓ p-AMPK, ↓ IL-1β, ↓ HMGB1, ↓ pro-caspase-1	[241]
	Piperine	LN	In vivo	BALB/c mice	↓ NLRP3 inflammasome activitation	[241]
	Chabamide	Inflammation	In vitro	RAW264.7	↑ HO-1, ↑ Nrf2, ↓ iNOS	[242]
Capsicum (Capsicum annum L.)	–C	–	In vivo	Wistar rats	↓ ALT, ↓ AST, ↓ ALP, ↓ TNF-α, ↓ IL-6, ↓ LPO,	[243]
					↓ Cu-Zn-SOD, ↓ GPx, ↑ CAT, ↑ Mn-SOD, ↑ GR,
					↓ VLDL, ↑ HDL
	–C	Asthma	In vivo	BALB/c mice	↓ IL-4, ↓ IL-5, ↓ IL-13, ↓ nuclear NF-κB p65	[244]
	Capsaicin	–	In vitro	THP-1	↓ IL-1β, ↓ IL-6, ↓ TNF-α, ↑ LXRα expression	[245]
	Capsaicin	SGI	In vitro	HSG	↓ IL-6, ↓ TNF-α	[246]
Cardamom (Elettaria cardamomum)	–C	Cardiotoxicity	In vivo	Albino rats	↓ NO, ↓ MDA, ↓ NF-κB, ↓ capase-3, ↑ VEGF,	[247]
					↑ catalase, ↑ SOD, ↑ GPx
Celery seeds (Apium graveolans)	–A, –C	Hyperuricemia	In vivo	BALB/c mice	↓ ROS ↑ SOD, ↑ GPx	[248]
	–C	Gouty arthritis	In vivo	Wistar rats	↓ IL‑1β, ↓ IL‑6, ↓ TNF-α, ↑ IL‑10	[248]
	–A	Gouty arthritis	In vivo	Wistar rats	↓ IL‑1β, ↓ TNF-α, ↑ IL‑10	[248]
	Sedanolide	Liver cancer	In vitro	J5 cells	↓ PI3K-I, ↓ mTOR, ↓ Akt, ↑ PI3K-III, ↑ LC3-II,	[249]
					↑ nuclear p53, ↑ DRAM, ↓ cytosolic p53, ↓ TIGAR,
					↑ Beclin-1
	–C	AD	In vivo	Hairless mice	↓ IL-4, ↓ TNF-α, ↓ IFN-γ, ↓ IL-6, ↓ TSLP, ↓ IL-31	[250]
	–C	AD	In vitro	RAW264.7	↓ NO, ↓ IgE	[250]
	Luteolin	AD	In vitro	RAW264.7	↓ NO	[250]
	–C	–	In vitro	RAW264.7	↓ IL-6, ↓ TNF-α, ↓ NF-κB	[251]
Cinnamon (Cinnamom sp.)	TCA	OA	In vitro	SW1353, HPC	↓ mRNA expression of MMP-1, -3 and -13,	[252]
					↓ mRNA expression of ADAMTS-4 and -5,
					↑ p-IκBα, ↓ NF-κB, ↓ IκBα, ↓ p-JNK 1/2, ↓ p-p38
	TCA	–	In vitro	RAW 264.7	↓ NO, ↓ iNOS	[253]
	TCA	Neuroinflammation	In vitro	BV2	↓ NO, ↓ iNOS, ↓ cox-2, ↓ IL-1β, ↓ IκBα, ↓ NF-κB	[254]
	–A	Skin disease	In vitro	HDF3CGF system	↓ MCP-1, ↓ MIG, ↓ IP‐10, ↓ IL-8, ↓ VCAM-1, ↓ M-CSF, ↓ PAI-1, ↓ ICAM-1, ↓ EFGR, ↓ MMP-1, ↓ TIMP-1, ↓ TIMP-2	[255]
	–C	Inflammation	In vitro	Murine macrophage	↓ mRNA expression of TNF-α, ↓ p-p38, ↓ IκBα degradation, ↓ p-ERK 1/2, ↓ p-JNK	[256]
	–C	Inflammation	In vivo	BALB/c mice	↓ TNF-α, ↓ IL-6	[256]
	–C	Inflammation	In vitro	Splenocytes	↑ IL-2, ↓ IL-4, ↓ IFN-γ, ↓ p-ERK1/2, ↓ p-p38,	[257]
					↓ p-STAT4, ↓ p-JNK
	–C	Inflammation	In vivo	BALB/c mice	↓ IFN-γ	[257]
	BCA, HCA	–	In vitro	Murine splenocytes	↓ IFN-γ, ↓ IL-2Rα, ↓ IgM	[258]
	BCA, HCA	–	In vivo	BALB/c mice	↓ AFC response	[258]
Coriander (Coriandrum sativum)	–C	Inflammation	In vitro	RAW264.7	↓ pro-IL-1β, ↓ PGE2, ↓ p-MAPK, ↓ NF-κB p65, ↓ cox-2, ↓ NO, ↓ iNOS	[259]
	–C	CD	In vivo	ICR mice	↓ IL-1, ↓ IL-4, ↓ IL-13, ↓ TNF-α, ↓ IFN-γ, ↓ IgE,	[260]
					↑ GSH, ↑ HO-1
	–C	Arthritis	In vivo	Wistar rat	↓ IL-1β, ↓ IL-6, ↓ TNF-R1	[261]
Cumin (Cuminum cyminum)	–E	Hypertension	In vivo	SD rats	↓ mRNA expression of IL-6, Bax, and TNF-α,	[262]
					↑ mRNA of expression TRX1, TRXR1, eNOS,
					and Bcl-2
	–E	Gastric ulcer	In vivo	SD rats	↓ TNF-α, ↓ MDA, ↑ GSH, ↑ catalase, ↑ ATPase activity	[263]
Curry leaves (Murraya koenigii)	–C	Pancreatic Inflammation	In vitro	RAW 264.7	↑ GSH, ↓ MDA, ↓ IL‐1β, ↓ IL‐6, ↓ TNF-α	[264]
	–C	Pancreatic Inflammation	In vivo	Swiss albino mice	↓ MDA, ↑ GSH, ↓ IL‐1β, ↓ IL‐6, ↓ TNF-α, ↑ Nrf2, ↓ NFκB p65 activity, ↓ cox-2, ↓ ICAM-1	[264]
	–C	Breast cancer	In vivo	4T1-inoculated	↓ NF-κB, ↓ IL-6, ↓ IL-1β, ↓ IL-10, ↓ iNOS,	[265]
				BALB/c mice	↓ ICAM, ↓ c-myc
	Mahanimbine	–	In vivo	Swiss albino	↓ TNF-α, ↓ IL‐1β, ↓ IL‐6	[266]
	Girinimbine	Peritonitis	In vivo	ICR mice	↓ TNF-α, ↓ IL-1β	[267]
Fenugreek (Trigonella foenum-graecum L.)	–E	IPF	In vivo	SD rats	↑ mRNA expression of Nrf2 and Bcl-2, ↓ mRNA expression of HO-1, TNF- α, IL-1β, IL-6, TGF-β, IL-8, NF-κB, Smad-3, collagen-1, ET-1, Bax and caspase-3	[268]
	–E	Testicular damage	In vivo	Wistar rats	↓ NF-κB p65, ↓ iNOS	[269]
	–E	Diabetes	In vivo	Wistar rats	↓ TNF-α, ↓ IL-1β, ↓ VEGF, ↓ PKC-β	[270]
	–D	RA	In vivo	SD rats	↓ TNF-α, ↓ IL-6, ↓ cox, ↓ 5-LOX	[271]
	Trigonelline	AD	In vivo	Wistar rats	↓ TNF-α, ↓ IL-6, ↓ cox-2, ↓ GFAP, ↓ MDA, ↓ LDH, ↓ protein carbonyl, ↑ SOD, ↑ GSH	[272]
Garcinia (Garcinia indica)	Garcinol	Colitis	In vivo	ICR mice	↓ iNOS, ↓ cox-2, ↓ PCNA	[273]
	Garcinol	Colon cancer	In vivo	ICR mice	↓ β-catenin, ↓ VEGF, ↓ cyclin D1, ↓ p-ERK1/2, ↓ p-Akt, ↓ p-p70S6K (Ser371 and Thr389), ↓ p-PI3K	[273]
	Garcinol	HNSCC	In vitro	CAL27	↓ p-STAT3, ↓ p-c-Src, ↓ p-JAK1, ↓ p-JAK2, ↓ NF-κB, ↓ TAK1, ↓ IKK, ↓ cyclin D1, ↓ Bcl-2, ↓ Bcl-xL, ↓ Mcl-1, ↓ survivin	[274]
	Garcinol	HNSCC	In vivo	Athymic nu/nu mice	↓ Tumor growth	[274]
Garlic (Allium sativum)	–C	Asthma	In vivo	BALB/c mice	↓ IgE, ↓ IgG1, ↑ IgG2a, ↓ IL-13, ↓ IL-5, ↓ IL-4, ↑ IL-12, ↑ IFN-γ, ↓ TNF-α, ↓ IL-1β, ↓ IL-6	[275]
	–C	–	In vitro	A549	↓ IL-6/PI3K/Akt/NF-κB pathway	[275]
	DADS	AP	In vivo	Swiss albino mice	↓ H2S, ↓ CSE, ↓ MPO, ↓ IκB degradation, ↓ TNF-α, ↓ mRNA expression of PPTA and NK1R	[276]
	DATS	RA	In vitro	RA-FLS	↓ IL-8, ↓ IL-1β, ↓ p-p65, ↓ p-NF-κB, ↓ p-IκBα, ↑ IκBα, ↓ c-myc, ↓ β-catenin	[277]
	DATS	RA	In vivo	DBA/1J mice	↓ IL-6, ↓ IL-1β, ↓ TNF-α	[277]
	SAC	PF	In vivo	C57BL/6 mice	↓ α-SMA, ↓ p-Akt, ↓ p-p65, ↓ mRNA expression of α-SMA, TNF-α, iNOS, IL-6, IL-12p35, and TGF-β	[278]
	SAMC	ALI	In vivo	BALB/c mice	↓ MPO, ↓ TNF-α, ↓ IL-1β, ↓ IL-6, ↓ NF-κB activation ↓ cox-2, ↓ p-NF-κB p65, ↑ Nrf-2, ↑ HO-1, ↑ GSH, ↑ NQO1, ↑ SOD, ↓ MDA	[279]
Ginger (Zingiber officinale)	6-Shogaol	Oral carcinogenesis	In vivo	Syrian hamsters	↓ c-jun, ↓ c-fos, ↓ AP-1, ↓ iNOS, ↓ TNF-α, ↓ IL-6, ↓ IL-1, ↓ cox-2, ↓ PCNA, ↓ cyclin D1, ↓ Ki-67	[280]
	6-gingerol	Steatohepatitis	In vitro	HepG2	↓ MCP-1, ↓ TNF-α, ↓ IL-6	[281]
	6-gingerol	Steatohepatitis	In vivo	C57BL/6 mice	↓ MCP-1, ↓ TNF-α, ↓ IL-6, ↓ IκBα degradation, ↓ NF-κB	[281]
Ginseng (Panax sp.)	Isofraxidin	ALI	In vivo	ICR mice	↓TNF-α, ↓ IL-1β, ↓ IL-6, ↓ MIP-2, ↓ p-PI3K, ↓ p-Akt	[282]
	–C	Lung injury	In vivo	BALB/c mice	↓ p38 MAPKs	[283]
	PNS	HAND	In vivo	SD rats	↓ Bax/Bcl-2 ratio, ↓ caspase-3, 8, and -9	[284]
	PNS	Colitis	In vivo	SD rats	↓ M1 macrophages, ↓ PI3K/Akt, ↑ M2 macrophages	[285]
	NR	Renal injury	In vivo	Wistar rats	↓ TNFα, ↓ TGF-ß1, ↓ INF-γ, ↓ IL-6, ↑ IL-10	[286]
	GRg3	RA	In vivo	C57BL/6 mice	↑ CD4+CD25+Foxp3+Treg cells, ↓ TNF-α, ↓ IL-6, ↑ IL-10	[287]
	GRg1	Lung injury	In vivo	SD rats	↓ TNF-α, ↓ α-SMA, ↓ Collagen I, ↓ TGF-β1, ↓ IL-6, ↓ TGF-βR1, ↓ p-Smad3	[288]
	GRg1	Lung injury	In vitro	MRC5	↓ IL-6, ↓ TNF-α, ↓-SMA, ↓ TGF-β1/Smad3	[288]
	Ginsenoside Rd	Ischemic stroke	In vivo	SD rats	↓ NF-κB activity, ↓ IκB, ↓ MMP-9	[289]
Long Pepper (Piper longum)	PL	Leukemia	In vitro	Leukemia	↓ p-p65, ↓ cox-2, ↓ NF-κB activation	[290]
	PL	LN	In vitro	Splenocytes	↓ IL-6, ↓ IL-17, ↓ IL-23, ↓ TNF-α, ↓ p-STAT3, ↓ p-JAK1	[291]
	PL	LN	In vivo	MRL-Fas(lpr) mice	↓ IL-6, ↓ IL-17, ↓ IL-23, ↓ TNF-α	[291]
