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Publications > Journals > Journal of Exploratory Research in Pharmacology > Article Full Text

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Plant-based Immunomodulators and Their Potential Therapeutic Actions

  • Sanmoy Pathak,
  • Joshuah Fialho and
  • Dipankar Nandi* 
 Author information
Journal of Exploratory Research in Pharmacology   2022;7(4):243-256

doi: 10.14218/JERP.2022.00033

Abstract

Immunomodulation is a diverse process by which immunomodulators enhance or suppress immune responses to control disease progression. Immunomodulators are a broad class of drugs that include immunosuppressants and immunostimulants. These agents have been used to fight against the dysregulated immune responses observed during tissue/organ transplantation and disorders, such as rheumatoid arthritis, ulcerative colitis, and cancers. Immunomodulators obtained from a myriad of plant sources are a major class of compounds that are known to have medicinal properties and are used for the treatment of various diseases. However, the mechanisms underlying the action of plant-derived compounds are poorly understood. Here, we discuss the major classes of plant-based immunomodulators with examples and their effects on the major signaling pathways, such as the nuclear factor kappa light chain enhancer of activated B cells (NF-κB), mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin pathways. Importantly, we discuss the preclinical and clinical research to date to understand the importance of these immunomodulators. Overall, this review highlights the significance of plant-based immunomodulators as an alternative therapeutic strategy for combating various diseases.

Keywords

Immunomodulators, Autoimmunity, Anti-inflammatory, T cell, Macrophage, Medicinal plants, Phytocompounds

Introduction

The immune system of the body is responsible for protecting it against infections, cancer, and other types of diseases. This highly evolved system is made up of innate and adaptive arms, each employing an intricate network of cellular and humoral entities to exert their function. However, dysregulation of the immune system due to various factors can cause excess autoreactive immune responses against the host, leading to autoimmunity,1 or impair immune surveillance or deficiency in individuals, increasing their susceptibility to pathogens and cancers.2 These dysregulated immune responses can be treated with natural and synthetic immunomodulators that are broadly classified as immunostimulators3 or immunosuppressors4 based on their ability to enhance or suppress immune responses, respectively (Fig. 1).

Immunomodulators are a class of molecules that modulate different immune cell responses, thereby preventing life-threatening diseases.
Fig. 1  Immunomodulators are a class of molecules that modulate different immune cell responses, thereby preventing life-threatening diseases.

Immunomodulators can be classified generally into two broad classes: immunosuppressants, which suppress the immune responses and prevent various autoimmune disorders such as rheumatoid arthritis, inflammatory bowel disease and graft-versus-host disease (GVHD); and immunostimulants, which enhance immune responses to interferons and recombinant interleukin-2 (aldesleukin) that are required to combat disease conditions such as cancer. GVHD, graft-versus-host disease; ICU, Intensive Care Unit.

According to the National Stem Cell Foundation, the global autoimmune disease burden stands at 4% and encompasses greater than 80 distinct diseases. Furthermore, 1 in 1,200 people in the United States suffer with primary immunodeficiency diseases.5 Given the range of immune-related disorders, there is a constant need for better and more potent immunomodulatory drugs to combat these disorders. Plant-based immunomodulators are one of the major classes of immunomodulators. Although beneficial, synthetic immunomodulators have the potential to cause many adverse side effects, ranging from skin rashes to systemic organ failures. These drugs can affect the nervous, respiratory, and digestive systems. For example, cyclosporine can cause side effects such as renal dysfunction and gum hyperplasia, while cyclophosphamide has cardiac toxicity.6 These immunosuppressants may increase the risk of malignancies and teratogenicity. Additionally, the use of synthetic drugs for chronic diseases may face ineffectiveness, drug resistance, and high costs.6,7 The synthetic immunomodulators may have a low selectivity and a high toxicity.6 Thus, it is imperative to uncover the therapeutic efficacy, safety, and potential mechanisms underlying the actions of plant-based immunomodulators as alternative therapeutic strategies for these dysregulated immune diseases.

Numerous herbal extracts and plant-based concoctions have been integral components of traditional medicine for many centuries. Two of the foremost types of ethnic medicinal practices that have stayed relevant across centuries belong to the Indian and Chinese cultures.7 Traditional Indian and Chinese medicines have accounted for a number of plant species with distinctive beneficial functions against various diseases.8 The pharmacological properties of these different plants include anticarcinogenic, anti-inflammatory, analgesic, and many others.9 Plant-based immunomodulators are highly diverse and can be classified based on the chemical structures of the compounds, as mentioned in Figure 2 (adapted from PubChem), and the types of functions.

