key: cord-1034150-jslzhhnk
authors: Kunnumakkara, Ajaikumar B.; Rana, Varsha; Parama, Dey; Banik, Kishore; Girisa, Sosmitha; Sahu, Henamayee; Thakur, Krishan Kumar; Dutta, Uma; Garodia, Prachi; Gupta, Subash C.; Aggarwal, Bharat B.
title: COVID-19, cytokines, inflammation, and spices: How are they related?
date: 2021-02-16
journal: Life Sci
DOI: 10.1016/j.lfs.2021.119201
sha: 8d5d18de9b78459a588e74283a812a6b83d40430
doc_id: 1034150
cord_uid: jslzhhnk

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-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 is low (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 some 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.

ACE2 + cells. Altogether, their 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. Their study showed that inhibition of any one of these proteases leads to partial inhibition of viral entry. This 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] . J o u r n a l P r e -p r o o f 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] .

A recent study was conducted to investigate the clinical features in deceased COVID-19 patients.

The study showed that a majority of deceased patients were associated with comorbidities like hypertension and cardiac anomalies. Further, the majority presented with complications such as ARDS, respiratory failure, sepsis, acute cardiac injury, heart failure, etc. Moreover, the concentrations of the IL-2 receptor, 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 sample obtained from severe patients revealed an increase in the levels of the interleukins (IL) like IL-6, IL-10, IL-2, and Interferon-γ (IFN-γ). Besides, it was also observed that the lymphocyte and T cell (especially CD8 + T) counts were substantially decreased while the neutrophil counts were 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 Alpha [69] .

Transcriptomic profiling of cytokines in SARS-CoV-2 infected patients have revealed elevated levels of cytokines MCP-1, CXCL10, MIP-1A, and MIP-1B [77] .

Increased 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, the elevated level of IL-2 receptors, IL-6, IL-8, and TNF-α was 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.

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 regulate 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, 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 J o u r n a l P r e -p r o o f 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, -6 and -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 J o u r n a l P r e -p r o o f 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) can regulate the IL-5 level and other cytokines during inflammation [14] , [96] .

The molecular pathogenesis of SARS-CoV-2 is not completely known and studies are conducted globally to investigate novel drugs and targets. However, at present, there are no available drugs or vaccines to treat COVID-19 specifically. 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 storms and complications are mentioned in Table: 1. Can potentially exert anti-viral and - [98] anti-inflammatory effects; BTK inhibitor Amphotericin B Blocks the interaction of SARS-CoV-2 - [99] S-protein with hACE-2 receptor Anakinra IL-1 inhibitor; Neutralizes SARS-CoV-2 Swedish Orphan [97] , [100] related hyperinflammation Biovitrum Arbidol Inhibit membrane fusion; Prevents the - [101] viral entry Atorvastatin Attenuates NF-κB activation; Decreases - [102] hazard for death Azithromycin Mechanism unknown; commonly used as - [97] adjunct with hydroxychloroquine Baricitinib JAK1 and JAK2 inhibtor, Can potentially - [103] inhibit SARS-CoV-2 entry Bemcentinib Can potentially reduce viral infection and BerGenBio ASA, [97] blocks SARS-CoV-2 spike protein Norway Bromhexine Transmembrane protease serine inhibitor - [104] Camostat Inhibits serine protease - [66] , [105] mesilate Chloroquine Changes the pH of endosomes; prevents - [106] viral entry, transport and post-entry events Cefuroxime Inhibits the viral RNA-dependent RNA - [107] Polymerase Ciclesonide Exerts anti-viral and anti-inflammatory - [108] effects; Treated pneumonia and lung injury Ciprofloxacin Binds to SARS-CoV-2 Mpro; Inhibits viral - [109] replication Clarithromycin Exerts anti-viral activity; Inhibits protein - [110] J o u r n a l P r e -p r o o f synthesis by binding to the 50S ribosomal subunit Daclatasvir Inhibits SARS-CoV-2 replication in vitro; - [111] Prevents the induction of pro-inflammatory cytokines Darunavir/ HIV protease inhibitor - [112] cobicistat Dasatinib Inhibits SARS-CoV-2 3CL protease - [99] Dexamethasone Reduces inflammation, modulates immune - [113] system Disulfiram Inhibits 3CL protease - [114] Doxycycline Decreases pro-inflammatory cytokines like - [115] IL-6, TNF-α; Inhibits SARS-CoV-2 papainlike protease, MMPs; Protects against lung injury Ergotamine Blocks the interaction of SARS-CoV-2 - [99] S-protein with human ACE-2 receptor

Inhibits the viral RNA-dependent RNA Toyama Chemical, [116] , [117] Polymerase Japan Galidesivir Binds to the viral RNA-dependent RNA - [118] polymerase HCQ Alters the pH of endosomes; prevents viral - [106] entry, transport and post-entry events J o u r n a l P r e -p r o o f Imatinib Suppresses THE NF-κB signaling pathway; - [119] Stimulates PGE2; Decreases the release of   TNF-α, IL1-β and IL-6 Indomethacin Blocks viral RNA synthesis - [120] Interferron γ/β Inhibits viral replication (SARS-CoV) - [121] Ivermectin Inhibits IMPα/β1-mediated nuclear import - [122] of viral proteins Povidone-Iodine Exerts virucidal activity - [132] Remdesivir Inhibits the viral RNA-dependent RNA Gilead Sciences, [133] polymerase USA

Binds to the viral RNA-dependent RNA - [118] polymerase Rivaroxaban Inhibits SARS-CoV-2 3CL protease - [99] Sacubitril/ Can potentially reduce pro-inflammatory - [134] Valsartan cytokines and neutrophil count; Increases lymphocyte count; reduces hs-CRP levels Sarilumab Blocks IL-6 receptor Regeneron Pharma- [97] ceuticals and Sanofi Saquinavir Inhibits SARS-CoV-2 3CL protease - [99] Setrobuvir Binds to the viral RNA-dependent RNA - [107] J o u r n a l P r e -p r o o f polymerase Sildenafil Inhibits SARS-CoV-2 3CL protease - [99] Siltuximab IL-6 blocker - [135] Sirolimus Modulates PI3K/AKT/mTOR pathway - [97] and inhibits MERS-CoV activity Sofosbuvir Binds to the viral RNA-dependent RNA - [118] polymerase Tacrolimus Inhibits replication and growth 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 - [118] Polymerase Thymosin α1 Restores T cell exhaustion; Recovers the - [137] immune reconstitution via promoting thymus output Tocilizumab Inhibits the IL-6 receptor Roche and Chugai [97] Pharmaceutical Vancomycin Blocks interaction of the SARS-CoV-2 - [99] S-protein with hACE-2 receptor Zilucoplan C5 inhibitor; can potentially block the severe - [98] inflammatory response in COVID-19

α-ketoamides Binds to SARS-CoV-2 main protease (Mpro) - [138] J o u r n a l P r e -p r o o f 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 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] .

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 checks the disease progression and results in faster viral clearance as compared to Lopinavir/Ritonavir. Favipiravir was administered orally for 14 days (1600mg twice on day 1 followed by 600mg, twice, daily for the remaining days) while IFN-α was administered via aerosol inhalation (5,000,000 U twice, daily) [116] .