	PL	RA	In vivo	DBA/1 mice	↓ TNF‑α, ↓ IL-1β, ↓ IL‑23, ↓ IL‑17	[292]
	PL	Asthma	In vivo	C57BL/6 mice	↓ TNF-α, ↓ IL-6, ↓ ICAM-1, ↓ IgE, ↓ MMP-9, ↓ IL-4, ↓ IL-5, ↓ IL-13	[293]
	PL	Asthma	In vitro	Beas-2B	↓ IL-6, ↓ IL-1β, ↓ ICAM-1, ↓ MCP-1	[293]
	PL	–	In vitro	HUVEC	↓ TNF-α, ↓ IL-6, ↓ NF-κB activation, ↓ p-p38, ↓ ICAM-1, ↓ VCAM-1, ↓ E-Selectin	[294]
	PL	Neuro-inflammation	In vitro	BV2	↓ PGE2, ↓ NO, ↓ iNOS, ↓ cox-2, ↓ TNF-α, ↓ IL-6, ↑ IL-10	[295]
	PA	–	In vitro	PBMC	↓ IL-1β, ↓ TNF-α, ↓ IFN-γ, ↓IL-2	[296]
	PA	–	In vivo	BALB/c mice	↓ IFN-γ, ↓ IL-2	[296]
	PL	AD	In vitro	Astrocytes	↓ cox-2, ↓ iNOS, ↓ NF-κB	[297]
	PL	AD	In vivo	ICR mice	↓ NF-κB, ↓ β-, γ-secretases	[297]
	–C	–	In vitro	HUVEC	↓ ICAM-1, ↓ VCAM-1, ↓ NF-κB activation	[298]
	PL	Atherosclerosis	In vitro	VSMC	↓ NF-κB p65, ↓ p-Akt, ↓ p-ERK1/2, ↓ p-PLC-γ1	[299]
	PL	Atherosclerosis	In vivo	ApoE KO mice	↓ NF-κB p65	[299]
	PL	–	In vitro	HUVEC	↓ TACE, ↓ p-p38, ↓ p-JNK, ↓ p-ERK1/2	[300]
	PL	COPD	In vivo	BALB/c mice	↑ AnxA1, ↓ cox-2, ↓ NF-κB,	[301]
Mint (Mentha sp.)	–C	–	In vitro	RAW 246.7	↓ MDA, ↓ NO	[302]
	–C	–	In vivo	SD rats	↓ MDA, ↓ NO, ↓ cox-2, ↓ MAPK signaling	[302]
	–C	–	In vitro	MH-S	↓ NO, ↓ TNF‐α, ↓ IL-1α, ↓ ROS, ↓ p38, ↓ JNK1/2, ↓ p-JNK1/2	[303]
Mustard seeds (Sinapis alba)	–C	Ear edema	In vivo	BALB/c mice	↓ MPO activity, ↓ TNF-α, ↓ ILβ, ↓ IL-6, ↓ mRNA expression of TNF-α and IL-6	[304]
	–E	Psoriasis-like inflammation	In vivo	BALB/c mice	↓ NLRP3, ↓ ASC, ↓ IL-1β, ↓ caspase-1 and 11, ↓ IL-18	[305]
	–E	Psoriasis	In vivo	BALB/c mice	↑ CD4+/CD8+ T cells ratio, ↑ CD4+ T cells, ↑ GPx,	[306]
					↓ NF-κB p65, ↓ IFN-α, ↓ IL-17, ↓ IL-22, ↑ SOD,
					↑ catalase, ↓ MDA, ↓ iNOS
Nutmeg (Myristica fragrans)	–C	Cortical injury	In vivo	Wistar rats	↓ TNF-α, ↓ IL-1β, ↓ iNOS, ↑ HO-1, ↑ Bcl-2, ↓ Bax	[307]
	Macelignan	Asthma	In vivo	C57BL/6J mice, OT-II mice	↓ IL-4	[308]
	Macelignan	Type I allergy	In vitro	RBL-2 H3	↓ PGE2, ↓ mRNA expression of cox-2, 5-LOX,	[309]
					TNF-α, IL-4, and IL-13, ↑ GSH
	Macelignan	Renal I/R injury	In vivo	SD rats	↓ IL-6, ↓ TNF-α, ↓ IFN-γ, ↑ catalase, ↑ SOD, ↓ MDA, ↓ Bax, ↓ caspase-3, ↑ Bcl-2	[310]
	Myrislignan	Inflammation	In vitro	RAW 264.7	↓ iNOS, ↓ IL-6, ↓ TNF-α, ↓ NF-κB activation,	[311]
					↓ cox-2
	Myristicin	Inflammation	In vitro	RAW 264.7	↓ NO, ↓ IL-6, ↓ IL-10, ↓ IP-10, ↓ GM-CSF, ↓ LIF,	[312]
					↓ MCP-1, ↓ MCP-3, ↓ MIP-1α
Onion (Allium cepa)	–C	IBD	In vivo	BALB/c mice	↓ p-ERK1/2, ↓ p-p38MAPK, ↓ p-Akt, ↓ mTOR, ↓ caspase-3, and -8, ↓ cox-2, ↓ cyt-c, ↓ Bcl-xL, ↓ IFN-γ, ↓ TIMP-1, ↓ MCP-1, ↓ MCP-5, ↓ MIG, ↓ MIP-1α, ↓ MIP-2, ↓ ACE-2, ↓ Bcl-2,	[313]
	–C	APH	In vivo	Wistar rats	↓ IL-6, ↓ IL-8, ↓ TNF-α	[314]
	Quercetin	Atherosclerosis	In vitro	VSMC	↓ IL-1β, ↓ IL-18, ↓IL-6, ↓TNF-α, ↑ HO-1, ↑ Nrf-2,	[315]
					↑ SOD1, ↑ SOD2
	Quercetin	Atherosclerosis	In vivo	C57BL/6 mice	↑ SOD, ↑ HO-1, ↑ Nrf-2, ↓ MDA, ↓ p-NF-kB,	[315]
					↓ TNF-α, ↓ IL-1β, ↓ ROS
	QG, QE	Inflammation, Hyperlipidemia	In vitro	THP-1	↓ TNF-α, ↓ IL-6, ↓ cox-2, ↓ PGE2	[316]
	QE	Inflammation, Hyperlipidemia	In vivo	Wistar rats	↓ IL-6	[316]
Rosmary (Rosmarinus officinalis L.)	Rosmarinic acid	Asthma	In vivo	Wistar rats	↓ IL-4, ↓ IgE, ↓ IFN-γ, ↓ PLA2, ↓ TP	[317]
	Rosmarinic acid	Asthma	In vivo	BALB/c mice	↓ IL-4, ↓ IL-13, ↓ p-JNK/JNK ratio, ↓ p-p38/p38 ratio,↓ p-IκBα, ↓ mRNA expression of Ym2, CCR3 CCL11, AMCase, E-selectin	[318]
Saffron (Crocus sativus)	Crocin	Inflammation	In vitro	H9c2	↓ TNF-α, ↓ PGE2, ↓ IL-1β, ↓ IL-6, ↓ mRNA expression of TNF-α, cox-2, IL-1β, IL-6, NO, iNOS	[319]
	Crocin	Osteoporosis	In vivo	Wistar rats	↓ IL-6, ↓ TNF-α, ↓ TRAP, ↓ CTXI, ↑ osteocalcin,	[320]
					↑ ALP
	Safranal	Colitis	In vitro	RAW264.7,	↓ NO, ↓ iNOS, ↓ cox-2, ↓ IL-6, ↓ TNF-α, ↓ p-ERK,	[321]
				BMDM	↓ p-p38, ↓ p-JNK
	Safranal	Colitis	In vivo	BALB/c mice	↓ IL-6, ↓ TNF-α, ↓ p-ERK, ↓ p-JNK, ↓ p-IκBα	[321]
					↓ p-p38
	Safranal	AD	In vivo	Wistar rats	↓ MDA, ↑ SOD, ↓ NF-κB, ↓ TNF-α, ↓ IL-6,	[322]
					↓ IL-1β, ↓ GFAP, ↓ MPO, ↓ ROS
	Safranal	Gastric ulcer	In vivo	Wistar rats	↑ SOD, ↑ TAC, ↓ MDA, ↓ TNF-α, ↓ caspase-3	[323]
Sesame (Sesamum indicum)	Sesamol	Asthma	In vivo	BALB/c mice	↑ GSH, ↓ MDA, ↓ ICAM-1 ↓ IL-4, ↓ IL-5, ↓ IL-13, ↓ IL-16, ↓ CCL11, ↓ CCL24, ↓ TNF-α	[324]
	Sesamol	Asthma	In vitro	BEAS-2B cells	↓ CCL11, ↓ CCL24, ↓ CCL5, ↓ MCP-1, ↓ IL-6,	[324]
					↓ IL-8
	Sesamin	ALI	In vivo	BALB/c mice	↓ MPO, ↓ TNF-α, ↓ IL-6, ↓ IL-1β, ↓ TLR4, ↓ NF-κB activation	[325]
	Sesamin	Kidney injury	In vivo	C57BL/6 mice	↑ GSH, ↓ MDA, ↑ SOD, ↑ Nrf2, ↑ catalase, ↓ IL-6,	[326]
					↓ NF-κB, ↓ TLR4, ↓ cox-2, ↓ TNF-α
	Sesamin	Neuroinflammation	In vivo	CD-1 mice	↓ iNOS, ↓ cox-2, ↓ TNF-α, ↓ IL-1β	[327]
	–A	Asthma	In vivo	BALB/c mice	↓ IL-1β, ↓ IL-6, ↓ NO, ↓ iNOS, ↓ IgE	[328]
Star anise (Illicium verum)	–C	Atherosclerosis	In vitro	HASMC	↓ TNF-α, ↓ IL-1β, ↓ NF-κB, ↓ cox, ↓ E-selectin, ↓ ICAM-1, ↓ VCAM-1	[329]
	–C	Atherosclerosis	In vivo	C57BL/6 mice	↓ TNF-α, ↓ IL-1β, ↓ NF-κB, ↓ cox, ↓ E-selectin,	[329]
					↓ ICAM-1, ↓ VCAM-1, ↓ iNOS
	–C	–	In vitro	HaCaT	↓ IFN-γ Rα, ↓ ICAM-1, ↑ SOCS1, ↓ p-JAK2,	[330]
					↓ p-STAT1
	Anethole	ALI	In vivo	BALB/c mice	↓ MMP-9, ↓TNF-α, ↓ NO, ↑ IκBα, ↓ NF-κB p65	[331]
	–C, AET	Asthma	In vitro	Splenocyte	↓ IL-4, ↑ IFNγ	[332]
	–C, AET	Asthma	In vivo	BALB/c mice	↓ IgE, ↓ IL-4, ↓ IL-5, ↓ IL-13, ↑ mRNA expression of Foxp3,↓ mRNA expression of IL-5, and IL-13	[332]
Tamarind (Tamarindus Indica)	–C	Pulmonary inflammation and fibrosis	In vivo	Wistar rats	↓ ROS, ↓ LPO, ↓ PCC, ↓ NF-κB, ↓ p38α MAPK, ↓ NOX4, ↓ cox-2, ↑ HO-1, ↑ SOD2, ↑ catalase, ↑ GST, ↑ GSH, ↑ GPx	[333]
	–C	Arthritis	In vivo	Wistar rats	↓ IL-1β, ↓ IL-6, ↓ IL-23, ↓ TNF-α, ↓ cox-2, ↓ MMP	[334]
	Xyloglucan	Ulcerative colitis	In vivo	C57Bl6 mice	↓ IL-1β, ↓ IL-6, ↓ TLR4, ↓ NF-κB	[335]
Turmeric (Curcuma longa)	Curcumin	PIVP	In vitro	A549, BMMF	↓ IL6, ↓ TNF-α, ↓ MCP-1, ↓ NF-κB, ↑ IκBα	[336]
	Curcumin	PIVP	In vivo	BALB/c mice	↑ HO-1	[336]
	Curcumin	Cystic fibrosis	In vitro	16HBE14o	↑ CFTR, ↓ cox-2, ↓ PGE2, ↓ IL-8	[337]
	Curcumin	Cystic fibrosis	In vivo	SD rats	↑ CFTR, ↓ cox-2, ↓ PGE2, ↓ IL-8	[337]
	Curcumin	Diabetes	In vivo	SD rats	↓ NF-κB, ↓ TNF-α, ↓ IL-1β, ↓ IL-6 ↓ NO, ↓ PGE2,	[338]
					↓ cox-2
	Curcumin	ALI	In vivo	SD rats	↓ TNF-α, ↓ IL-8, ↓ MIF	[339]
	Curcumin	Asthma	In vivo	BALB/c mice	↓ NICD1, ↓ Notch 1/2 receptors	[340]
	Curcumin	Cerebral I/R injury	In vivo	SD rats	↓ IL-1β, ↓ IL-8, ↑ p-JAK2, ↑ p-STAT3	[341]
	ATM	Psoriasis	In vivo	BALB/c mice	↓ NF-κB, ↓ cox-2, ↓ p-p38 MAPK, ↓ TNF-α,	[342]
					↓ IL-6, ↓ mRNA synthesis of IL-17, -22, and -23
	MTrPP	Ulcer	In vivo	Wistar rats	↓ TNF-α, ↓ IL-8, ↓ NF-κB, ↓ p-p38, ↓ MMP-9,	[343]
					↓ cox-1 and -2