Structures of key plant-based immunomodulators that have been demonstrated to inhibit major immune cell responses in both preclinical and clinical studies.
Fig. 2  Structures of key plant-based immunomodulators that have been demonstrated to inhibit major immune cell responses in both preclinical and clinical studies.

The structures have been adapted from PubChem. EGCG: Epigallocatechin gallate.

Here, we discuss the importance of the major classes of immunomodulators and their therapeutic effects in preclinical and clinical studies. Additionally, we highlight the pharmacological actions of these immunomodulators in regulating the major signaling pathways to elucidate their molecular mechanisms.

Therapeutic effects of plant-based immunomodulators

In recent years, the quest for alternative medicine has been fueled largely by safety concerns and economical options; therefore, it has catapulted natural compounds into the spotlight. Furthermore, plant immunomodulators that are extracted from abundant renewable sources and have low toxicity have increasingly yielded positive results in clinical trials.10,11 This reinforces the therapeutic potential of plant-based compounds to modulate aberrant immune responses. Owing to the large-scale research conducted on bioactive phytochemicals, certain compounds have been exhaustively studied for their immunomodulatory roles.

Phytocompounds are broadly classified according to their molecular weights into high- and low-molecular-weight compounds. High-molecular-weight compounds are often primary metabolites required for plant growth and development and include glycoproteins, peptides, polysaccharides, and glycolipids.9,12 On the other hand, low-molecular-weight compounds consist of alkaloids, phenolic compounds, quinones, terpenoids, saponins, phytoestrogen, and others.9,12 These mostly overlap with secondary metabolites that themselves have been derived from primary metabolites. The major phytochemical groups and their components with immunomodulatory function are outlined in Table 1.13–47 We focus on some plant-based immunomodulators that have been tested in vivo and even in clinical trials.

Table 1

List of major classes of plant-based immunomodulators with examples of each class and their roles in inhibiting various immune responses and thereby preventing diseases

ClassSource from which it is obtainedMechanism of action
Alkaloids
  LycorineLycoris radiataInhibits iNOS and COX-2 levels15
  PiperinePiper longum LinnInhibits proinflammatory cytokine production, NOS2, COX-2 production16,17
  TinosporinTinospora cordifolia (Willd.)Antidiabetic, antihyperlipidemic, and antioxidant properties18
Essential oils
  TetramethylpyrazineLigusticum chuanxiong HortInhibits NOS2, IFN-γ, TNF-α, ROS, chemotaxis, etc. production in macrophages19,20
  Z-ligustilideAngelica sinensis (Oliv.) DielsInhibits MAPK and NF-κB and thus inhibits NOS2 and COX-221
Chalcones
  ButeinDalbergia odorifera, Semecarpus anacardium Linn, Toxicodendron vernicifluumBlocks NOS2 expression and thus NO production, inhibits NF-κB translocation22
  Licochalcone EGlycyrrhiza inflataInhibits NF-κB- and activator protein-1-mediated IL-6, IL-1β, and TNF-α production23
Flavonols
  RutinRuta graveolens L.Suppresses leukocyte migration, reduces NF-κB activation, TNF-α, and IL-6 production24
  QuercetinDysosma veitchii (Hemsl. et Wils)Ameliorates the activity of NF-κB and NOS2, reduces cytokine production, and reduces VCAM-1, E-selectin2527
  Flavones
  ApigeninCynodon dactylon, Salvia officinalis L., Portulaca oleracea, Mentha longifoliaReduces IL-1α and TNF-α levels with lower COX-2, NOS2, ICAM, and VCAM expression28,29
  LuteolinLonicera japonicaDecreases in IFN-γ, IL-6, COX-2, and ICAM-1 levels13,14
Flavanols
  Epigallocatechin-3-gallate (EGCG)Camellia sinensis L.Reduces ROS, MAPK phosphorylation, adhesion protein expression, and STAT3 levels30
Isoflavones
  GenisteinGlycine maxDecreases NOS2 and COX-2 levels along with lower proinflammatory cytokine amounts31
PuerarinPueraria lobata (wild) OhwiReduces NF-κB and STAT3 levels32
Quinones
  ShikoninLithospermum erythrorhyzon Sieb. Et Zucc.Increases Th2 response and reduces Th1 via inhibition of NF-κB activity33
  ThymoquinoneNigella sativa L.Blocks LPS-induced fibroblast proliferation. Inhibits an increase in IL-1β, matrix metalloproteinase-13, and COX-2 via blocking NF-κB and MAPK pathways34
Stilbenes
  PiceatannolFallopia japonica, nuts, etc.Decreases NF-κB, NOS2, ERK, and STAT3 levels35
  ResveratrolFallopia japonica, Vitis vinifera (grapes), etc.Inhibits Th1 cytokine responses, MPO activity, and NOS2 and COX-2 expression36
Phloroglunicols
  ArzanolHelichrysum italicumInhibits COX activity with reduced production of eicosanoids37
  MyrtucommuloneMyrtus communis L.Inhibits PGE2 production via inhibition of COX activity38
Saponins
  DiosgeninDioscorea villosa, Trigonella foenum graecumProtects against neuroinflammation by inhibiting inflammatory mediators such as COX-2, NF-κBp65, and TNF-α.39
  PanaxadiolPanax ginsengEnhances hematopoietic progenitor proliferation, T helper and regulatory T cell numbers while reducing the peripheral cytotoxic T cell population in a mouse model of aplastic anemia.40
Terpenoids
  GinsanPanax ginsengEnhances cytokine production, ROS production, and macrophage phagocytic activity41,42
  TriptolideTripterygium wilfordiiBlocks lymphocyte activation and expression of genes, causing reductions of IL-2, COX-2, and TNF-α levels43
Other Polyphenols
  Ellagic acidFragaria sppAntioxidant and anticancer activity by regulation of STAT3, transforming growth factor-β/Smad3, etc.4446
Others
  ApocyninPicrorhiza kurroa Royle ex Benth, Tripterygium wilfordii m L. (Canadian hemp),Suppresses NADPH oxidase activity with lower proinflammatory cytokine production. Also decreases both CD4+ and CD8+ production47