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. It also inhibits the enzymes which metabolize lopinavir and further enhances its antiviral effect [97] . A recent in vitro study reported that lopinavir exhibits antiviral effects 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] . WHO recently discontinued the Lopinavir/Ritonavir arm for its WHO-led Solidarity Trial conducted for the treatment of J o u r n a l P r e -p r o o f Journal Pre-proof COVID-19 hospitalized patients. This was done as the drug exerted little or no decrease in mortality [152] .

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 is efficacious against novel coronavirus infection [106] . The synergistic inhibitory effect of Remdesivir with emetine (a protein synthesis inhibitor) against SARS-CoV-2 is also observed in vitro [154] . Furthermore, Remdesivir also induced substantial clinical improvement, Ivermectin and niclosamide are potent anti-helminthic 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, this broad-spectrum anti-helminthic drug might be quite promising in inhibiting SARS-CoV-2 [129] .

Glucocorticosteroids 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 glucocorticoid 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 welltolerated and may help in attenuation of the hyper-inflammatory phase [113] .

Methylprednisolone is an anti-inflammatory and anti-fibrotic drug [97] . It 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 J o u r n a l P r e -p r o o f 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 interleukin-6 inhibitors Tocilizumab, Sarilumab, and Siltuximab are hypothesized to be effective against COVID-19 patients. These IL-6 receptors antagonists are also tested against SARS-CoV-2 in both clinical and preclinical studies [97] , [135] . Early treatment with Tocilizumab reportedly improves the clinical outcome as well as 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 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-1 α 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 decreases the SARS-CoV-2 viral load pneumonia as well as the COVID-19-associated mortality rate [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 inhibits the SARS-CoV-2 infection in vitro. Further, it blocked the viral S protein-mediated J o u r n a l P r e -p r o o f 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 prove promising in the treatment pf COVID-19 patients [66] , [105] .

Several studies have shown that the administration of the anti-diabetic drug metformin in diabetic COVID-19 patients is associated with a decrease in mortality [168] , [169] , [170] , [171] .

A limited study has 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 anti-retroviral 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 anti-viral effect activity 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-α1supplement 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 in vitro. It inhibits the infection by interacting with the viral non-structural protein 13 (NSP13) [176] . A study reported three cases where ciclesonide, an inhaled steroid, attenuated COVID-19 associated pneumonia [108] .

Imatinib is an Abelson (Abl) kinase inhibitor and a potent anti-cancer drug. It also modulates immune response and exerts anti-inflammatory effects. Further, it also exhibits anti-viral effects against SARS-CoV and MERS-CoV. Therefore, it is believed that Imatinib might also be effective against SARS-CoV-2 and have an immunomodulatory effect against COVID-19

pneumonia [119] , [177] . Lactoferrin exerts immunomodulatory and anti-inflammatory properties. Therefore, it has been proposed lactoferrin might be used with other drugs as an adjunct to treat COVID-19 [123] . Povidone-Iodine also exhibits potent virucidal activity against SARS-CoV-2 [132] . The drug Tacrolimus (FK506) has been previously tested effective in inhibiting the replication of HCoVs such as SARS-CoV, NL63, and 229E. Therefore, it is proposed that it might be inhibitory against SARS-CoV-2 [136] . Pirfenidone is an anti-fibrotic drug which is used to treat idiopathic pulmonary fibrosis. Further, this drug inhibits IL-1β as well as IL-4 and thus exerts an anti-inflammatory effect, which might be effective in combating cytokine storm [131] . It also modulates the angiotensin II type 1 receptor/p38 MAPK/reninangiotensin system (AT1R/p38 MAPK/RAS axis) [178] . Therefore, it has been hypothesized that J o u r n a l P r e -p r o o f Pirfenidone might be useful in combating COVID-19 associated cytokine storm as well as lung fibrosis [131] .

Sirolimus (rapamycin) is a commonly used immunosuppressant. It exerts inhibition on the mammalian target of rapamycin (mTOR) kinase. [97] , [125] A study showed that sirolimus inhibits MERS-CoV infection effectively [179] . A Phase II clinical study is initiated to investigate if sirolimus is associated with the improvement of outcomes in COVID-19 patients placebo (NCT04341675) [180] Atorvastatin treatment was also reported to be related to a reduction in the progress to death in COVID-19 patients [102] .

Another study showed that the administration of Chloroquine and Clarithromycin in a COVID-19 patient with pneumonia improved the outcome [110] .

The ACCORD study (EudraCT 2020-001736-95) is initiated to investigate the efficacy of drugs such as Bemcentinib, MEDI3506, Acalabrutinib, Zilucoplan, and Nebulised heparin in COVID-19 patients [98] . A study hypothesized that blocking the AT1R might be beneficial to COVID-19

patients. Losartan and Telmisartan effectively blocks the AT1R and might be useful against SARS-CoV-2 [124] .

Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor [181] . Further, it has antiinflammatory activity and hence decreases the pro-inflammatory cytokines. It has been suggested that Sacubitril/valsartan can be used for the treatment of COVID-19 patients [134] .

An in silico study shows that Disulfiram inhibits the 3CLpro enzyme. This property of disulfiram may be further tested in clinical and preclinical studies for further validation [114] . 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 J o u r n a l P r e -p r o o f 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 [119] .

Another in silico study reported that Rivaroxaban, Saquinavir, Tadalafil, Sildenafil, Dasatinib inhibits the SARS-CoV-2 3CL protease. Further, it showed that Ergotamine, Amphotericin B, Vancomycin blocks interaction of SARS-CoV-2 S-protein with the ACE2 receptor in silico [99] .

IFN-β and IFN-γ exert synergistic inhibitory effects on SARS-CoV replication [121] .

Nitazoxanide is reported to inhibit inflammation. Apart from this, it also exerts antiviral activity against SARS-CoV, MERS-CoV, and influenza virus in vitro [130] .

Daclatasvir inhibits SARS-CoV-2 in vitro by inhibiting the viral replication. Further, it also prevented the production of pro-inflammatory cytokines [111] .

Various studies have also suggested that compounds derived from natural products can also be effective in 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 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 3 C-like 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 and 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] . (Figure: 3) 

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 phytochemical and natural compounds obtained from different parts of plants have been a part of traditional medicine for ages and consumed for their health benefits as well as efficacy against a plethora of diseases [201] , [202] , [203] , [204] , [205] , [206] , [2017, [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, as well as their active components, 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, J o u r n a l P r e -p r o o f 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: 

(Ferula asafetida L.) 