^A : Oil, ^B: Resin, ^C : Extract, ^D : Mucilage, ^E : Seed.

Abbreviations: AA: Arachidonic acid, Ach: Acetylcholine, AChE: Acetylcholinesterase, AD: Alzheimer's disease, ADAMTS: a disintegrin and metalloproteinase with thrombospondin motifs, AET: Trans-Anethole, AFC: Antibody forming cell, Akt: Protein kinase B, ALI: Acute lung injury, ALP: Alkaline phosphatase, ALT: Alanine aminotrans-ferase, AMCase: Acidic mammalian chitinase, AMPK: Adenosine monophosphate-activated protein kinase, AP: Acute pancreatitis, AP-1: Activator protein-1, APH: Atypical prostatic hyperplasia, AR: Allergic rhinitis, AST: Aspartate aminotransferase, ATM: Aromatic-turmerone, ATPase: Adenosine triphosphatase, Bax: B-cell lymphoma 2 (Bcl-2)-associated X protein, BCA: 2′-benzoxy-cinnamaldehyde, Bcl-2: B-cell lymphoma 2, CCL: C-C Motif Chemokine Ligand, CCR3: C-C chemokine receptor type 3, CD: Contact dermatitis, CHLS: total cholesterol, CFTR: Cystic fibrosis transmembrane conductance regulator, COPD: Chronic obstructive pulmonary disease, cox-2: cyclooxygenase-2, CSE: Cystathionine-γ-lyase, CTXI: Collagen cross-linking carboxyterminal telopeptide, type I, DADS: Diallyl disulfide, DATS: Diallyl trisulfide, DNMT3A: DNA methyltransferase 3A, DRAM: Damage-regulated autophagy modulator, EFGR: Epidermal growth factor receptor, eNOS: endothelial nitric oxide, EPCR: Endothelial protein C receptor, ERK: Extracellular signal-regulated kinase, ET-1: endothelin-1, Foxp3: Forkhead Box Protein 3, GFAP: Glial fibrillary acidic protein, GGT: Gamma-glutamyl transpeptidase, GM-CSF: Granulocyte macrophage colony-stimulating factor, GPx: glutathione peroxidase, GR: Glutathione reductase, GRg1: Ginsenoside Rg1, GRg3: Ginsenoside Rg3, GSH: Glutathione, GSK3β: glycogen synthase kinase 3β, GST: Glutathione S-transferase, G-6P-D: Glucose-6-phosphate dehydrogenase, HAND: Human immunodeficiency virus, HAND: (HIV)- associated neurocognitive disorders, HCA: 2′-hydroxycinnamaldehyde, HDAC1: Histone Deacetylase 1, HDL: High-density lipoprotein, HO-1: Heme oxygenase-1, HMGB1: High mobility group box-1 protein, HNSCC: Squamous cell carcinoma of the head and neck, H₂O₂: Hydrogen peroxide, H₂S: Hydrogen sulfide, IBD: Inflammatory bowel disease, ICAM-1- intercellular cell adhesion molecule-1, IFN: Interferon, IFN-γRα: IFN-γ receptor α, IKK: Inhibitor of M kinase, IL: Interleukin, iNOS: Inducible nitric oxide synthase, IPF: Idiopathic pulmonary fibrosis, IP-10: Interferon-inducible protein 10, IRF-3: Interferon regulatory factor 3, I/R: ischemia-reperfusion, JAK: Janus kinase 2: JNK: c-Jun N-terminal kinase, LC3: Light chain 3, LDH: Lactate dehydrogenase, LDL: Low density lipoprotein, LIF: leukemia inhibitory factor, LN: Lupus nephritis, LOX: Lipoxygenase, LPO: Lipid peroxidation, LXRα: Liver X receptor α, MAPK: Mitogen-activated protein kinase, MDA: Malondialdehyde, MCP: Monocyte chemoattractant protein, M-CSF: Macrophage colony-stimulating factor, MIF: Migration inhibitory factor, MIG: Monokine induced by gamma, MIP: Macrophage inflammatory protein, MMP: matrix metalloproteinases, MPO: Myeloperoxidase, mTOR: mammalian target of rapamycin, MTrPP: Modified pectin polysaccharide from turmeric, MyD88: Myeloid differential factor 88, NAFLD: Non-alcoholic fatty liver disease, NF-κB p65: Nuclear factor-κB p65, NICD: Notch intracellular domain, NK1R: Neurokinin-1-receptor, NLRP3: Nucleotide oligomerization domain (NOD)-like receptor protein 3, NO: Nitric oxide, NOX4: Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4, NR: Notoginsenoside R1, Nrf2: Nuclear factor erythroid 2-related factor 2, OA: Osteoarthritis, OSCC: Oral squamous cell carcinoma, p: phosphorylated, PA: Piperinic acid, PAI-1: Plasminogen activator inhibitor-1, PCC: Protein carbonyl content, PCNA: Proliferating cell nuclear antigen, PF: Pulmonary fibrosis, PGE2: prostaglandin E2, PIVP: Primary influenza viral pneumonia, PI3K: Phosphoinositide 3-kinases, PKC-β: Protein kinase C-β, PL: Piperlongumine, PLA2: Phospholipase 2, PNS: Panax notoginseng saponins, PPTA: Preprotachykinin A, p-YSTAT3: phosphorylated signal transducer and activator of transcription 3, QE: Quercetin-3-O-glucoside, QG: Quercetin-3-O-glucoside, RA: Rheumatoid arthritis, RA-FLS: Rheumatoid arthritis synovial fibroblast, ROS: Reactive oxygen species, RORγt: Retinoic acid-related orphan receptor-γt, SA: serum sialic acid, SAC: S-allyl-L-cysteine, SAMC: S-allyl-mercapto cysteine, SD: Sprague- Dawley, SGI: Salivary gland inflammation, Smad-3: small mothers against decapentaplegic homolog 3, SMC: S-allyl-mercapto cysteine, SOCS1: Suppressor of cytokine signaling 1, SOD: Superoxide dismutase, STAT: Signal transducer and activator of transcription, STZ: Streptozotocin, TACE: Tumor necrosis factor alpha converting enzyme, TBARS: Thiobarbituric acid reactive substances, TAC: Total anti-oxidant capacity, TAK1: TGF-β-activated kinase 1, TCA: Trans-cinnamaldehyde, TG: Triglyceride, TGF-β: Transforming growth factor-β, TIGAR: Tp53 induced glycolysis and apoptosis regulator, TIMP-1: Tissue inhibitor of metalloproteinase, TLRs: Toll-like receptors, TNF-α: Tumor necrosis factor-α, TP: Total protein, TQ: Thymoquinone, TRAP: Tartrate-resistant acid phosphatase, TRX1: Thioredoxin 1, TRXR1: Thioredoxin reductase 1, TSLP: Thymic stromal lymphopoietin, VCAM-1: Vascular cell adhesion protein 1, VEGF: Vascular endothelial growth factor, VLDL: Very low density lipoprotein, α-SMA: α-smooth muscle actin, ↓: Downregulation/Inhibition, ↑: Upregulation/Activation.

Fig. 4.

Spices regulates the expression of different inflammatory cytokines.

Several studies documented the role of spices in the modulation of different inflammatory proteins.

Abbreviations: GCSF: Granulocyte colony-stimulating factor, GM-CSF: Granulocyte-macrophage colony-stimulating factor, IFN: Interferon,; IL-Interleukin, M-CSF: Macrophage colony-stimulating factor, TNF-α: Tumor necrosis factor-α

7.1. Asafetida (Ferula asafetida Linn.)

It is derived from the roots of the F. asafetida (Umbelliferae family). Several studies have reported that asafetida exhibits protective effects against cancer, obesity, hepatotoxicity, etc. [344]. It has also been extensively used in traditional medicine for ages for the treatment of whooping cough, asthma, bronchitis, etc. [345]. The essential oil extracted from F. asafetida induces apoptosis and cytotoxicity against hepatocellularcarcinoma. It modulated the NF-κB and transforming growth factor (TGF)-β pathway by downregulating the expression of NF-κB1 and TGF-β1. Furthermore, it enhanced the production of caspase-3 and TNF-α [221]. Asafetida exhibits potent antitumor effects against breast cancer in BALB/c nude mice [222]. It also enhanced the activities of antioxidant enzymes such as catalase, glutathione (GSH), glutathione-s-transferase (GST), superoxide dismutase (SOD) in N-methyl-N-nitrosourea (MNU)-induced breast cancer in Sprague-Dawley rats [223]. The activity of LOX was also decreased by asafoetida [222,224].

7.2. Basil (Ocimum sp.)

Basil is a popular spice consumed all over the world [346]. It belongs to the Lamiaceae family [347]. Studies have shown that basil possesses medicinal properties such as gastroprotective, antioxidant, antimicrobial, etc. [226,348]. An in vivo study has also demonstrated the cardioprotective effects of basil leaves against isoproterenol-induced myocardial infarction in rats [349]. Hydro-ethanolic extract of basil leaf attenuated airway inflammation and exerted immunoprotective effects against asthma in the ovalbumin-sensitized rat model. It decreased the levels of IL-4, IgE, phospholipase A₂ (PLA₂), and increased the IFN-γ/IL-4 ratio in the bronchoalveolar lavage fluid (BALF) of the rats [225]. Furthermore, the hexane extract of basil (whole plant) modulated the expression of inflammatory markers such as TNF-α, IL-6, Prostaglandin E₂ (PGE₂), and IL-4. It also exerted anti-inflammatory as well as gastroprotective effects against an aspirin-induced gastric ulcer in vivo [226].

7.3. Bay leaf (Laurus nobilis)

Bay leaves belong to the family Lauraceae and are commonly used in cuisine for flavoring [227,350]. The administration of L. nobilis leaf extract attenuated the lipopolysaccharide (LPS)-induced mRNA expression of IL-6, TNF-α, and iNOS. It also inhibited the phosphorylation of IκB and STAT3 in vitro. Further, it inhibited the nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome activation via the suppression of apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization. In the BALF of the acute lung injury (ALI) model, the extract reduced the activity of the myeloperoxidase (MPO) enzyme as well as the levels of cytokines such as IL-1β, IL-6, and TNF-α. This suggests that bay leaf extract exerts ameliorative effects against ALI [227]. 1,8-Cineole is a bioactive component of L. nobilis. Similar to the leaf extract, 1,8-Cineole also downregulated the elevated LPS-induced mRNA expression of IL-6, TNF-α, and iNOS. It also inhibited the activation of NF-κB and STAT3 [227].