Curcumin

Curcumin is a naturally occurring diarylheptanoid molecule that can be obtained from the rhizome of Curcuma longa. This polyphenol has been extensively studied and is known for its diverse anti-inflammatory properties. Curcumin can downregulate the expression of proinflammatory factors, such as cyclooxygenase-2 (COX-2), nitric oxide (NO), tissue necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ), in activated macrophages.48,49 Curcumin inhibits nuclear factor kappa light chain enhancer of activated B cells (NF-κB) activation in phorbol 12-myristate 13-acetate (PMA)- and H2O2-stimulated human myelomonoblastic leukemia cells by preventing the phosphorylation and degradation of IκB-α.50 Additionally, curcumin can block the binding of NF-κB to AP-1 in glioma cells.51 Moreover, curcumin has been reported to affect the crosstalk between the NF-κB and Wnt/β-catenin pathways in cervical cancer cells.52 More importantly, curcumin can be used as an adjunct therapy for maintaining the remission of ulcerative colitis in human patients,53 and treatment with curcumin inhibits the proliferation of pathogenic T cells as well as reduces platelet hyper-responsiveness and neutrophil infiltration in a rat model of adjuvant-induced rheumatoid arthritis (RA).54 Similarly, treatment with curcumin effectively downregulates the activation of the proinflammatory mammalian target of rapamycin pathway in synoviocytes and suppresses signal transducer and activator of transcription 1 (STAT1) signaling to reduce B cell activity in mice with collagen-induced arthritis as well as inhibits COX-2 expression and induces apoptosis in primary canine chondrocytes.55 Furthermore, treatment with curcumin also decreases the expression of interleukin (IL)-1β, IL-6, IL-8, IL-17, IL-18, and TNF-α in animal models of RA.55 In mouse models of experimental autoimmune encephalomyelitis, curcumin targets inflammatory monocytes and prevents their trans endothelial migration across the blood-brain barrier through inhibition of the NF-κB pathway as well as the expression of the cell adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and macrophage-1 antigen.56 Treatment with curcumin reduces the numbers of splenic T and B cells by downregulating the expression of NF-κB, AKT, and extracellular signal-regulated kinase (ERK) 1/2 and Bcl2 in rodents.57 A balance between T cell subtypes is necessary not only for an optimal immune response but also for control of disease progression. Classically, aberrant type 1 helper T cell (Th1) responses contribute to the development of type 1 diabetes, while strong type 2 helper T cell (Th2) responses are crucial for the onset of asthma.58,59 In some comorbid cases, the simultaneous existence of these antagonizing conditions may lead to an intermediate but distinct immune profile. In comorbid diabetic asthmatic murine models, oral treatment with curcumin reduces the levels of circulating IL-4 and eosinophils as well as mucus cell metaplasia and inflammation-induced nasal hyper-responsiveness in bronchoalveolar lavage fluid. Treatment with higher doses of curcumin also decreases the blood glucose levels.60