Piperine Lupus in vitro HK-2 cells ↓p-AMPK, ↓ IL-1β, ↓ HMGB1, ↓ pro-caspase-1, [241] nephritis in vivo BALB/c mice ↓ NLRP3 inflammasome activitation [241] Chabamide Inflammation in vitro RAW264.7 ↑ HO-1, ↑ Nrf2, ↓ iNOS [242] Capsicum -C in vivo Wistar rats ↓ ALT, ↓ AST, ↓ ALP, ↓ TNF-α, ↓ IL-6, ↓ LPO , [243] (Capsicum annum L.) ↓ Cu-Zn-SOD, ↓ GPx, ↑ CAT, ↑ Mn-SOD, ↑ GR,

Capsaicin -in vitro THP-1 ↓ IL-1β, ↓ IL-6, ↓ TNF-α, ↑ LXRα expression [245] Capsaicin SGI in vitro HSG ↓ IL-6, ↓ TNF-α [246] J o u r n a l P r e -p r o o f 

BCA, HCA -in vitro Murine ↓ IFN-γ, ↓ IL-2Rα, ↓ IgM [258] splenocytes BCA, HCA -in vivo BALB/c mice ↓ AFC response [258] Coriander

↑ GSH, ↑ HO-1 J o u r n a l P r e -p r o o f

Wistar rat ↓ IL-1β, ↓ IL-6, ↓ TNF-R1 [261] Cumin -E Hypertension in vivo SD rats ↓ mRNA expression of IL-6, Bax, and TNF-α, [262] (Cuminum cyminum) ↑ mRNA of expression TRX1, TRXR1, eNOS, and Bcl-2

activity

Fenugreek -E IPF in vivo SD rats ↑ mRNA expression of Nrf2 and Bcl-2, ↓ mRNA [268] (Trigonella foenum-graecum L.) expression of HO-1, TNF-α, IL-1β, IL-6, TGF-β, 

Trigonelline AD in vivo Wistar rats ↓ TNF-α, ↓ IL-6, ↓ cox-2, ↓ GFAP, ↓ MDA, [272] ↓ LDH, ↓ protein carbonyl, ↑ SOD, ↑ GSH

↓ p-Akt, ↓ p-p70S6K (Ser371 and Thr389), SAC PF in vivo C57BL/6 mice ↓ α-SMA, ↓ p-Akt, ↓ p-p65, ↓ mRNA expression [278] of α-SMA, TNF-α, iNOS, IL-6, IL-12p35, and TGF-β Star anise -C Atherosclerosis in vitro HASMC ↓ TNF-α, ↓ IL-1β, ↓ NF-κB, ↓ cox, ↓ E-selectin, [329] (Illicium verum)

↓ p-STAT1 [332] of Foxp3,↓ mRNA expression of IL-5, and IL-13 

↓ IL-6, ↓ mRNA synthesis of IL-17, -22, and -23

↓ cox-1 and -2 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 [223] . The activity of LOX is reportedly decreased by asafoetida [222] , [224] .

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,

anti-oxidant, anti-microbial, etc. [226] , [348] . An in vivo study has also demonstrated the cardioprotective effects of basil leaves against isoproterenol-induced myocardial infarction in rats [349] . 

Bay leaves belong to the family Lauraceae and are commonly used in cuisine for flavoring [227] , [350] . TQ also significantly reduces the expression of the pro-inflammatory cytokines TNF-α and IL-1β [233] .

Black pepper from the Piperaceae family is a popular spice due to its dietary importance and beneficial agent for various chronic health ailments [353] . 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 has also decreased the expression of STAT3, 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 PGE 2 in RAW 264.7 cells. It also reduced the degradation of IκB and targets IKK-β that inhibits p65, which leads to decrease 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 it 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 could reduce the condition of acute pancreatitis through reduction of TNF-α, IL-1β, IL-6, p-ERK1/2, p-p38, p-JNK, and MAPKs expressions [240] . 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 ameliorates 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 reduces the mRNA as well as protein expression of TNF-α and IL-6 in HSG cells [246] .

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, anti-diabetic, anti-cancer, gastroprotective, etc. [354] , [355] .

Treatment with cardamom extract ameliorates oxidative stress by enhancing the levels of antioxidant enzymes. It also attenuates inflammation by downregulating the expression of NF-κB and NO. Further, it also exerts protective effects against doxorubicin-induced cardiotoxicity in rats [247] .

J o u r n a l P r e -p r o o f

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 anti-oxidant properties. The administration of the extracts reduced the pro-inflammatory cytokines like IL-1β, TNF-α, and enhanced anti-inflammatory IL-10 levels [248] . Sedanolide, celery (A. graveolens) seed essential oil, induces autophagy to kill the 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 

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 inhibits NF-κB as well as the p38-JNK signaling pathway in the IL-1β-induced osteoarthritis model. Furthermore, it inhibits 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 is also observed after TCA treatment in RAW 264.7 cells [253] . The administration J o u r n a l P r e -p r o o f of TCA also suppresses the production of NO in LPS-induced BV2 microglial cells.

Furthermore, it also downregulates the expression of iNOS, cox-2, as well as IL-1β and induces NF-κB inactivation [254] . The essential oil extracted from cinnamon also possesses antiinflammatory properties. A study showed that it downregulates inflammatory biomarkers such as 

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, anti-microbial, 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 downregulates the expression of inflammatory mediators, including IL-1β, NO, and cox-2, as well as decreases the production of PGE2 and iNOS. It further inhibits NF-κB activation as well as MAPK signaling in LPS-induced RAW 264.7 cells [259] . It also substantially attenuates 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 induces a reduced production of TNF-R1 protein as well as downregulates the levels of the cytokines IL-1β and IL-6 [261] .

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

Curry leaves belong to the Rutaceae family. Curry leaves are popularly used in Indian cuisine and have been a part of Indian traditional medicine for centuries due to its versatile medicinal properties [363] . downregulates the activity of p65-NFκB as well as the expression of cox-2 and intercellular adhesion molecule-11 (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 inflammation regulator NF-kB [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 antiinflammatory effect [266] . Girinimbine, another carbazole alkaloid, is also a potent antiinflammatory agent. It reduced the production of TNF-α and IL-1β in carrageenan-induced peritonitis [267] .

Fenugreek (Trigonella foenum-graecum L.):

Fenugreek belongs to the Fabaceae family [364] . It is rich in pharmaceutical and nutritional

properties. It possesses different activities such as anti-carcinogenic, anti-inflammatory, antidiabetic, etc. [365] . [268] . A study has demonstrated that the extract of fenugreek seeds exerts inhibitory effects on cisplatin-induced enhanced expression of iNOS and NF-κB-p65 in testicular tissues of Wistar rats [269] . It also reduces 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-J o u r n a l P r e -p r o o f inflammatory cytokines TNF-α and IL-6 is significantly down-regulated 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 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, anti-ulcer, anti-arthritis, etc. [366] . Garcinol is a major component of Garcinia which possesses medicinal properties such as anti-proliferative, 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 prevents DSS/azoxymethane (AOM)-induced colon tumorigenesis by inhibiting the PI3K/Akt/p70S6K, as well as ERK signaling pathways [273] . Garcinol inhibits NF-κB activation in head and neck cancer cells -CAL27. It mediates the inhibition by suppressing TGF-β-activated kinase 1 (TAK1) as well as an inhibitor of IkB kinase (IKK). Further, it also inhibits STAT3 as well as its upstream kinases c-Src, JAK1, and JAK2.

Moreover, it exerts anti-tumor effects in nude mice with CAL27 xenografts [274] .

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 downregulates the levels of cytokines such as IL-13, IL-5, IL-4 but upregulates the levels of IFN-γ and IL-12 in the BALF of the experimental mice.

Moreover, it also decreases the levels of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 and thereby induces anti-inflammatory effects [275] . The treatment of Der p-stimulated A549 cells with aqueous garlic extract also inhibits inflammation by suppressing the IL-6/PI3K/Akt/NF-κB pathway [275] .

Different bioactive components present in garlic are associated with its anti-inflammatory property 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 ameliorates 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), inhibits the NF-κB and Wnt pathway in human fibroblastlike 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 contains S-allyl-L-cysteine (SAC), an organosulfur compound [368] . An in vivo study revealed that in a bleomycin-induced pulmonary fibrosis model, SAC reduces the mRNA expression of fibrosis markers such as α-smooth muscle actin (α-SMA), fibronectin, collagen-I, and -III. Additionally, it also downregulates the mRNA expression of markers associated with inflammatory responses such as TNF-α, iNOS, IL-6, and IL-12p35.