7.4. Black cumin (Nigella sativa)

Black cumin belongs to the family Ranunculaceae. It is consumed as a spice or seasoning predominantly in the Middle Eastern as well as Mediterranean countries [351]. N. sativa plant is widely known for its medicinal properties such as antidiabetic, anti-inflammatory, hepatoprotective, hypotensive, etc. [352]. Cumin effectively ameliorated LPS-induced lung damage as well as inflammation. It also downregulated the expression of the inflammatory mediators such as IFN-γ, TGF-β1, and PGE₂ but also upregulated the anti-inflammatory cytokine IL-4. It also exhibits potent antioxidant properties by enhancing the activity of SOD and catalase [228]. Besides, it attenuated low-grade inflammation in vitro by reducing the levels of IL-1β and MCP-1 [229]. It also increased the mRNA expression of endothelial nitric oxide synthase (eNOS) in a streptozotocin (STZ)-induced diabetic rat model. However, it decreased the mRNA expression of vascular cell adhesion molecule-1 (VCAM-1) and LOX-1 in this model [230]. N. sativa demonstrated renal and hepatoprotective effects in LPS-treated rats. Moreover, it also exhibited anti-inflammatory effects by decreasing the levels of cytokine IL-6 as well as NO [231]. Further, it also declined the levels of IL-4 and nitric oxide (NO) in an allergic asthma model in Wistar rats [232]. Thymoquinone (TQ) is one of the major active components of cumin seeds. Studies have shown that TQ exerted an anti-inflammatory effect on Alzheimer's disease (AD) by downregulating the expression of toll-like receptor (TLR)-2 and -4. This leads to a decrease in the production of their downstream effectors NF-κB and interferon regulatory factor 3 (IRF-3). TQ also significantly reduced the expression of the pro-inflammatory cytokines TNF-α and IL-1β [233].

7.5. Black pepper (Piper nigrum)

Black pepper from the Piperaceae family is a popular spice due to its dietary importance and beneficial agent against various chronic health ailments [353].

The administration of ethanol extracts of Piper nigrum in ovalbumin-induced asthma mice model decreased IL-4, IL-6, IL-1β, retinoic acid-related orphan receptor gamma t (RORγt), IL-17A, TNF-α, IgE, and increased the levels of IL-10, INF-γ. It decreased the state of fibrosis and inflammatory cells infiltration and also regulated the production of cytokines like Th1, Th2, and Th17. Further, the treatment of the extract blocked allergy through the prevention of degranulation of peritoneal mast cells [234]. Further, the effect of fruit extract from P. nigrum in allergic rhinitis ovalbumin-induced BALB/c mice model prevented allergic reactions by reducing antibodies, histamine release by mast cells. It has also decreased E-cadherin and was protective against nasal epithelial barrier impairment through increased Nrf2 leading to elevated heme oxygenase-1 (HO-1) level [235]. Similarly, the extract also decreased the expression of tyrosine phosphorylated STAT3 (p-YSTAT3), IL-6, IL-1β, TNF-α, and NF-κB p65 [236].

The ethanolic extract containing pipernigramides A-G decreased iNOS-induced NO and levels of IL-1β, IL-6, TNF-α, and PGE₂ in RAW 264.7 cells. It also reduced the degradation of IκB and targets IKK-β that inhibits p65, which suppressed inflammation [237]. Further, the treatment of piperine in B16F-10-induced lung metastasis in C57BL/6 mice decreased collagen hydroxyproline in lungs, hexosamine level, uronic acid, serum sialic acid, and gamma-glutamyl transpeptidase, and increased the lifespan of treated animals [238].

Piperine was showed to be effective against bacterial sepsis by preventing pyroptosis through the reduction of IL-1β and adenosine monophosphate-activated protein kinase (AMPK) levels, both in vitro and in vivo [239]. Piperine also attenuated the condition of acute pancreatitis through the reduction of TNF-α, IL-1β, IL-6, p-ERK1/2, p-p38, p-JNK, and MAPKs expressions [240]. It improved lupus nephritis in HK-2 cells by inhibiting pyroptosis, NLRP3 inflammasome, HMGB1, caspase-1, and activation of AMPK. Similarly, piperine inhibited NLRP3 inflammasome and serum IL-1β in the BALB/c mice model of lupus nephritis [241]. The effect of chabamide from fruits of P. nigrum in LPS-stimulated RAW264.7 cells produced an anti-inflammatory effect via the Nrf2/HO-1 pathway through the reduction in iNOS and increased Nrf2 and its targets-NAD(P)H: quinone oxidoreductase 1 and γ-glutamyl cysteine synthetase [242].

7.6. Capsicum (Capsicum annum L.)

Capsicum belongs to the family Solanaceae. It exerts anti-inflammatory effects against ethanol-induced inflammation in rats by reducing the expression of pro-inflammatory cytokines TNF-α and IL-6. Additionally, it also exerts potent hepatoprotective effects by attenuating the elevated levels of malondialdehyde (MDA) in the liver, a marker for lipid peroxidation, as well as enzymes like alanine aminotransferase (ALT), aspartate transaminase (AST), which are the markers for liver damage. Capsicum also restores the abnormal levels of cytosolic Cu-Zn-SOD, mitochondrial Mn-SOD, as well as critical antioxidant enzymes [243]. The extract of capsicum also significantly elevated the expression of Th type 2 cytokines such as IL-4, IL-5, IL-13 in an ovalbumin-induced asthma mouse model [244].

Capsaicin is one of the major active components of capsicum. It is known to possess protective activities against asthma, cancer, diabetes, etc. [14]. It also ameliorated inflammation by reducing the levels of TNF-α, IL-6, and IL-1β. Enhanced expression of liver X receptor α (LXRα) is also regulated by capsaicin via the peroxisome proliferator-activated receptor γ (PPARγ) pathway [245]. Inflammation of the salivary glands is also attenuated by capsaicin. It markedly reduced the mRNA as well as protein expression of TNF-α and IL-6 in HSG cells [246].

7.7. Cardamom (Elettaria cardamomum)

Cardamom belongs to the Zingiberaceae family. It is commonly referred to as the “queen of spices” [354]. Several studies indicated that cardamom possesses different therapeutic activities such as chemopreventive, antidiabetic, anticancer, gastroprotective, etc. [354,355]. Treatment with cardamom extract ameliorated oxidative stress by enhancing the levels of antioxidant enzymes. It also attenuated inflammation by downregulating the expression of NF-κB and NO. Further, it also exerted protective effects against doxorubicin-induced cardiotoxicity in rats [247].

7.8. Celery seeds (Apium graveolens)

Celery seeds belong to the Apiaceae (Umbelliferae) family. It is consumed as a spice and herbal medicine [251]. Preclinical studies conducted on hyperuricemia mice model and monosodium urate-induced gouty arthritis rats reported that the aqueous and oil extracts of celery seeds exhibit anti-inflammatory and antioxidant properties. The administration of the extracts reduced the pro-inflammatory cytokines like IL-1β, TNF-α, and enhanced IL-10 levels [248]. Sedanolide, a compound isolated from celery seed essential oil, induced autophagy in human hepatocarcinoma cells, due to the reduced phosphatidylinositol-3-kinase (PI3K), mTOR, Protein kinase B (Akt) expression levels in those cells [249]. Another recent study shows that the hydrolyzed celery extract suppressed the inflammation in the chronic atopic dermatitis mice model. It effectively reduced the pro-inflammatory cytokines like IL-4, TNF-α, IFN-γ, IL-6, IL-31, and IgE as demonstrated from the preclinical experimental models [250]. The extract of celery seeds also exerts anti-inflammatory effects by downregulating IL-6, TNF-α, and NF-κB levels [251].

7.9. Cinnamon (Cinnamomum sp.)

The spice cinnamon is derived from the bark of plants belonging to the family Lauraceae and genus Cinnamomum [356]. It is a multipotential medicinal plant that possesses diverse properties such as antiseptic, antifungal, antiviral, anti-inflammatory, immunomodulatory, etc. [357].

Trans-cinnamaldehyde (TCA) is one of the components of Cinnamon. TCA inhibited NF-κB as well as the p38-JNK signaling pathway in the IL-1β-induced osteoarthritis model. Furthermore, it inhibited the activation of NF-κB as well as the degradation of IκB. It also slowed down the progression of osteoarthritis in vivo [252]. Suppression of NO due to a decrease in iNOS expression was also observed after TCA treatment in RAW 264.7 cells [253]. The administration of TCA also suppressed the production of NO in LPS-induced BV2 microglial cells. Furthermore, it also downregulated the expression of iNOS, cox-2, as well as IL-1β and inhibited NF-κB activation [254]. The essential oil extracted from cinnamon also possesses anti-inflammatory properties. A study showed that it downregulated inflammatory biomarkers, such as MCP-1, interferon gamma-induced protein 10 (IP-10), interferon-inducible T-cell alpha chemoattractant (I-TAC) monokine induced by gamma interferon (MIG) as well as IL-8 in a human skin disease model [255]. The water extract of cinnamon (CWE) substantially reduced the secretion of TNF-α, and IL-6 in LPS-induced in vivo model. In LPS-induced macrophages, the extract did not reduce the secretion of TNF-α; however, a substantial decrease in its mRNA expression was observed. Additionally, it also inhibited IκBα degradation as well as MAPK phosphorylation [256]. CWE also significantly decreased the levels of anti-CD3-induced IFN-γ in the serum of mice model. It also decreased the mRNA expression as well as the release of IFN-γ, and IL-4 in murine splenocytes. Additionally, CWE increased the secretion of IL-2 in splenocytes [257]. 2′-Hydroxycinnamaldehyde (HCA) and 2′-benzoxycinnamaldehyde (BCA) are the derivatives of cinnamaldehyde. A study showed that both HCA and BCA exhibit an inhibitory effect on the secretion of IgM as well as IFN-γ in murine splenocytes [258].

7.10. Coriander (Coriandrum sativum)

Coriander is an annual herb of the Apiaceae family [358]. It is commonly known as coriander, and its different parts are consumed worldwide. In addition to its culinary values, coriander is also often consumed as a traditional medicine against different ailments, such as diabetes, cancer, hypertension, etc. [359]. It also possesses different pharmacological activities such as hepatoprotective, antihelminthic, neuroprotective, antimicrobial, etc. [[359], [360], [361]].

Numerous studies have suggested that extracts prepared from different parts of coriander also induce potent anti-inflammatory effects in both in vitro as well as in vivo models [[259], [260], [261]]. A study demonstrated that the ethanolic extract of coriander leaves and stem downregulated the expression of inflammatory mediators, including pro-IL-1β, NO, and cox-2, as well as decreased the production of PGE₂ and iNOS. It further inhibited NF-κB activation as well as MAPK signaling in LPS-induced RAW 264.7 cells [259]. It also substantially attenuated the 2,4-dinitrochlorobenzene-induced elevated expression of IL-1, IL-4, IL-13, TNF-α, IFN-γ as well as immunoglobulin E (IgE) in the contact dermatitis in vivo model [260]. The hydroalcoholic extract of coriander reduced the production of TNF-R1 protein as well as downregulated the levels of the cytokines IL-1β and IL-6 [261].

7.11. Cumin (Cuminum cyminum)

Cumin belongs to the Apiaceae family. It is commonly used for the treatment of diseases like diabetes, cancer, hypolipidemia, etc. [362]. In renal hypertension in vivo model, the aqueous extract of cumin seeds attenuated inflammation and oxidative stress and induced antihypertensive effects by modulating the gene expression of IL-6, TNF-α, thioredoxin 1 (TRX1), and eNOS [262]. The methanol extract of cumin also ameliorated inflammation and imparted protection against diabetes-associated gastric ulcer in vivo [263].

7.12. Curry leaves (Murraya koenigii)

Curry leaves belong to the Rutaceae family. They are are popularly used in Indian cuisine and have been a part of Indian traditional medicine for centuries due to its versatile medicinal properties [363]. A recent study showed the anti-inflammatory effect of the hydroalcoholic extract of curry leaves in vitro and in vivo. It reduced the expression of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 in LPS-induced macrophages. Similar effects were observed in the cerulein-induced acute pancreatitis in vivo model. Additionally, it also downregulated the activity of NFκB p65 as well as the expression of cox-2 and intercellular adhesion molecule-1 (ICAM-1) in vivo [264]. The aqueous extract reduced the levels of cytokines such as IL-6, IL-1β, and IL-10 in 4T1-inoculated mice. It also downregulated the expression of the inflammation regulator NF-κB [265]. Mahanimbine is a carbazole alkaloid found in curry leaves. It attenuated the elevated levels of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 in high-fat diet (HFD)-induced mice, thereby exerting a potent anti-inflammatory effect [266]. Girinimbine, another carbazole alkaloid, is also a potent anti-inflammatory agent. It reduced the production of TNF-α, and IL-1β in carrageenan-induced peritonitis [267].