It is important to note that the immunomodulatory role of curcumin is dependent on its dose in tumor models. Unlike inflammatory diseases, neoplasms often rely on immune evasion for their unchecked growth and progression. Curcumin treatment may modulate immunosuppression through multiple actions.61 Curcumin intervention can increase the effector T cell number and their activity by mitigating the NF-κB dysregulation in T cell tumor infiltrates to increase the susceptibility of tumor cells to TNF-α-mediated apoptosis. Furthermore, treatment with curcumin can attenuate regulatory T cell proliferation; IL-2, IL-10, and IL-6 production; M2 macrophage polarization; and natural killer T cell activation.62 Previous studies have shown that curcumin treatment can effectively inhibit the growth of a wide range of cancers, including colon cancer, lung cancer, lymphoma, breast cancer, and others, in rodents and human patients.63 However, curcumin treatment has the major disadvantage of a low bioavailability, which is now being investigated and enhanced by making chemical modifications to increase the potency of this molecule.64 To increase the bioavailability of curcumin, a new modified compound known as nanocurcumin is being used in animal models such as chronic hypobaric hypoxia in rats.65 More recently, nanocurcumin treatment in severe and mild coronavirus disease 2019 (COVID-19) patients has been demonstrated to ameliorate adverse inflammation by reducing T helper 17 cell (Th17) responses.66

Resveratrol

Resveratrol is chemically known as 5-[(E)-2-(4-hydroxyphenyl) ethenyl] benzene-1,3-diol and is derived from stilbene and phytoalexin. Resveratrol is found in different dietary and plant products and is a major component of red wine and peanuts.67 Resveratrol can regulate a number of inflammatory parameters in various immune cells: inhibition of NF-κB activation induced by lipopolysaccharide (LPS), PMA, and TNF-α in macrophages, Jurkat, myeloid, and epithelial (HeLa) cells through inhibition of IκB kinase.68–71 It also downregulates COX-2 expression and NO levels in cytokine-stimulated human primary airway epithelial cells72 as well as COX-2 expression in melanocytes by attenuating the ERK1/2 and PI3K/AKT pathways.73 Moreover, resveratrol decreases the production of IL-12, IL-6, TNF-α, and others in lymphocytes and macrophages.74,75 This molecule also inhibits the expression of adhesion molecules such as ICAM-1 on the surface of endothelial cells, thereby inhibiting cell recruitment.76 The therapeutic effects of resveratrol in dysregulated immune disorders have been further studied in a range of animal models. Treatment with resveratrol can reduce lower airway inflammation and protect against infection-induced sepsis in mice and zebrafish as well as alleviate chronic obstructive pulmonary disease caused by nontypable Haemophilus influenzae.77 In rat models of experimental arthritis and periodontitis, resveratrol treatment increases IL-4 expression in gingival tissue and decreases the levels of serum rheumatoid factor and anticitrullinated protein antibodies, thus emphasizing its anti-inflammatory effects.78 Diabetic nephropathy is another dysregulated immune disorder characterized by chronic inflammation. In nonobese diabetic mice, resveratrol treatment reduces the expression of inflammatory mediators, like NF-κB, receptors for advanced end glycation products, and NADPH oxidase 4; improves renal pathology; and reduces blood urea nitrogen, serum creatinine, and blood glucose levels as well as hyperglycemia.79 Furthermore, resveratrol has potent neuroprotective effects by increasing the expression of anti-oxidant enzymes, like superoxide dismutase and glutathione peroxidase, while reducing oxidative reactive oxygen species (ROS), nitric oxide synthase 2 (inducible) (NOS2), and COX-2 via modulating nuclear factor erythroid 2-related factor 2 activation in vitro and in vivo.80 Interestingly, resveratrol also has been shown to support immune function in splenic lymphocytes of immunocompromised mice by increasing activation of the c-Jun N-terminal kinase/NF-κB pathway to enhance cytokine expression, peripheral T cell numbers, and splenic lymphocyte proliferation.81,82 However, how resveratrol treatment causes such opposite effects in different disease models remains to be further explored. Resveratrol has been tested in clinical trials for patients with type 2 diabetes, nonalcoholic fatty liver syndrome, or polycystic ovary syndrome by modulating the expression of transcription factors and cytokines in circulating immune cells.83,84 Additionally, a recent meta-analysis concluded that resveratrol treatment effectively reduces inflammation and cytokine storms as well as regulates pathways involved in antiviral defense in COVID-19 patients.85