Furthermore, SAC also suppresses the Akt/NF-кB pathway in the in vivo model [278] . The bioactive component S-allyl-mercapto cysteine (SAMC) found in garlic also exerts potent anti-J o u r n a l P r e -p r o o f inflammatory, anti-fibrotic, anti-oxidative, as well as anti-metastatic effects [369] , [370] . A study demonstrated that SAMC attenuates inflammation by inducing inhibitory effects on proinflammatory cytokines such as TNF-α, IL-1β, IL-6 and suppressing the NF-кB pathway in LPS-induced ALI in mice model [279] .

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

An in vivo study revealed that 6-shogaol exerts anti-inflammatory effects in 7,12dimethylbenz[a]anthracene induced oral cancer mice model by modulating the NF-κB pathway.

It downregulates the lvels of cytokines such as IL-1, IL-6, and TNF-α [280] . A study demonstrated that 6-gingerol shows protective effects against steatohepatitis in both in vivo and in vitro. In the HepG2 cells, gingerol reduces the enhanced levels of a pro-inflammatory cytokine such as 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] .

Ginseng belongs to the Araliaceae family and is commonly used in herbal therapies. Both its extract and isolated active compounds are reported to show extensive biological properties [372] , [373] . Rg1 significantly suppresses the TGF-β1/Smad3 signaling pathway and Rg3 mitigated neutrophilic inflammation, migration, and the levels of PI3K thus exerting protective effects [288] . Ginsenoside Rd was found to prevent neuroinflammation in the case of ischemic stroke via significantly inhibiting the NF-κB/MMP-9 signaling pathway [289] .

The powdered dry fruits of P.longum (family Piperaceae), are used as a hot spice and seasoning.

The whole plant of this spice is known to yield many biologically important chemicals, for example, alkaloids like piperine and piperlongumine (PL), piperinic acid, etc. It is used to treat numerous inflammation-mediated diseases like cancer, allergy, lupus nephritis, arthritis, asthma, J o u r n a l P r e -p r o o f inflammatory bowel disease, etc. [290] , [291] , [292] , [293] . This is mediated by suppressing the activity of proinflammatory cytokines such as TNF-α and IL-6 and inducing the antiinflammatory cytokines like IL-10, as depicted in several pre-clinical studies [294] , [295] , [296] .

The compound PL is known to relieve the inflammation-associated neurotoxicity upon the activation of stress-inducing molecules like NO, PGE2, etc. in the cultured LPS-stimulated BV2 cells [295] , [297] . The pathogenesis in the vasculature is a crucial step that leads to cardiovascular diseases, atherosclerosis, etc. which is mostly due to the modulation of NF-κB signaling molecules, cox-2, etc. PL is shown to reduce the expression of these inflammation mediators in VSMC (vascular smooth muscle cells) and HUVEC (human umbilical vein endothelial cells) as demonstrated in vitro [298] , [299] . In the disease-induced mice models of sepsis and asthma, PL and other long pepper extracts prevent the cell-adhesion and migration of leukocytes to sites of inflammation by reducing the expression of cell adhesion molecules like ICAM-1, VCAM-1, etc. [293] , [294] , [298] . The systemic downregulation of elevated expression levels of MAPK proteins like p38, ERK1/2, JNK by PL is also involved in showing antiinflammation activity. [294] , [299] , [300] . In the ovalbumin-induced asthmatic lung tissue of mice and bronchial epithelial cell line Beas-2B, PL alleviates the overactivation of Th2 cytokines IL-4, IL -5, and IL -13 as well as the IgE levels. Besides, PL prevented the airway remodeling in the mice models caused due to extracellular matrix degradation, by reducing expression levels of MMP-9, collagen deposition, elastase, etc. [298] , [301] In the collagen-induced arthritis mice model, PL is shown to suppress the expression of TNF-α, IL-1β, IL-23, and IL-17 [292] . as herbal tea and spice. It is rich in antimicrobial, anti-inflammatory, neuroprotective, cardiovascular, and antitumor properties [374] , [375] .

A study reported that Mentha spicata exerts ameliorative effects against acute and chronic inflammation in vivo [376] . 

White mustard belongs to the family of Brassicaceae [377] . They 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 inhibits the mRNA as well as protein expression of inflammatory cytokines such as TNF-α, IL-6, and IL-1β in vivo. Further, it also suppresses the activity of MPO, which is a marker for inflammation [304] . Mustard seeds also ameliorate inflammation in psoriasis models. They repress the expression of NLRP3 inflammasome. This further leads to the inhibition of IL-1β and IL-18 induced inflammation [305] . Furthermore, it induces an increased 

Onion belongs to the Liliaceae family. It is consumed widely for its flavor and nutritional value.

Moreover, it is also used in traditional medicine for its variety of therapeutic properties such as anti-cancer, cardioprotective, anti-microbial, anti-fungal, anti-viral, etc. [381] . The extract of onion bulb exerted protective effects in the DSS-induced colitis rat model by downregulating MAPK/Akt/mTOR signaling as well as the cox-2 levels. Moreover, pro-inflammatory cytokines and chemokines were also downregulated [313] . The extract of red onion scales decreases the levels of IL-6, IL-10, and TNF-α in atypical prostatic hyperplasia in vivo model [314] . Quercetin is a flavonoid found in onion [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 expression 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-1 β, IL-18, TNF-α, and IL-6. Additionally, it also improved LPS-induced atherosclerosis by inhibiting PI3K/AKT-regulated NF-κB [315] .

Quercetin Rosmarinic acid is one of the major components of rosemary. It is a phenolic compound that possesses anti-inflammatory, hepatoprotective, anti-hyperlipidemic property, etc. [383] , [384] A study has shown that rosmarinic acid downregulates 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 modulates the MAPK and NF-κB signaling pathways in ovalbumin-induced asthma in mice model [318] 7.24.

Saffron belongs to the Iridaceae family. It is known to exert therapeutic effects such as anticonvulsant, anti-depressant, anti-inflammatory, antitumor, etc. [385] . Crocin ameliorates LPSinduced sepsis as well as cardiotoxicity in H9c2 cells. It significantly downregulating the inflammatory mediators TNF-α, PGE2, IL-1β, and IL-6. It also decreases the mRNA expression of cox-2, iNOS, as well as NO [319] . Crocin exerts an osteoprotective effect by inhibiting inflammation in a metabolic syndrome (MeS)-induced osteoporosis model. It exhibits antiinflammatory activity by reducing the levels of the pro-inflammatory cytokines IL-6 and TNF-α.

Furthermore, it suppresses and elevates the levels of markers for bone resorption and bone formation respectively in (MeS)-induced osteoporosis model [320] . Safranal is another major component of saffron. A study shows that safranal inhibits MAPK and NF-κB pathways which lead to a reduction in the expression of pro-inflammatory cytokines such as IL-6 and TNF-α. It also inhibits 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 J o u r n a l P r e -p r o o f the hippocampus of the amyloid β-induced AD model. It also attenuated cognitive deficits and exhibited anti-oxidant effects in the AD model [322] . In addition to the anti-inflammatory effect, safranal also exhibits potent anti-oxidant and gastro-protective effects [323] .