7.13. Fenugreek (Trigonella foenum-graecum L.)

Fenugreek belongs to the Fabaceae family [364]. It is rich in pharmacological and nutritional properties. It possesses different activities such as anticarcinogenic, anti-inflammatory, antidiabetic, etc. [365].

A study showed that standardized fenugreek seed extract-glycoside base (SFSE-G) exhibited potent anti-inflammatory effects by downregulating the expression of inflammatory mediators, including TNF-α, IL-1β, IL-6, IL-8 in a bleomycin-induced pulmonary fibrosis model. It also inhibited the mRNA expression of the fibrotic markers such as small mothers against decapentaplegic homolog 3 (Smad-3), collagen-I, endothelin-1 (ET-1), etc. eventually leading to amelioration of pulmonary fibrosis in vivo [268]. A study has demonstrated that the extract of fenugreek seeds suppressed cisplatin-induced expression of iNOS and NF-κB p65 in testicular tissues of Wistar rats [269]. It also reduced the expression of retinal inflammatory markers, such as TNF-α and IL-1β, in STZ-induced diabetic rat retina [270]. In RA, expression of the pro-inflammatory cytokines TNF-α, and IL-6 is significantly downregulated by fenugreek mucilage prepared from fenugreek seeds, thereby asserting its anti-inflammatory role [271]. The pretreatment of trigonelline derived from fenugreek exerts neuroprotective effects against amyloid β-induced AD in vivo. The mechanism is attributed to a decrease in hippocampal glial fibrillary acidic protein (GFAP) as well as pro-inflammatory cytokines [272].

7.14. Garcinia (Garcinia indica)

Garcinia is a spice which belongs to the family of Clusiaceae. Its fruit is commonly called kokum and it exhibits various pharmacological effects such as cardioprotective, hepatoprotective, antibacterial, antiulcer, antiarthritis, etc. [366]. Garcinol is a major component of Garcinia which possesses medicinal properties such as antiproliferative, antibacterial, anti-inflammatory, etc. [367]. A study showed that it significantly reduced the expression of inflammatory mediators like iNOS and cox-2 in a dextran sulfate sodium (DSS)-induced colitis mice model. Furthermore, it also prevented DSS/azoxymethane (AOM)-induced colon tumorigenesis by inhibiting the PI3K/Akt/p70S6K, as well as ERK signaling pathways [273]. Garcinol inhibited NF-κB activation in CAL27 cells suppressing TGF-β–activated kinase 1 (TAK1) and an inhibitor of IκB kinase (IKK). Further, it also inhibited the constitutive activation of STAT3 as well as its upstream kinases c-Src, JAK1, and JAK2. Moreover, it inhibited CAL27 xenograft tumors in nude mice [274].

7.15. Garlic (Allium sativum)

Garlic is a bulbous plant belonging to the family Liliaceae. It is commonly used as a spice and flavor additive in many cuisines across the globe. Apart from this, garlic has been used since ancient times in different cultures for its medicinal values [275].

An in vivo study has demonstrated that the aqueous extract of garlic exerts inhibitory effects against Dermatophagoides pteronyssinus (Der p)-induced allergic asthma. The study showed that aqueous extract of garlic substantially downregulated the levels of cytokines such as IL-13, IL-5, and IL-4 but upregulated the levels of IFN-γ and IL-12 in the BALF of the experimental mice. Moreover, it also decreased the levels of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 and thereby induced anti-inflammatory effects [275]. The treatment of Der p-stimulated A549 cells with aqueous garlic extract also inhibited inflammation by suppressing the IL-6/PI3K/Akt/NF-κB pathway [275].

Different bioactive components present in garlic are associated with anti-inflammatory as well as other pharmacological activities. Diallyl disulfide (DADS) is an organosulfur compound and is one of the key components of garlic. A study has shown that DADS ameliorated cerulein-induced acute pancreatitis in vivo by suppressing the substance P/neurokinin 1 receptor (SP/NK1R) signaling as well as the NF-кB pathway [276]. Another organosulfur compound diallyl trisulfide (DATS), inhibited the NF-κB and Wnt pathway in human fibroblast-like synoviocytes (FLS) obtained from RA patients. Moreover, key inflammatory mediators such as IL-1β, IL-6, and TNF-α are also downregulated by DATS in collagen-induced arthritis (CIA) mouse model [277]. Garlic, also another organosulfur compound namely S-allyl-L-cysteine (SAC) [368]. An in vivo study revealed that in a bleomycin-induced pulmonary fibrosis model, SAC reduced the mRNA expression of fibrosis markers such as α-smooth muscle actin (α-SMA), fibronectin, collagen-I, and –III. Additionally, it also downregulated the mRNA expression of markers associated with inflammatory responses, such as TNF-α, iNOS, IL-6, and IL-12p35. Furthermore, SAC also suppressed the Akt/NF-кB pathway in vivo [278]. The bioactive component S-allyl-mercapto cysteine (SAMC) found in garlic also exerts potent anti-inflammatory, antifibrotic, antioxidative, as well as antimetastatic effects [369,370]. A study demonstrated that SAMC attenuated inflammation by inducing inhibitory effects on pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 and suppressing the NF-кB pathway in LPS-induced ALI in mice model [279].

7.16. Ginger (Zingiber officinale)

Ginger is a widely consumed spice which belongs to the Zingiberaceae family. It is also known for its medicinal properties such as antitumor, anti-inflammatory, antioxidant, etc. [14,280,371]. Some of the active components of ginger are 6-shogaol, 6-gingerol, 6-paradol, and 6-gingerdiol. [14].

An in vivo study revealed that 6-shogaol inhibited 7,12-dimethylbenz[a]anthracene induced oral cancer by modulating the NF-κB pathway. It downregulated the levels of cytokines such as IL-1, IL-6, and TNF-α [280]. Another study demonstrated that 6-gingerol imparted protective effects against steatohepatitis in both in vitro and in vivo. In the HepG2 cells, gingerol reduced the enhanced levels of MCP-1, TNF-α, and IL-6. A similar effect of 6-gingerol was observed in the methionine and choline-deficient (MCD) diet-fed animal model. Besides, the upregulated NF-кB level was also attenuated by 6-gingerol [281].

7.17. Ginseng (Panax sp.)

Ginseng belongs to the Araliaceae family and is commonly used in herbal therapies. Both its extract and isolated active compounds were reported to possess extensive biological properties [372,373]. For instance, an active compound, isofraxidin (IFD), isolated from Siberian ginseng, exerted significant anti-inflammatory effects on a mouse model of ALI. The property of the compound was attributed to its ability to reduce the serum levels of various inflammatory cytokines such as TNF-α, IL-1β, IL-6, and MIP-2. Besides, IFD modulated various inflammatory factors linked to the PI3K/Akt and MAPK signaling pathways [282]. Black ginseng (BG) also displayed efficient activity against lung injury through modulation of Akt and reactive oxygen species (ROS)-induced p38-MAPK signaling [283]. Additionally, saponins isolated from Panax ginseng displayed a wide range of efficacy against various diseases. These saponins imparted protective roles against HIV-associated neurocognitive disorders (HAND) and DSS-induced colitis by regulating the levels of caspase-3, 8, 9, and PI3K/Akt signaling pathway respectively [284,285]. Further, notoginsenoside R1 (NR), isolated from Panax notoginseng, imparted protective effects against the rat model of renal ischemia-reperfusion (I/R) injury via downregulation of certain oxidative and inflammatory factors such as TNF-α, TGF-ß1, IFN-γ, and IL-6 [286]. Ginsenoside Rg3 (GRg3) induced anti-inflammatory effects and ameliorated RA in vivo via the regulation of CD4⁺CD25⁺Foxp3⁺Treg cells [287]. In vitro and in vivo studies reported that ginsenosides Rg1 suppressed the TGF-β1/Smad3 signaling pathway while Rg3 mitigated neutrophilic inflammation, migration, and the levels of PI3K, thereby exerting protective effect against chronic obstructive pulmonary disease (COPD) [288]. Another compound isolated from ginseng, ginsenoside Rd, prevented neuroinflammation in ischemic stroke by suppressing the NF-κB/MMP-9 signaling pathway [289].

7.18. Long pepper (Piper longum L.)

The powdered dry fruits of P. longum (family Piperaceae), are used in Ayurveda for the preparation of several medicines. The whole plant of this spice is known to yield many biologically important compounds, such as piperine, piperlongumine (PL), and piperinic acid and are used to treat numerous inflammation-mediated diseases like cancer, lupus nephritis, arthritis, and asthma due its ability to supress pro-inflammatory cytokines such as TNF-α, and IL-6 and induce the expression of anti-inflammatory cytokine IL-10 [[290], [291], [292], [293], [294], [295], [296]]. The compound PL is known to relieve the inflammation-associated neurotoxicity upon the activation of stress-inducing molecules like NO, PGE₂, and cox-2 in the cultured LPS-stimulated BV2 cells. Further, it also ameliorated LPS-induced amyloidogenesis by inhibiting the NF-κB pathway [295,297]. Long pepper extracts and PL also prevented the cell-adhesion and migration of leukocytes to sites of inflammation by reducing the expression of cell adhesion molecules like ICAM-1, and VCAM-1 [293,294,298]. The anti-inflammatory activity of PL is also attributed to the downregulation of elevated expression levels of MAPK proteins like p38, ERK1/2, and JNK [294,299,300]. PL alleviated the overactivation of Th2 cytokines IL-4, IL-5, and IL-13 as well as the IgE levels in the ovalbumin-induced asthmatic lung tissue of mice. Besides, PL also prevented the airway remodeling in vivo via the inhibition of the NF-κB pathway [293]. Moreover, it attenuated systemic and pulmonary inflammation by inhibiting cox-2 and NF-κB [301]. In the collagen-induced arthritis mice model, PL suppressed the expression of TNF-α, IL-1β, IL-23, and IL-17 [292].

7.19. Mint (Mentha sp.)

Mint belongs to the genus Mentha of the Lamiaceae family. M. spicata, M. pulegium, and M. rotundifolia are some of the species belonging to the mint family. They are commonly consumed as herbal tea and spice. Moreover, mint is rich in antimicrobial, anti-inflammatory, neuroprotective, cardiovascular, and antitumor properties [374,375].

A study reported that M. spicata exerts ameliorative effects against acute and chronic inflammation in vivo [376]. In another study, M. arvensis was shown to reduce the levels of MDA and NO in LPS-induced RAW 246.7 cells. It also attenuated the elevated levels of NO, which was induced due to immobilization stress in the rat model. Further, it also inhibited the MAPK signaling and inflammatory mediator cox-2. These results suggested that M. arvensis might attenuate stress and associated inflammation [302]. The ethyl acetate extract of M. arvensis reduced the levels of the cytokines TNF-α, and IL-1α. It also modulated the LPS-activation of MAPK. Rosmarinic acid and L-menthone are some of the constituents of M. arvensis, which decreased the LPS- or H₂O₂-induced ROS levels in vitro [303].

7.20. Mustard (Sinapis alba)

White mustard belongs to the family of Brassicaceae [377]. These are widely consumed as a condiment. The dried mature seed of white mustard is also known as Sinapsis semen [304]. The extract of S. alba efficiently inhibited the mRNA as well as protein expression of inflammatory cytokines such as TNF-α, IL-6, and IL-1β in vivo. Further, it also suppressed the activity of MPO, which is a marker for inflammation [304]. Mustard seeds also ameliorated inflammation in psoriasis model. They repressed the expression of NLRP3 inflammasome. This further led to the inhibition of IL-1β and IL-18 induced inflammation [305]. Furthermore, it increased CD4⁺ T cell count and decreased the plasmacytoid dendritic cells (pDC) and macrophages. Low levels of pDC resulted in a decrease in the secretion of IFN-α. The expression of the NF-κB p65 subunit, as well as IL-17 and IL-22, were significantly inhibited which indicated that mustard seeds further abrogated inflammation. Moreover, the expression of the antioxidant enzymes such as GSH, glutathione peroxidase (GPx), and SOD were also enhanced by mustard seeds. This results in the inhibition of oxidative stress which was further evidenced by a decrease in the lipid peroxidation marker MDA as well as the reactive nitrogen species (RNS) generating iNOS [306].

7.21. Nutmeg (Myristica fragrans)

Nutmeg belongs to the Myristicaceae family and is a widely consumed spice [378,379]. Many studies have been conducted to evaluate the potential of its extract and isolated phytochemicals in the treatment and prevention of different diseases. Nutmeg extracts displayed significant antioxidant and anti-inflammatory activities and thus imparted protection against cortical liver injury in vivo [307,380]. Macelignan, an active compound of M. fragrans, was reported to exhibit anti-inflammatory effects in vivo in an asthmatic model by significantly reducing the expressions of IL-4 and Th2 cell-specific master transcription factor, GATA3 [308]. The compound was further reported to exert significant anti-allergic and anti-inflammatory effects via the modulation of p-Akt, p38-MAPK, and JNK. It also inhibited the expression of other inflammatory mediators such as cox-2, 5-LOX, IL-4, IL-13, and TNF-α [309]. Moreover, macelignan induced protective effect against renal I/R injury by imparting antioxidant activity as well as regulating the inflammatory and apoptotic mediators such as IL-6, TNF-α, IFN-γ and B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase-3, respectively [310]. Myrislignan, a lignan found in M. fragrans, also ameliorated inflammation by inhibiting the activation of the NF-κB pathway as well as the expression of inflammatory mediators such as IL-6, TNF-α, and cox-2 [311]. Myristicin is an aromatic compound isolated from nutmeg. It suppressed the production of cytokines (such as IL-6, IL-10), chemokines (such as MCP-1, MCP-3, MIP-1α, MIP-1β) granulocyte-macrophage colony-stimulating factor (GMCSF), and leukemia inhibitory factor (LIF) [312].

7.22. Onion (Allium cepa)

Onion belongs to the Liliaceae family. It is consumed widely for its flavor and nutritional value. Moreover, it is also used in traditional medicine due to its variety of therapeutic properties such as anticancer, cardioprotective, antimicrobial, antifungal, and antiviral [381]. The extract of onion bulb suppressed DSS-induced colitis in a rat model by downregulating MAPK/Akt/mTOR signaling as well as the cox-2 levels. Moreover, pro-inflammatory cytokines and chemokines were also downregulated by the treatment with this extract [313]. The extract of red onion scales decreased the levels of IL-6, IL-8, and TNF-α in atypical prostatic hyperplasia in an in vivo model [314]. Quercetin, a major flavonoid found in onion, also possesses therapeutic properties [315]. A recent study demonstrated that it exerted protective effects against high fructose-induced atherosclerosis in mice. The protective effect was attributed to the suppression of ROS, by modulating the levels of SOD, HO-1, Nrf-2, H₂O₂, O₂, and MDA. Quercetin also suppressed inflammation and apoptosis by regulating the NF-κB and PI3K/Akt pathway, respectively. In LPS-induced VMSCs, it down-regulated the cytokines such as IL-1β, IL-18, TNF-α, and IL-6. Additionally, it also improved LPS-induced atherosclerosis by inhibiting PI3K/Akt-regulated NF-κB [315].

In another study, quercetin-3-O-glucoside and eicosapentaenoic acid ester of quercetin-3-O-glucoside (QE) was shown to reduce the levels of TNF-α, IL-6, cox-2, PGE₂ in vitro. The treatment of QE in hyperlipidemic rats also decreased the expression of LPS-induced IL-6 [316].

7.23. Rosemary (Rosmarinus officinalis L.)

Rosemary belongs to the Lamiaceae family. It possesses several therapeutic properties such as hepatoprotective, antifungal, antioxidant, antibacterial, etc. [382]. Rosmarinic acid is one of the major components of rosemary. It is a phenolic compound that possesses anti-inflammatory, hepatoprotective, and antihyperlipidemic properties [383,384]. A study showed that rosmarinic acid downregulated the enhanced levels of key inflammatory as well as immunological mediators such as IL-4, IgE, IFN-γ, and PLA₂ induced by ovalbumin in asthmatic rats [317]. Another study revealed that it also modulated the MAPK and NF-κB signaling pathways in ovalbumin-induced asthma in a mice model [318].

7.24. Saffron (Crocus sativus)

Saffron belongs to the Iridaceae family. It is known to possess various therapeutic properties, such as anticonvulsant, antidepressant, anti-inflammatory, antitumor, etc. [385]. Crocin ameliorated LPS-induced sepsis as well as cardiotoxicity in H9c2 cells. It significantly downregulated the inflammatory mediators TNF-α, PGE₂, IL-1β, and IL-6. It also decreased the mRNA expression of cox-2, iNOS, as well as NO [319]. Crocin induced osteoprotective effect by inhibiting inflammation in a metabolic syndrome (MetS)-induced osteoporosis model. It exhibited anti-inflammatory activity by reducing the levels of the pro-inflammatory cytokines IL-6 and TNF-α. Furthermore, it suppressed and elevated the levels of markers for bone resorption and bone formation, respectively, in (MetS)-induced osteoporosis model [320]. Safranal is another major component of saffron. A study showed that safranal inhibited MAPK and NF-κB pathways which led to a reduction in the expression of pro-inflammatory cytokines, such as IL-6 and TNF-α. It also inhibited the expression of iNOS and cox-2 in vitro. Furthermore, safranal exhibited similar anti-inflammatory responses in DSS-induced colitis mice [321]. Safranal also partially restored the levels of inflammatory mediators, such as IL-1β, IL-6, TNF-α, and NF-κB to normal levels, in the hippocampus of the amyloid β-induced AD model. It also attenuated cognitive deficits and exhibited antioxidant effects in the AD model [322]. In addition to the anti-inflammatory effect, safranal also exhibits potent antioxidant and gastroprotective effects [323].

7.25. Sesame (Sesamum indicum)

Sesame belongs to the Pedaliaceae family and is rich in medicinal properties such as anticancer, hepatoprotective, antihypertensive, etc. [386]. Sesamol is an active compound of sesame. A study reported that it decreased the eosinophil infiltration in lungs, Th2 cytokines, and MDA levels in asthmatic BALB/c mice, and BEAS-2B cells, which might attenuate inflammation in the lungs [324].

Sesamin is a lignan isolated from S. indicum [387]. The administration of sesamin attenuated LPS-induced ALI by reducing the expression of TNF-α, IL-6, and IL-1β. It also inhibited the TLR4 pathway and NF-κB activation [325]. It also ameliorated renal oxidative stress and inflammation by upregulating antioxidant enzymes such as SOD, GSH, and catalase, and downregulating inflammatory mediators such as TNF-α, IL-6, and cox-2, respectively [326]. Sesamin also attenuated the levels of iNOS, cox-2, TNF-α, and IL-1β in a stressed mice and thereby exerted antidepressant effects [327]. Similarly, sesame oil exerted a protective effect against the asthmatic mice model by reducing the levels of IL-1β, IL-6, IgE, and iNOS [328].

7.26. Star anise (Illicium verum)

The spice star anise belongs to the Illiciaceae family [388]. It possesses a variety of pharmacological properties such as anti-bacterial, anti-nociceptive, anthelmintic, antiviral, gastroprotective, etc. [389,390].

The extract of star anise exerted inhibitory effects on key inflammatory biomarkers such as TNF-α, IL-1β, NF-κB, and cox in an apolipoprotein E-knockout (ApoE^−/−) mice. Similar findings were observed when TNF-α-stimulated-HASMC cells were treated with this extract [329]. Another study revealed that star anise extract exhibited potent anti-inflammatory effects by substantially reducing the expression of IFN-γ receptor α (IFN-γRα) as well as a suppressor of cytokine signaling 1 (SOCS1) protein in IFN-γ-induced human keratinocytes. Moreover, it also inhibited JAK/STAT signaling and decreased the production of ICAM-1 [330].

Anethole is one of the compounds responsible for the aroma and flavor of star anise. It exerts a potent anti-inflammatory effect by inhibiting the activation of NF-κB. It also substantially reduced the levels of pro-inflammatory mediators such as TNF-α, and IL-6 [331]. Trans-anethole is another major constituent found in star anise. It attenuated the elevated level of cytokines such as IL-4, IL-5, and IL-13, in the asthmatic in vivo model. The mRNA expression of forkhead box P3 (Foxp3), a transcription factor involved in the development and function of regulatory T cells, was also upregulated by trans-anethole. Besides, it also modulated the production of IL-4, and IFN-γ in vitro [332].

7.27. Tamarind (Tamarindus indica L.)

Tamarind (family Fabaceae) is one of the highly diverse and ethnopharmacologically valuable plant species known to man. A recent study showed that tamarind seed coat extract (TSCE) possesses antioxidant property that prevented oxidative stress-induced-erythrocyte loss. It is also known to prevent anemia, reduce lipid peroxidation, and regulated glutathione levels [391]. Besides, TSCE attenuates the pulmonary inflammation which is attributed to the reduced levels of inflammation-inducing NF-κB and cox-2 levels as well as oxidative stress-inducers such as nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase 4 (NOX4) and p38α MAPK. It also attenuated pulmonary fibrosis in vivo [333]. The seed extract also exerted antiarthritic effect in vivo by modulating the levels of anti-inflammatory mediators such as IL-10, TNF-α, IL-1β, IL-6, cox-2, and IL-23 [334]. Its fruit extract also possesses anti-inflammatory properties [392]. In another study mucoadhesive tamarind xyloglucan (TXG) was shown to exert anti-inflammatory effects against ulcerative colitis in vivo. TXG inhibited the levels of pro-inflammatory cytokines IL-1β, and IL-6 and further attenuated inflammation by inhibiting the TLR4/NF-κB signaling pathway [335].

7.28. Turmeric (Curcuma longa)

Turmeric from the Zingiberaceae family has been used since ancient times in various traditional medicines. It is profoundly rich in therapeutic activities such as anti-inflammatory, anticancer, antiatherosclerotic, antidepressant, antidiabetic, antiarthritic, etc. Its potent biological properties can be mostly attributed to one of its active components namely “Curcumin” [[393], [394], [395], [396], [397]]. Curcumin possess several pharmacological activities such as antiviral, antifungal, anticancer, etc., and is therefore rightfully proclaimed to be the “Golden nutraceutical” [14,394,398]. Moreover, it is highly efficacious against cancer (breast, cervical, colorectal, ovarian, pancreatic, prostate, etc.) RA, inflammatory bowel disease, psoriasis, neurological diseases, etc. [393,[399], [400], [401], [402], [403]].

Congregated evidence from various preclinical and clinical studies has shown the efficacy of curcumin in the prevention and treatment of diverse health ailments [[404], [405], [406], [407], [408], [409], [410], [411]]. Studies have shown that curcumin helps in regulating the cytokine storm both in vitro and in vivo in case of influenza virus A (IAV) infection thereby relieving chronic influenza, pneumonia, and lung injuries associated with these conditions. It attenuated the elevated levels of IL-6, MCP-1, TNF-α as well as inhibited NF-κB, besides inhibiting the replication of IAV. Curcumin also elevated HO-1 which ameliorated lung injuries [336]. An in vivo study on experimentally induced pulmonary inflammation in a rat model evidenced that curcumin significantly regulated the expressions of various inflammatory and fibrotic mediators, such as cystic fibrosis transmembrane conductance regulator (CFTR) and cox-2/PGE₂/IL-8 [337]. Moreover, the anti-inflammatory and antioxidative potential of curcumin helped in relieving lung injury in diabetic rats through the inhibition of NF-κB, NO, PGE₂, iNOS and cox-2 [338]. An in vivo study also evidenced the efficacy of curcumin against cecal ligature puncture (CLP)-induced lung injury through the suppression of the inflammatory mediators such as TNF-α, IL-8, and MIF [339]. The protective effects of curcumin against asthma were also reported where the compound significantly modulated the Notch1-GATA3 signaling pathway and thus inhibited the inflammation of the airways [340]. Curcumin imparted neuroprotective effects against cerebral I/R injury as well via downregulation of IL-1β and IL-8 besides triggering the JAK2/STAT3 signaling [341]. Apart from curcumin, modified polysaccharides and components of essential oils obtained from C. longa were also reported to have diverse biological activities. An important component of the essential oil is aromatic-turmerone (ATM), which is reported to have strong anti-inflammatory and antioxidant properties and thus proved to be useful in the treatment of psoriasis. It significantly inhibited the expressions of NF-κB, cox-2, p-p38 MAPK, TNF-α, and IL-6. ATM further suppressed the mRNA synthesis of IL-17, IL-22, and IL-23 [342]. Furthermore, the anti-inflammatory activity of a modified pectin polysaccharide from turmeric (MTrPP) contributed to its antiulcer activity and thus it aided in the treatment of LPS-induced ulcer in a rat model. MTrPP inhibited the release of inflammatory markers such as TNF-α, IL-8, NF-κB, MMP-9, cox-1, and cox-2. It also prevented the phosphorylation of p38, thus imparting protective effects [343].