Sesame belongs to the Pedaliaceae family and is rich in medicinal properties such as anti-cancer, hepatoprotective, anti-hypertensive, 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. Further, it reduced the levels of eotaxin, ROS, and ICAM-1 (suppressing adherence of monocytic cell), which might attenuate inflammations in the lungs [324] Sesamin is a lignan isolated from S. indicum [387] The administration of sesamin attenuated LPS-induced acute lung injury by reducing the expression of NF-κB, TNF-α, IL-6, and IL-1β. It also inhibited the TLR4 pathway [325] . It also ameliorated renal oxidative stress and inflammation by upregulating antioxidant enzymes such as SOD, GSH, catalase, and downregulating inflammatory mediators such as TNF-α, IL-6, cox-2, respectively.326 Similarly, sesame oil exerted a protective effect against the asthmatic mice model by resulted in reducing the levels of IL-1 β, IL-6, IgE, and iNOS [327] .

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 TNFα, IL-1β, NF-κB, and cox in an apolipoprotein E-knockout (ApoE −/− ) mice. Similar findings were J o u r n a l P r e -p r o o f observed when TNF-α-stimulated-HASMC cells on the administration of star anise 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 inhibits JAK/STAT signaling and leads to a decreased 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 reduces the levels of pro-inflammatory mediators such as TNF-α, and IL-6 [331] . 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 an anti-oxidant property that prevents oxidative stress-induced-erythrocyte loss. It is also known to prevent anemia, reduces lipid peroxidation, and regulates 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 anti-arthritic effects in vivo by modulating the levels of anti-inflammatory mediators such as IL-10, TNF-α, J o u r n a l P r e -p r o o f IL-1β, IL-6, cox-2, and IL-23 [334] . Its fruit extract also possesses anti-inflammatory properties [392] . The mucoadhesive tamarind xyloglucan (TXG) was shown to exert anti-inflammatory effects against ulcerative colitis in vivo. TXG inhibits the levels of pro-inflammatory cytokines IL-1β and IL-6 and further attenuates inflammation by inhibiting the TLR4/NF-κB signaling pathway [335] .

Turmeric from the Zingiberaceae family has been used since ancient times in various traditional medicines. It is profoundly rich in activities such as anti-inflammatory, anti-cancer, antiatherosclerotic, anti-depressant, anti-diabetic, anti-arthritic, etc. Its potent biological properties can be mostly attributed to one of its active components namely "Curcumin" [393] , [394] , [395] , [396] , [397] . Curcumin is enriched in several pharmacological activities such as anti-viral, antifungal, anti-cancer, 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 amelioration lung injuries [336] . An in vivo study on experimentally induced pulmonary inflammation in a rat model has evidenced that J o u r n a l P r e -p r o o f curcumin significantly upturned the expressions of various inflammatory and fibrotic mediators involved such as Cystic fibrosis transmembrane conductance regulator (CFTR) and cox-2/PGE2/IL-8 [337] . Moreover, the anti-inflammatory and anti-oxidative 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 thus inhibiting 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 anti-ulcer activity and thus it aided in the treatment of LPSinduced ulcer in a rat model. MTrPP worked through inhibiting the release of inflammatory markers such as TNF-α, IL-8, NF-κB, MMP-9, and cox-1, -2. It also prevented the phosphorylation of p38 thus imparting protective effects [343] .

J o u r n a l P r e -p r o o f 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, 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 safe to use [414] .

β-caryophyllene, one of the active compounds of cinnamon, was found to be effective against gastrointestinal disease caused due to Helicobacter pylori (H. pylori) infections. A randomized double-blind placebo-controlled study has reported that administration of 126 mg βcaryophyllene daily for 8 weeks showed significant anti-inflammatory properties via 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 gastrointestinal ailments [415] .

J o u r n a l P r e -p r o o f

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 minimal antiinflammatory activity and well-tolerated when applied on the skin of healthy volunteers [416] .

Clinical trials investigating the potency of garlic extracts 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 extracts (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 for 12 weeks significantly reduced the level of resistin, an inflammatory cytokine, thus displaying anti-inflammatory effects [418] .

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. properties [421] .

Furthermore, a pilot clinical study on the subjects at an increased risk of colorectal cancer (CRC) has shown that ginger extract was found to be 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. Thus further studies are essential to investigate the exact mechanism behind the chemopreventive effects of this spice [422] .

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 [423] . 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 inflammation post-surgery in patients [424] .

J o u r n a l P r e -p r o o f

The anti-inflammatory property of saffron is evaluated by many studies and thus it was thought 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, usage of salbutamol inhaler, 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 anti-oxidant properties. It was found that the administration of two capsules of crocin (15mg) for 28 days showed an improvement in the antioxidant status of the body. Additionally, a reduction in inflammatory mediators such as TNFα and IL-17 in the blood of the patients was also found [426] .

Sesame seed therapy was found to improve the factors 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] .

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, SOD in patients thus imparting significant anti-J o u r n a l P r e -p r o o f Journal Pre-proof inflammatory and anti-oxidant effects [428] . In the case of patients with obesity/hypertension, the hot water extract of C. longa L. (WEC) was found to reduce the levels of CRP, TNF-α, IL-6, and soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1), thereby amending chronic lowgrade 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 inclined 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 antiinflammatory activity [430] , [431] . The compounds are further found effective against osteoarthritis and RA. In the case of osteoarthritis, Curcuma longa L. (CL) extract showed significant anti-inflammatory effects via the down-regulation of IL-1β and anti-oxidant effects via the down-regulation 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 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 J o u r n a l P r e -p r o o f 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 via 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] .

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] .

J o u r n a l P r e -p r o o f 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, the coronavirus 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 viral 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] . 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 J o u r n a l P r e -p r o o f inhibition of the viral replication by binding with Nsp15 [182] . Curcumin has also been reported as a potential inhibitor of 

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 a specific drug 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 labelled 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 J o u r n a l P r e -p r o o f 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 anti-viral 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 these 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 help mitigate the exaggerated J o u r n a l P r e -p r o o f

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Sedanolide inducesautophagy through the PI3K, p53 and NF-κB signaling pathways in human livercancer cells

Anti-atopic dermatitis effects of hydrolyzed celery extract in mice

Celery Seed Extract Blocks Peroxide Injury in Macrophages via Notch1/NF-κB Pathway

Trans-Cinnamaldehyde Inhibits IL-1β-Stimulated Inflammation in Chondrocytes by Suppressing NF-κB and p38-JNK Pathways and Exerts Chondrocyte Protective Effects in a Rat Model of Osteoarthritis

Suppression effect of Cinnamomum cassia bark-derived component on nitric oxide synthase

trans-Cinnamaldehyde Inhibits Microglial Activation and Improves Neuronal Survival against Neuroinflammation in BV2 Microglial Cells with Lipopolysaccharide Stimulation

Antiinflammatory Activity of Cinnamon (Cinnamomum zeylanicum) Bark Essential Oil in a Human Skin Disease Model

Anti-inflammatory activity of cinnamon water extract in vivo and in vitro LPS-induced models

Immunomodulatory effect of water extract of cinnamon on anti-CD3-induced cytokine responses and p38, JNK, ERK1/2, and STAT4 activation

Cinnamaldehyde inhibits lymphocyte proliferation and modulates T-cell differentiation

Suppressive effects of extracts from the aerial part of Coriandrum sativum L. on LPS-induced inflammatory responses in murine RAW 264.7 macrophages