8. Anti-inflammatory spices in clinical trials

Apart from the aforementioned preclinical studies, the anti-inflammatory activity of many of these spices has been evaluated in clinical trials and these were found to be very efficacious against many diseases. The administration of spices to the patients regulate cytokine storm and several other inflammatory mediators. This leads to an improvement of symptoms as well as treatment of various diseases. Some of the important clinical studies which show the modulation of inflammatory mediators by spices are summarized below and are mentioned in Table 3 .

Table 3.

Anti-inflammatory activity of spices against different diseases in clinical trials.

Spice	Active compound	Health issues	Phase	Pts no.	Dosage ranges (mg)/day	Clinical outcome (mechanism)	References
Cardamom	–	Pre-diabetic subjects	–	80	3000	Significant anti-inflammatory and antioxidant effects (↓ hs-CRP, ↓ hs-CRP:IL-6 ratio)	[412]
	–	T2D	–	83	3000	Improvement in clinical symptoms (↓ TG, ↑ Sirt1)	[413]
	–	NAFLD	–	87	3000	Improvement in clinical symptoms, safe to use (↑ Sirt1, ↑ irisin)	[414]
Cinnamon	β-caryo phyllene	H. pylori infection	–	66	126	Improvement in clinical symptoms (↓ IL-1β)	[415]
Coriander	–	Erythema	–	40	0.5%a	Moderate anti-inflammatory effect	[416]
Garlic	–	Obesity	–	51	3600b	Significant anti-inflammatory effect (↓ TNF-α, ↓ IL-6, ↓ LDL)	[417]
	–	OA	–	80	1000	Relieved pain (↓ Resistin)	[418]
Ginger	–	RA	–	70	1500	Improvement in clinical symptoms (↓ gene expression of NFκB, RORγt and T-bet)	[419]
	–	OA	–	120	1000	Significant anti-inflammatory effect (↓ IL-1β, ↓ TNF-α)	[420]
	–	TB	–	69	3000	Significant anti-inflammatory and antioxidant effect (↓ TNF-α)	[421]
	–	CRC	–	20	2000	Well-tolerated and safe (↑ LTB4)	[422]
Ginseng	–	CHD	–	24	1.35/kgc	Inhibition of gastrointestinal injury and inflammatory response (↓ IL-6, ↓ LPS, ↓ MDA)	[423]
	–	RA	–	84	–d	Improved anti-inflammatory immunity, and analgesic effect (↓ CRP)	[424]
Saffron	–	Asthma	–	80	100	Improvement in clinical symptoms, safe to use (↓TG, ↓ LDL cholesterol, ↓ basophil, ↓ eosinophil)	[425]
	Crocin	MS	–	40	30	Significant anti-inflammatory and antioxidant effects (↓ TNF-α, ↓ IL-17)	[426]
Sesame seed	–	OA	–	50	40,000	Significant anti-inflammatory effects, safe to use (↓ IL-6)	[427]
Turmeric	CU	MetS	–	117	1000e	Significant anti-inflammatory and antioxidant effect, Safe to use (↓ hs-CRP)	[428]
	CU	Obesity/hypertension	–	90	900h	Significant anti-inflammatory effect, improvement in general health, safe to use (↓ CRP, ↓ TNF-α, ↓ IL-6, ↓ sVCAM-1)	[429]
	Curcumin	T2D	–	118	1000e	Significant anti-inflammatory effects (↓ TNF-α)	[430]
	Curcumin	T2D	–	44	1500	Significant anti-inflammatory effect, reduced complications (↓ hs-CRP, ↓ TG)	[431]
	–	KOA	–	160	500	Significant anti-inflammatory and antioxidant effects, improvement in clinical symptoms (↓ IL-1β)	[432]
	–	OA	–	42	1300–1950f	Significant anti-inflammatory effects, relieved pain, well-tolerated	[433]
	Curcumin	RA	–	36	500–1000	Significant anti-inflammatory and analgesic effects, relieved pain, safe to use, well-tolerated (↓ CRP)	[434]
	–	CKD	–	16	–g	Significant anti-inflammatory effects, safe to use, well-tolerated (↓ IL-6)	[435]
	Curcumin	Hemodialysis	–	71	1500	Significant anti-inflammatory effects, (↓ hs-CRP, ↓ IL-6, ↓ TNF-α)	[436]
	CU	SM-induced CPC	–	89	1500j	Significant anti-inflammatory and pulmonoprotective effects, safe to use, well-tolerated (↓ IL-6, ↓ IL-8, ↓ TNF-α, ↓ TGF-β, ↓ hs-CRP,↓ CGRP, ↓ MCP-1)	[437]
	Curcumin	COPD	–	39	180k	Significant anti-inflammatory effects, safe to use (↓ AT-LDL)	[438]
	Curcumin	Migraine	–	74	80i	Significant neuromodulatory effects, relieved headache, safe to use (↓ cox-2/iNOS)	[439]

^a: Coriander oil; ^b: Aged Garlic Extract; ^c: Shen-fu injection (the major component=extract of Panax ginseng); ^d: Panax notoginseng Saponins; ^e: Combination with piperine (10 mg/day); ^f: Combination of H. procumbens, C. longa, and bromelain (AINAT); ^g: Herbal supplement composed of purified turmeric extract (824 mg), curcuminoids (95%), and Boswellia serrata extract (516 mg), 3-acetyl-11-keto-β-boswellic acid (10%); ^h: Combination of bisacurone (400 μg), turmeronol A (80 μg) and turmeronol B (20 μg); ⁱ: Combination with ω-3 fatty acids (5000 mg/day); ^j: Curcumin C3 Complex® capsules containing 500 mg curcuminoids plus 5 mg bioperine®; ^k: Theracurmin® capsules

Abbreviations: AGE: Aged garlic extract, AT-LDL: α1-antitrypsin-low-density lipoprotein, CGRP: Calcitonin gene related peptide; CHD: Congenital heart disease, CKD: Chronic kidney disease, COPD: Chronic obstructive pulmonary disease, cox-2: Cyclooxygenase-2, CP/CPPS: chronic prostatitis/chronic pelvic pain syndrome type III, CPM: Chronic pulmonary complications, CRC: Colorectal cancer, CU: Curcuminoids, CVD: Cardiovascular disease, H. pylori: Helicobacter pylori, hs-CRP: High-sensitivity C-reactive protein, IL: Interleukin, iNOS: Inducible nitric oxide synthase, KOA: Osteoarthritis of knee, LDL: Low density lipoprotein, LPS: Lipopolysaccharide, LTB4: Leukotriene B4, MCP-1: Monocyte chemotactic protein-1, MS: Multiple sclerosis, NAFLD: Non-alcoholic fatty liver disease, OA: Osteoarthritis, Pts: Patients, SM: Sulfur Mustard; RA: Rheumatoid Arthritis, Sirt1: Sirtuin-1, sVCAM-1: soluble vascular cell adhesion molecule-1, TB: Tuberculosis TG: Triglycerides, TGFβ: Transforming growth factor-β, TNF: Tumor necrosis factor, T2D: Type 2 diabetes, WEC: Water extract of C. longa L, ↓: Downregulation/Inhibition, ↑: Upregulation/Activation.

8.1. Cardamom

Clinical studies on cardamom have shown that this spice is effective against metabolic disorders, such as diabetes and non-alcoholic fatty liver disease (NAFLD). Randomized double-blind clinical trials evaluating the effects of cardamom on both pre-diabetic and diabetic subjects have reported significant clinical improvements. A dosage of 3 g cardamom supplement daily for 8 weeks regulated the levels of high-sensitivity C-reactive protein (hs-CRP): IL-6 ratio in pre-diabetic, obese subjects thus showing significant anti-inflammatory and antioxidant effects. Likewise, in the case of type 2 diabetes (T2D) patients, administration of the same dose of cardamom for 10 weeks regulated the serum levels of triglycerides, insulin, sirtuin-1 (SIRT1) besides improving the glycemic indices [412,413]. Moreover, the efficacy of this spice was also evaluated against NAFLD where it was found that treatment with 3 g of supplement for 3 months significantly improved the grade of fatty liver in overweight or obese individuals. It further improved the clinical symptoms of the disease by modulating the levels of glucose indices, lipids, and other biomarkers of the disease. Moreover, the administration of cardamom supplement did not show any side-effects and thus it was found to be safe [414].

8.2. Cinnamon

β-caryophyllene, one of the active compounds of cinnamon, was found to be effective against gastrointestinal disease caused due to Helicobacter pylori (H. pylori) infection. A randomized double-blind placebo-controlled study has reported that administration of 126 mg β-caryophyllene daily for 8 weeks showed significant anti-inflammatory properties by downregulating the level of IL-1β. It further improved conditions of nausea, epigastric pain, and dyspepsia associated with the disease thereby proving that it can stand as a potential therapy against inflammation and gastrointestinal ailments [415].

8.3. Coriander

A study evaluating the potency of essential oil from coriander has evidenced that topical administration of a lipolotion (containing 0.5% coriander oil) during UV exposure reduced the risk of UV-induced erythema to some extent. The treatment was found to show anti-inflammatory activity and was well-tolerated when applied on the skin of healthy volunteers [416].

8.4. Garlic

Clinical trials investigating the potency of garlic extract and its supplements against different diseases have reported that the spice showed significant anti-inflammatory and other beneficial properties. Supplementation of 3.6 g aged garlic extract (AGE) daily was found to diminish the serum levels of TNF-α and IL-6 in obese adults, thus lessening the risk of occurrence of multiple inflammatory chronic diseases associated with obesity [417]. Garlic extract supplementation also relieved pain and other clinical symptoms associated with knee osteoarthritis. Administration of 1 g of the supplement twice daily for 12 weeks significantly reduced the level of resistin, an inflammatory cytokine, thus displaying anti-inflammatory effects [418].

8.5. Ginger

Ginger powder supplementation was found to be effective against both RA and osteoarthritis as evidenced by several clinical studies. In the case of RA patients, on receiving 1.5 g ginger supplements daily for 12 weeks, an improvement in the clinical symptoms were observed. Ginger powder effectively regulated the levels of NF-κB, RORγt, T-box transcription factor TBX21 (T-bet) genes, thus leading to a decline in the severity of the disease. Similarly, the administration of ginger powder to osteoarthritis patients displayed potent anti-inflammatory effects by downregulating the inflammatory cytokines IL-1β and TNF-α [419,420]. A clinical trial of ginger extract on tuberculosis patients has conveyed that administration of 3 g of the supplement daily for 3 months reduced the blood levels of inflammatory cytokine TNF-α and other markers of the disease such as ferritin and MDA, thus displaying anti-inflammatory and antioxidant properties [421].

Furthermore, a pilot clinical study on the subjects at an increased risk of colorectal cancer (CRC) has shown that ginger extract was well tolerated by the subjects and did not show any adverse side effects. It regulated the levels of arachidonic acid (AA) and leukotriene B4 (LTB4) but did not show any change in the levels of eicosanoid [422].

8.6. Ginseng

Ginsenosides, the saponins extracted from ginseng, are found effective against many diseases. A clinical study investigating the potency of Panax notoginseng saponins (PNS) against RA, which displayed that the saponins, when administered for 28 days, led to significant improvement in clinical symptoms of the disease in terms of joint pain, swelling, tenderness, and stiffness. It also managed the dysregulated immune response and displayed significant anti-inflammatory and analgesic effects [424]. Further, the efficiency of ginsenosides therapy (in the form of shen-fu injection) was also evaluated against gastrointestinal mucosal injury which is associated with cardiopulmonary bypass in children suffering from congenital heart disease (CHD). It was found that administration of the intravenous injection before and during the bypass surgery resulted in a reduction of characteristic injury and post-surgery inflammation in patients [423].

8.7. Saffron

The anti-inflammatory property of saffron is evaluated by many studies and it was found to have protective effects against allergies such as asthma. Asthmatic patients, on receiving 100 mg/day saffron capsules for 8 weeks, showed improvement in clinical symptoms of the disease such as frequency of asthmatic attacks, waking up at night due to asthmatic symptoms, and limitation in the activity. The severity of the disease declined, and the supplement was well-tolerated by the patients without any adverse side-effects [425].

Crocin, an active component of saffron, was found to be an effective therapy against multiple sclerosis due to its efficient anti-inflammatory and antioxidant properties. It was found that the administration of two capsules of crocin (15 mg) for 28 days showed an improvement in the antioxidant status of the body. Additionally, a reduction in inflammatory mediators such as TNF-α, and IL-17 in the blood of the patients was also observed [426].

8.8. Sesame seed

Sesame seed therapy was found to improve the mediators of inflammation and oxidation in patients suffering from osteoarthritis of the knee. Consumption of 40 g of sesame seed daily for 2 months resulted in a decrease in the level of IL-6 in the serum of patients, thus proving that it can serve as a potential supplementary therapy in patients with osteoarthritis [427].

8.9. Turmeric

A handful of clinical studies have been performed to examine the potency of turmeric against various diseases. Curcumin and curcuminoids, the active components of turmeric, are found as effective therapies over the years. These are found to be very helpful in managing metabolic syndrome and disorders. For instance, a classic combination of curcuminoid-piperine in the ratio of 100:1 was administered daily for 8 weeks to patients with metabolic syndrome. It was found to regulate the levels of CRP, MDA, and SOD in patients thus imparting significant anti-inflammatory and antioxidant effects [428]. In the case of patients with obesity/hypertension, the hot water extract of C. longa L. (WEC) reduced the levels of CRP, TNF-α, IL-6, and soluble vascular cell adhesion molecule-1 (sVCAM-1), thereby amending chronic low-grade inflammation and overall health of patients [429]. Furthermore, in T2D patients, the uptake of curcuminoid-piperine has shown a decline in the level of TNF-α and an increased level of adiponectin. Furthermore, another study evaluating the effects of curcumin against T2D showed that the compound modulated the levels of hs-CRP and TG thereby imparting significant anti-inflammatory activity [430,431]. The compounds are further found to be effective against osteoarthritis and RA. In the case of osteoarthritis, C. longa L. (CL) extract showed significant anti-inflammatory effects via the downregulation of IL-1β and anti-oxidant effects via the downregulation of MDA and ROS. Thus, the administration of the extract was found to improve clinical symptoms of the disease such as pain and inflammation [432]. Another clinical study showed that the administration of a combination of H. procumbens, C. longa, and bromelain in the form of AINAT capsules showed similar improvements in terms of pain in osteoarthritis patients. Further, the capsules were well-tolerated and thus can be used as a safe and effective replacement for non-steroidal anti-inflammatory drugs (NSAIDs) [433]. Besides, the intake of 0.5–1 g of curcumin formulation daily for 90 days in two different treatment groups has shown significant anti-inflammatory and analgesic effects in patients suffering from RA. The treatment caused improvements in the levels of CRP and rheumatoid factor (RF) values without causing any adverse side-effects [434].

A clinical study evaluating the effects of a combination of turmeric extract and Boswellia serrata as a treatment of patients with chronic kidney disease (CKD) has reported that the supplement is well-tolerated by the patients and is safe to use. The treatment efficiently enhanced the inflammatory status of the patients via the downregulation of the inflammatory cytokine, IL-6 [435]. Moreover, regular intake of curcumin was found to impart anti-inflammatory effects in patients undergoing hemodialysis. The supplement helped in reducing the levels of hs-CRP, IL-6, and TNF-α in plasma without causing any side-effects [436].

Curcuminoids were also found to relieve chronic inflammation in patients suffering from chronic pulmonary complications (CPC) resulting from sulfur mustard (SM) intoxication. Treatment with curcuminoids supplement helped in modulating inflammatory responses by reducing the levels of IL-6, IL-8, TNF-α, TGF-β, hs-CRP, calcitonin gene-related peptide (CGRP), substance P, and MCP-1. The supplements were also well-tolerated and did not cause any adverse side-effects in the patients [437]. Also, in the case of chronic obstructive pulmonary disease (COPD), a curcumin supplement namely Theracurmin(®) was found to significantly amend the inflammatory status and levels of α1-antitrypsin-low-density lipoprotein (AT-LDL) in the blood of patients when taken for 24 weeks. This change might be useful in reducing the risk of any further cardiovascular events in COPD patients [438].

Furthermore, a nano-curcumin formulation in combination with omega-3 fatty acids was found to show neuroprotective effects against migraines. The therapy significantly reduced the levels of cox-2/iNOS which is associated with neuroinflammation and pain of the CNS. Hence, a decline in the rate and duration of repeated painful attacks and the severity of the disease was observed, making this a safe and useful therapy for the treatment and prevention of migraine [439].

9. Curcumin and COVID-19

Curcumin is a multipotential compound from C. longa that possesses diverse medicinal properties. It is a potent anti-inflammatory agent that is effective against numerous chronic diseases [14,[440], [441], [442], [443]].

Elevated cytokine levels or cytokine storm is considered as one of the critical process responsible for multi-organ failure and death in COVID-19 infected patients [[444], [445], [446]]. TNF-α also plays a pivotal role in pulmonary edema caused during COVID-19-associated lung diseases. Natural compounds like curcumin downregulate the levels of TNF-α [447].

Moreover, COVID-19 is also associated with the symptoms of pneumonia that causes severe respiratory distress. The treatment of the pneumonia model with curcumin was shown to decrease lung injury and inflammation through the modulation of HIF and NF-κB [448]. The treatment of curcumin in virus infected models has exhibited inhibition of cytokines, MMPs, and inflammatory cells. It also inhibited the fibrosis and expression of myofibroblasts in the lung tissues [449]. A study demonstrated the potency of a novel combination of vitamin C, curcumin and glycyrrhizic acid (VCG) against SARS-CoV-2 infection. System biology tools also found that VCG modulated various genes associated with immune and inflammatory responses via the regulation of crucial pathways such as NOD-like, Toll-like, PI3K/Akt, NF-κB, and MAPK signaling pathways [450]. TMPRSS2 is a crucial protease involved in the priming of ACE2 receptor-bound viral S protein and thus acts a therapeutic target for COVID-19 therapy [451]. Bromolein, a cysteine protease traditionally used for the treatment of arthritis, possesses potent immunomodulatory properties. Besides, studies have demonstrated that bromolein inhibits the expression of ACE-2 and TMPRSS2 in vitro. It has been hypothesized that the combination of curcumin and bromolein might exert a beneficial synergistic effect against SARS-CoV-2 infection [452,453]. Another study reported the potential immunomodulatory and antiviral efficacy of the combination of black pepper and curcumin extract along with multiactive ingredients such as pentatricontane, sitosterol, termerone, lupeol, amyrines, and vitamin D3 (EGYVIR). The administration of EGYVIR in SARS-CoV-2 infected cells decreased the levels of inflammatory mediators, such as TNF-α and IL-6, which might be effective in attenuating the virus-induced cytokine storm [454]. The combination of curcumin and zinc has also been hypothesized as an effective therapeutic strategy against COVID-19 [455,456].

A randomized clinical trial has been initiated to investigate the potency of the co-administration of curcumin and piperine on COVID-19 patients [457]. Another randomized clinical trial has been initiated to determine the efficacy of nano micelles containing curcumin on the levels of various serum cytokines, such as IFN-γ, IL-17, IL-4, and TGF-β in COVID-19 patients [458]. Nanonutraceuticals of vitamins, antioxidants, probiotics, etc. can modulate immune responses and therefore effectively strengthen the immune system of COVID-19 patients [459]. Nano-curcumin also significantly reduced the expression of serum IL-6 and IL-1β in COVID-19 patients [460]. Furthermore, nano-formulation of curcumin is also associated with faster recovery of COVID-19 patients [461]. It also exerted immunomodulatory effects and also decreased the levels of Th17 cell-related cytokines in the patients [462]. Therefore, curcumin might be useful as a traditional medicine to treat COVID-19-associated complications such as cytokine storm, ALI, ARDS, and pneumonia [463,464].

Apart from the anti-inflammatory effects, several studies have also reported that curcumin exhibits antiviral effects [[465], [466], [467]]. Curcumin was reported to inhibit the replication of the SARS-CoV in vitro. Therefore, the potency of curcumin as an antiviral agent might also be effective against the SARS-CoV-2 [465]. Numerous molecular docking studies have shown the efficacy of curcumin to target various key components of the novel SARS-CoV-2 in silico. A study reported that curcumin showed high-affinity binding towards the viral spike glycoprotein and ACE2 receptor [185]. Another study demonstrated its binding affinity towards the viral Nsp15 protein which is associated with replication. Therefore, curcumin might cause the inhibition of the viral replication by binding with Nsp15 [182]. Curcumin has also been reported as a potential inhibitor of Mpro protein of SARS-CoV-2 [[468], [469], [470], [471], [472]]. Moreover, it also inhibits the human cellular transmembrane serine proteinase [473]. Furthermore, curcumin and catechin also bind to the RBD of the viral S protein and inhibit the entry of SARS-CoV-2 in the host cell [474]. Multi-omics analyses have also demonstrated the potential of compounds such as curcumin, resveratrol, etc., as effective agents to inhibit SARS-CoV-2 viral infection [475].

Thus, several studies have hypothesized that the immunomodulatory and antiviral activities of curcumin might be beneficial in the treatment of SARS-CoV-2 and COVID-19 associated diseases [182,440,470,[476], [477], [478], [479], [480], [481]]. Curcumin possesses a huge potential as a drug against SARS-CoV-2 as well as COVID-19-associated diseases. Therefore, it should be further evaluated in the pre-clinical and clinical studies to determine its efficacy [479].

10. Discussion and conclusion

The COVID-19 pandemic has posed a great threat to healthcare across the globe. The causative pathogen is a novel coronavirus and there are currently no specific treatment strategies against it. Although several studies are going on to develop specific drugs targeted towards SARS-CoV-2, it might take some more time. Several vaccine development trials are also underway, but the end products will require some time to clear the safety studies. Moreover, a new variant of the SARS-CoV-2 had been reported for the first time on 14^th December 2020 in the United Kingdom (UK). This variant of concern (VOC) had been labeled as the VOC 202012/01 and had been detected in over 50 countries in the UK. Other variants such as 501Y.V2 and B.1.1.28 were also reported from South Africa (18^th December 2020) and Japan (9^th January 2021), respectively. Therefore, considering the rapid evolution of this virus and urgency of the situation, one of the best options for management and treatment is repurposed drugs. These drugs are already approved for the treatment of some diseases in humans and are thus readily available in the market. In the paucity of SARS-CoV-2 specific drugs, these repurposed drugs with antiviral or inhibitory effects are prescribed to hospitalized patients [4,97]. Cytokine storm or hyper inflammation is commonly observed in severe COVID-19 patients. It is associated with the progression of the disease and poor clinical outcome [482]. Respiratory failure, ARDS, and pneumonia are some of the most common and fatal COVID-19 associated complications. Therefore, some repurposed drugs are known to exhibit potent anti-inflammatory effects and are thus used to combat COVID-19-associated inflammatory complications [76,97].

Some of the repurposed drugs show very promising results. However, most of them raise serious concerns as they are reported to have adverse side-effects [97]. Therefore, it is necessary to look for alternative medicines that may be effective against the novel virus and associated health complications which cause little or no side-effects.

Mother Nature has provided us with several natural compounds that have been used throughout the ages for the treatment of various diseases like cancer, asthma, diabetes, respiratory and cardiovascular disorder, etc. Spices are Nature's most potent anti-inflammatory and antioxidant agents. Besides enhancing the taste, flavor, aroma, and color of food and beverages but also imparts protection against various health ailments. These therapeutic properties of spices and culinary herbs are due to the presence of various bioactive components with significant biological activities. Besides, the consumption of spices has been proven to reduce inflammation and boost our immune response [14]. Therefore, in the absence of a drug or vaccine against SARS-CoV-2, spices might serve as an alternative treatment for infected patients. It can serve a dual purpose of both as a means of primary prevention, as well as to help mitigate the exaggerated immune response and cytokine storm. However, pre-clinical and clinical studies should be conducted to validate its efficacy in COVID-19 patients1 .

Credit authorship contribution statement

BBA and ABK contributed to the conceptualization of the study design. VR, DP, SG, HS, KB and KKT performed the bibliographic search and contributed to the writing of the manuscript. VR, DP, SG, and HS contributed to the tables. VR and DP contributed to the reference editing. KB contributed to the figures. BBA, ABK, UD, PG, and SCG contributed in the reviewing and proofreading of the manuscript.

Declaration of competing interest

The authors declare no conflict of interests related to this study.