Coriander alleviates 2,4-dinitrochlorobenzene-induced contact dermatitis-like skin lesions in mice

Anti-granuloma activity of Coriandrum sativum in experimental models

Cuminum cyminum, a dietary spice, attenuates hypertension via endothelial nitric oxide synthase and NO pathway in renovascular hypertensive rats

Vulnerability of Gastric Mucosa in Diabetic Rats, Its Pathogenesis and Amelioration by Cuminum cyminum

Modulation of ceruleininduced pancreatic inflammation by hydroalcoholic extract of curry leaf (Murraya koenigii)

Chemopreventive and immunomodulatory effects of Murraya koenigii aqueous extract on 4T1 breast cancer cell-challenged mice

Effect of mahanimbine, an alkaloid from curry leaves, on high-fat diet-induced adiposity, insulin resistance, and inflammatory alterations

Anticancer and anti-inflammatory activities of girinimbine isolated from Murraya koenigii

Effect of glycosides based standardized fenugreek seed extract in bleomycin-induced pulmonary fibrosis in rats: Decisive role of Bax, Nrf2, NF-κB, Muc5ac, TNF-α and IL-1β

Fenugreek seed extract attenuates cisplatin-induced testicular damage in Wistar rats

Effects of Trigonella foenum-graecum (L.) on retinal oxidative stress, and proinflammatory and angiogenic molecular biomarkers in streptozotocin-induced diabetic rats

Evaluation of anti-arthritic potential of Trigonella foenum graecum L. (Fenugreek) mucilage against rheumatoid arthritis

Trigonelline protects hippocampus against intracerebral Aβ(1-40) as a model of Alzheimer's disease in the rat: insights into underlying mechanisms

Garcinol suppresses inflammationassociated colon carcinogenesis in mice

Garcinol, a polyisoprenylated benzophenone modulates multiple proinflammatory signaling cascades leading to the suppression of growth and survival of head and neck carcinoma

Comparing the Protection Imparted by Different Fraction Extracts of Garlic (Allium sativum L.) against Der p-Induced Allergic Airway Inflammation in Mice

Protective effect of diallyl disulfide against ceruleininduced acute pancreatitis and associated lung injury in mice

Diallyl Trisulfide can induce fibroblast-like synovial apoptosis and has a therapeutic effect on collagen-induced arthritis in mice via blocking NF-κB and Wnt pathways

S-allyl-l-cysteine attenuates bleomycin-induced pulmonary fibrosis and inflammation via AKT/NF-κB signaling pathway in mice

S-allylmercaptocysteine ameliorates lipopolysaccharide-induced acute lung injury in mice by inhibiting inflammation and oxidative stress via nuclear factor kappa B and Keap1/Nrf2 pathways

Shogaol attenuates inflammation, cell proliferation via modulate NF-κB and AP-1 oncogenic signaling in 7,12-dimethylbenz[a]anthracene induced oral carcinogenesis

6-gingerol protects against nutritional steatohepatitis by regulating key genes related to inflammation and lipid metabolism

Isofraxidin ameliorated influenza viral inflammation in rodents via inhibiting platelet aggregation

Inhibitory Effects of Black Ginseng on Particulate Matter-Induced Pulmonary Injury

Pananx notoginseng saponins attenuate CCL2-induced cognitive deficits in rats via antiinflammation and anti-apoptosis effects that involve suppressing over-activation of NMDA receptors

Protective effects of panax notoginseng saponin on dextran sulfate sodium-induced colitis in rats through phosphoinositide-3-kinase protein kinase B signaling pathway inhibition

Notoginsenoside R1 Suppresses Inflammatory Signaling and Rescues Renal Ischemia-Reperfusion Injury in Experimental Rats

Ginsenoside Rg3 Alleviates Complete Freund's Adjuvant-Induced Rheumatoid Arthritis in Mice by Regulating CD4 + CD25 + Foxp3 + Treg Cells

Ginsenoside Rg1 protects against cigarette smoke-induced airway remodeling by suppressing the TGF-β1/Smad3 signaling pathway

Ginsenoside Rd attenuates blood-brain barrier damage by suppressing proteasome-mediated signaling after transient forebrain ischemia

PL chemosensitizes tumor cells through interaction with cysteine 179 of IκBα kinase, leading to suppression of NF-κB-regulated gene products

Piperlongumine alleviates lupus nephritis in MRL-Fas(lpr) mice by regulating the frequency of Th17 and regulatory T cells

Piperlongumine attenuates collagen-induced arthritis via expansion of myeloid-derived suppressor cells and inhibition of the activation of fibroblast-like synoviocytes

PL reduces ovalbumin-induced asthma and airway inflammation by regulating nuclear factor-κB activation

Vascular barrier protective effects of piperlonguminine in vitro and in vivo

PL inhibits neuroinflammation via regulating NF-κB signaling pathways in lipopolysaccharidestimulated BV2 microglia cells

Immunomodulation exhibited by piperinic acid through suppression of proinflammatory cytokines

PL Improves Lipopolysaccharide-Induced Amyloidogenesis by Suppressing NF-KappaB Pathway

Extract inhibits TNF-alpha-induced expression of cell adhesion molecules by inhibiting NF-kappaB activation and microsomal lipid peroxidation

PL inhibits atherosclerotic plaque formation and vascular smooth muscle cell proliferation by suppressing PDGF receptor signaling

Piperlonguminine downregulates endothelial protein C receptor shedding in vitro and in vivo

Effect of PL during exposure to cigarette smoke reduces inflammation and lung injury

The Anti-Stress Effect of Mentha arvensis in Immobilized Rats

Modulation of alveolar macrophage innate response in proinflammatory-, pro-oxidant-, and infection-models by mint extract and chemical constituents: Role of MAPKs

Comparison of the antiinflammatory effects of Sinapis alba and Brassica juncea in mouse models of inflammation

Expression of NLRP3 inflammasome in BALB/c mice with imiquimod-induced psoriasis-like inflammation and therapeutic effect of mustard seed

Mustard seed (Sinapis Alba Linn) attenuates imiquimod-induced psoriasiform inflammation of BALB/c mice

Abdel Moneim AE. Myristica fragrans seed extract reverses scopolamine-induced cortical injury via stimulation of HO-1 expression in male rats

Macelignan attenuated allergic lung inflammation and airway hyper-responsiveness in murine experimental asthma

Macelignan inhibits histamine release and inflammatory mediator production in activated rat basophilic leukemia mast cells

Macelignan protects against renal ischemiareperfusion injury via inhibition of inflammation and apoptosis of renal epithelial cells

Myrislignan attenuates lipopolysaccharide-induced inflammation reaction in murine macrophage cells through inhibition of NF-κB signalling pathway activation

Anti-inflammatory effect of myristicin on RAW 264.7 macrophages stimulated with polyinosinic-polycytidylic acid

Onion bulb extract reduces colitis severity in mice via modulation of colonic inflammatory pathways and the apoptotic machinery

Immunomodulatory effect of red onion (Allium cepa Linn) scale extract on experimentally induced atypical prostatic hyperplasia in Wistar rats

Quercetin attenuates high fructose feeding-induced atherosclerosis by suppressing inflammation and apoptosis via ROS-regulated PI3K/AKT signaling pathway

Novel quercetin-3-O-glucoside eicosapentaenoic acid ester ameliorates inflammation and hyperlipidemia

Rosmarinic acid affects immunological and inflammatory mediator levels and restores lung pathological features in asthmatic rats

Therapeutic effects of rosmarinic acid on airway responses in a murine model of asthma

Crocin protects cardiomyocytes against LPS-Induced inflammation

Crocin attenuates metabolic syndrome-induced osteoporosis in rats

Safranal Alleviates Dextran Sulfate Sodium-Induced Colitis and Suppresses Macrophage-Mediated Inflammation

Safranal, an active ingredient of saffron, attenuates cognitive deficits in amyloid β-induced rat model of Alzheimer's disease: underlying mechanisms

Safranal, a constituent of saffron, exerts gastro-protective effects against indomethacin-induced gastric ulcer

Sesamol Alleviates Airway Hyperresponsiveness and Oxidative Stress in Asthmatic Mice

Jian-An W. Sesamin Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Inhibition of TLR4 Signaling Pathways

Protective effect of sesamin in lipopolysaccharideinduced mouse model of acute kidney injury via attenuation of oxidative stress, inflammation, and apoptosis

Sesamin attenuates chronic unpredictable mild stress-induced depressive-like behaviors and memory deficits via suppression of neuroinflammation

Sesame oil attenuates ovalbumin-induced pulmonary edema and bronchial neutrophilic inflammation in mice

Protective activity ethanol extract of the fruits of Illicium verum against atherogenesis in apolipoprotein E knockout mice

Illicium verum extract suppresses IFN-γ-induced ICAM-1 expression via blockade of JAK/STAT pathway in HaCaT human keratinocytes

Anti-inflammatory effects of anethole in lipopolysaccharide-induced acute lung injury in mice

Illicium verum Extract and Trans-Anethole Attenuate Ovalbumin-Induced Airway Inflammation via Enhancement of Foxp3 + Regulatory T Cells and Inhibition of Th2 Cytokines in Mice

Possible Modulatory Effect of Tamarind Seed Coat Extract on Fluoride-Induced Pulmonary Inflammation and Fibrosis in Rats

Tamarind Seed (Tamarindus indica) Extract Ameliorates Adjuvant-Induced Arthritis via Regulating the Mediators of Cartilage/Bone Degeneration

Mucoadhesive role of tamarind xyloglucan on inflammation attenuates ulcerative colitis

Curcumin ameliorates severe influenza pneumonia via attenuating lung injury and regulating macrophage cytokines production

CFTR-regulated MAPK/NF-κB signaling in pulmonary inflammation in thermal inhalation injury

Curcumin alleviates lung injury in diabetic rats by inhibiting nuclear factor-κB pathway

Curcumin protects against sepsis-induced acute lung injury in rats

Protective effect of curcumin on acute airway inflammation of allergic asthma in mice through Notch1-GATA3 signaling pathway

Curcumin protects against cerebral ischemia-reperfusion injury by activating JAK2/STAT3 signaling pathway in rats

Aromatic-turmerone ameliorates imiquimod-induced psoriasis-like inflammation of BALB/c mice

A modified pectic polysaccharide from turmeric (Curcuma longa) with antiulcer effects via anti-secretary, mucoprotective and IL-10 mediated anti-inflammatory mechanisms

Biological activities and medicinal properties of Asafoetida: A review

Ferula asafoetida: Traditional uses and pharmacological activity

The potential effects of Ocimum basilicum on health: a review of pharmacological and toxicological studies

The phytochemical variability of fatty acids in basil seeds (Ocimum basilicum L.) affected by genotype and geographical differences

Ocimum basilicum affects tracheal responsiveness, lung inflammatory cells and oxidant-antioxidant biomarkers in sensitized rats

Amelioration of inflammation by phenolic rich methanolic extract of Ocimum sanctum Linn. leaves in isoproterenol induced myocardial infarction

The Health Benefits of Selected Culinary Herbs and Spices Found in the Traditional Mediterranean Diet

Investigation of the Protective Effect of Nigella Sativa Oil in Cisplatin Induced Oral Mucositis: An Experimental Study

Black Cumin (Nigella sativa) and Its Active Constituent, Thymoquinone: An Overview on the Analgesic and Anti-inflammatory Effects

Black pepper and health claims: a comprehensive treatise

Chemopreventive Effect of Cardamom (Elettaria cardamomum L.) Against Benzo(α)Pyrene-Induced Forestomach Papillomagenesis in Swiss Albino Mice

Botany, traditional uses, phytochemistry and biological activities of cardamom [Elettaria cardamomum (L.) Maton] -A critical review

Cinnamon and Chronic Diseases

Pharmacological properties and their medicinal uses of Cinnamomum: a review

Effect of Coriandrum sativum hydroalcoholic extract and its essential oil on acetic acid-induced acute colitis in rats

Coriandrum sativum): A promising functional food toward the well-being

In vitro and in vivo anthelmintic activity of crude extracts of Coriandrum sativum against Haemonchus contortus

Pharmacological screening of Coriandrum sativum Linn. for hepatoprotective activity

Cuminum cyminum L.) from traditional uses to potential biomedical applications

Prevention of Cardiovascular Diseases with Anti-Inflammatory and Anti-Oxidant Nutraceuticals and Herbal Products: An Overview of Pre-Clinical and Clinical Studies

A small plant with big benefits: Fenugreek (Trigonella foenum-graecum Linn.) for disease prevention and health promotion

Toxicological properties of fenugreek (Trigonella foenum graecum)

Anti-Arthritic Effect of Garcinol Enriched Fraction Against Adjuvant Induced Arthritis

Molecular Targets and Therapeutic Uses of Spices: Modern Uses for Ancient Medicine

Effective production of S-allyl-L-cysteine through a homogeneous reaction with activated endogenous γ-glutamyltranspeptidase in garlic (Allium Sativum)

Anti-cancer activities of S-allylmercaptocysteine from aged garlic

S-Allylmercaptocysteine attenuates Bleomycininduced pulmonary fibrosis in mice via suppressing TGF-β1/Smad and oxidative stress pathways

A review of the gastroprotective effects of ginger (Zingiber officinale Roscoe)

Role of ginsenosides, the main active components of Panax ginseng, in inflammatory responses and diseases

Chemical Structures and Pharmacological Profiles of Ginseng Saponins

Molecular Targets and Therapeutic Uses of Spices: Modern Uses for Ancient medicine

Evidence of biological activity of Mentha species extracts on apoptotic and autophagic targets on murine RAW264.7 and human U937 monocytic cells

Anti-inflammatory activity of four solvent fractions of ethanol extract of Mentha spicata L. investigated on acute and chronic inflammation induced rats

White Mustard (Sinapis alba L.) Oil in Biodiesel Production: A Review

Nutmeg (Myristica fragrans Houtt

Phytochemical investigation on Myristica fragrans stem bark

PPARα Mediates the Hepatoprotective Effects of Nutmeg

Onion: nature protection against physiological threats

Antioxidant and Antimicrobial Properties of Rosemary

Anti-inflammatory effect of rosmarinic acid and an extract of Rosmarinus officinalis in rat models of local and systemic inflammation

Antihyperlipidemic and Radical Scavenging Activity of Hawthorn (Crataegus oxyacantha) and Rosemary (Rosmarinus officinalis) on Alcoholic Liver Disease

Clinical Applications of Saffron (Crocus sativus) and its Constituents: A Review

A comprehensive review on the anti-cancer properties and mechanisms of action of sesamin, a lignan in sesame seeds (Sesamum indicum)

Sesamin Enhances Nrf2-Mediated Protective Defense against Oxidative Stress and Inflammation in Colitis via AKT and ERK Activation

Inhibitory effect of anethole in nonimmune acute inflammation

Antimicrobial properties of star anise (Illicium verum Hook f)

Star anise (Illicium verum): Chemical compounds, antiviral properties, and clinical relevance

Protective Effect of Tamarind Seed Coat Ethanol Extract on Eryptosis Induced by Oxidative Stress

Mat-Junit S. Effects of Tamarindus indica fruit pulp extract on abundance of HepG2 cell lysate proteins and their possible consequential impact on metabolism and inflammation

Curcumin as "Curecumin": from kitchen to clinic

Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases

Curcumin and endometriosis: Review on potential roles and molecular mechanisms

Role of pro-oxidants and antioxidants in the anti-inflammatory and apoptotic effects of curcumin (diferuloylmethane). Free Radic

Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature

Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products

Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic mouse model

Curcumin mediates anticancer effects by modulating multiple cell signaling pathways

Bioavailability of curcumin: problems and promises

Curcumin inhibits tumor growth and angiogenesis in ovarian carcinoma by targeting the nuclear factor-kappaB pathway

Curcumin: A Potential Molecule for the Prevention and Treatment of Inflammatory Diseases. The Chemistry and Bioactive Components of Turmeric

Curcumin and pancreatic cancer: phase II clinical trial experience

Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins

Curcumin and colorectal cancer: add spice to your life

Multi-Targeted Agents in Cancer Cell Chemosensitization: What We Learnt from Curcumin Thus Far

Is curcumin bioavailability a problem in humans: lessons from clinical trials

The potential of curcumin: a multitargeting agent in cancer cell chemosensitization. Role of Nutraceuticals in Cancer Chemosensitization

Phase II trial of curcumin in patients with advanced pancreatic cancer

Curcumin sensitizes human colorectal cancer xenografts in nude mice to gamma-radiation by targeting nuclear factor-kappaB-regulated gene products

Cardamom supplementation improves inflammatory and oxidative stress biomarkers in hyperlipidemic, overweight, and obese pre-diabetic women: a randomized double-blind clinical trial

Beneficial effects of green cardamom on serum SIRT1, glycemic indices and triglyceride levels in patients with type 2 diabetes mellitus: a randomized double-blind placebo controlled clinical trial

Green cardamom supplementation improves serum irisin, glucose indices, and lipid profiles in overweight or obese nonalcoholic fatty liver disease patients: a double-blind randomized placebo-controlled clinical trial

Inhibitory Effects of β-caryophyllene on Helicobacter pylori Infection: A Randomized Double-blind

Antiinflammatory potential of a lipolotion containing coriander oil in the ultraviolet erythema test

Aged garlic extract supplementation modifies inflammation and immunity of adults with J o u r n a l P r e -p r o o f obesity: A randomized, double-blind, placebo-controlled clinical trial

The effect of a garlic supplement on the pro-inflammatory adipocytokines, resistin and tumor necrosis factor-alpha, and on pain severity, in overweight or obese women with knee osteoarthritis

The effect of ginger supplementation on some immunity and inflammation intermediate genes expression in patients with active Rheumatoid Arthritis

Effect of Ginger Supplementation on Proinflammatory Cytokines in Older Patients with Osteoarthritis: Outcomes of a Randomized Controlled Clinical Trial

Anti-inflammatory and antioxidant effect of ginger in tuberculosis

Pilot clinical study of the effects of ginger root extract on eicosanoids in colonic mucosa of subjects at increased risk for colorectal cancer

Clinical study on effect of total panax notoginseng saponins on immune related inner environment imbalance

Ginsenosides compound (shen-fu) attenuates gastrointestinal injury and inhibits inflammatory response after cardiopulmonary bypass in patients with congenital heart disease

An evaluation of the effects of saffron supplementation on the asthma clinical symptoms and asthma severity in patients with mild and moderate persistent allergic asthma: a double-blind, randomized placebo-controlled trial

Effects of crocin in reducing DNA damage, inflammation, and oxidative stress in multiple sclerosis patients: A double-blind, randomized, and placebo-controlled trial

Effects of sesame seed supplementation on inflammatory factors and oxidative stress biomarkers in patients with knee osteoarthritis

Antioxidant and anti-inflammatory effects of curcuminoid-piperine combination in subjects with J o u r n a l P r e -p r o o f metabolic syndrome: A randomized controlled trial and an updated meta-analysis

Hot Water Extract of Curcuma longa L. Improves Serum Inflammatory Markers and General Health in Subjects with Overweight or Prehypertension/Mild Hypertension: A Randomized, Double-Blind, Placebo-Controlled Trial

Curcuminoids Plus Piperine Modulate Adipokines in Type 2 Diabetes Mellitus

The effects of curcumin supplementation on high-sensitivity C-reactive protein, serum adiponectin, and lipid profile in patients with type 2 diabetes: A randomized, double-blind, placebocontrolled trial

Curcuma longa extract reduces inflammatory and oxidative stress biomarkers in osteoarthritis of knee: a fourmonth, double-blind, randomized, placebo-controlled trial

A complex of three natural anti-inflammatory agents provides relief of osteoarthritis pain

A Novel Highly Bioavailable Curcumin Formulation Improves Symptoms and Diagnostic Indicators in Rheumatoid Arthritis Patients: A Randomized, Double-Blind, Placebo-Controlled, Two-Dose, Three-Arm, and Parallel-Group Study

The use of an anti-inflammatory supplement in patients with chronic kidney disease

Evaluation of Curcumin's effect on inflammation in hemodialysis patients

Short-term Curcuminoid Supplementation for Chronic Pulmonary Complications due to Sulfur Mustard Intoxication: Positive Results of a Randomized Double-blind Placebo-controlled Trial

Highly absorptive curcumin reduces serum atherosclerotic low-density lipoprotein levels in patients with mild COPD

The Neuromodulatory Effects of ω-3 Fatty Acids and Nano-Curcumin on the COX-2/ iNOS Network in Migraines: A Clinical Trial Study from Gene Expression to Clinical Symptoms

Curcumin (a constituent of turmeric): New treatment option against COVID-19

COVID-19 and heme oxygenase: novel insight into the disease and potential therapies

Pathways in the Pathophysiology of Coronavirus 19 Lung Disease Accessible to Prevention and Treatment

Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms

Potential Role of Nrf2 Activators with Dual Antiviral and Anti-Inflammatory Properties in the Management of Viral Pneumonia

The Inhibitory Effect of Curcumin on Virus-Induced Cytokine Storm and Its Potential Use in the Associated Severe Pneumonia

Curcumin, a traditional spice component, can hold the promise against COVID-19?

Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus

A review on antibacterial, antiviral, and antifungal activity of curcumin

Antiviral and virucidal effects of curcumin on transmissible gastroenteritis virus in vitro

Virtual screening and repurposing of FDA approved drugs against COVID-19 main protease

Immune-Boosting, Antioxidant and Anti-inflammatory Food Supplements Targeting Pathogenesis of COVID-19

Curcumin as a potential treatment for COVID-19

Potential effects of curcumin in the treatment of COVID-19 infection

The cytokine storm and COVID-19