Quercetin

Quercetin is a plant pigment of flavonoids that is chemically known as 2-(3,4-dihydroxyphenyl)3,5,7-trihydroxychromen-4-one. It belongs to the family of polyphenols and is a major plant secondary metabolite. Quercetin has many beneficial properties, such as anti-inflammatory, anticancer, anti-oxidant, and antihyperglycemic activities.86 Quercetin can inhibit eukaryotic translation by activating a number of kinases, which activate eukaryotic initiation factor 2.87 It also efficiently scavenges nitrogen and ROS as well as inhibits the activation of NF-κB, mitogen-activated protein kinase (MAPK), and STAT1. Additionally, it stalls the replication of viruses and reduces viral infection.88–90 On the other hand, quercetin enhances the antiproliferative function of IFN-α by inhibiting hepatocellular carcinoma growth through activating the JAK/STAT pathway, suggesting its differential roles in combating various diseases.91 In LPS-stimulated human umbilical vein endothelial cells and macrophages, quercetin reduces the levels of COX-2 and NOS2 expression by suppressing activator protein-1, NF-κB, and STAT1 signaling.92 Quercetin treatment inhibits the expression of ICAM-1 in PMA- or TNF-α-stimulated endothelial cells93 and ICAM-1 expression in pulmonary epithelial cells, which is dependent on the IL-1-activated MAPK1 pathway.94In vivo, quercetin has potent anti-inflammatory activity in Wister rats with carrageenan-induced inflammation, in C57BL/6J mice fed with a high-fat diet, and in a murine model of airway allergic inflammation. Evidently, quercetin treatment decreases serum TNF-α, regulated on activation, normal T expressed and secreted, prostaglandin E2 (PGE2), IL-4, IL-5, and IFN-α levels in rodents and reduces NF-κB activation, P-selectin expression, and eosinophil recruitment to bronchoalveolar lavage fluid in airway allergic inflammatory models.95–97 Interestingly, quercetin is a natural ligand of aryl hydrocarbon receptors, which are expressed on immune cells, partially explaining its immunomodulation.98 In human dendritic cells, engagement of high expression of aryl hydrocarbon receptors by quercetin reduces T cell activation and migration by downregulating CD83 expression.99 Moreover, quercetin treatment also downregulates the expression of immunoglobulin-like transcripts 3–5, disabled adaptor protein 2, and ectonucleotidases of CD39 and CD73 as well as IL-12. Thus, quercetin induces immunotolerogenic responses in human dendritic cells.99 Actually, treatment with a hydrogel containing sodium alginate/bioglass and quercetin inhibits inflammation by inducing M2 macrophages and reducing inducible nitric oxide synthase (iNOS) expression, matrix degradation, and inflammatory infiltrates in a rat model of articular cartilage defects.100 Another study indicates that quercetin treatment facilitates M2 polarization as well as reduces intracellular ROS and caspase 3-mediated chondrocyte apoptosis, ameliorating osteoarthritis in rats.101 These anti-inflammatory effects of quercetin are associated with inhibition of the Akt/NF-κB signaling in IL-1β-treated chondrocytes.101 The anti-oxidant and anti-inflammatory activities of quercetin have also been evaluated in multiple in-vivo models of sepsis. The results indicate that treatment with quercetin decreases the levels of COX-2, MDA, and nitrates but increases the expression of the anti-oxidants glutathione, glutathione peroxidase, superoxide dismutase, and catalase, accompanied by downregulation of NF-κB activation and expression of the pro-inflammatory molecules TNF-α, IL-1β, IL-6, and high-mobility group box 1 protein.102 A combination of quercetin and vitamin C also has been advocated to ameliorate respiratory infections, such as COVID-19, due to their synergistic antioxidant role.103 Clinical trials have revealed that quercetin has successfully reduced oxidative stress, IL-8, and TNF-α levels in sarcoidosis patients.104 Additionally, this molecule has shown some beneficial effects in patients with cardiovascular diseases.105

Epigallocatechin-3-gallate (EGCG)

This component is an active molecule present in copious amounts in green tea, Camellia sinensis (Theaceae), and is chemically known as [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3-yl]3,4,5-trihydroxybenzoate. EGCG has antiproliferative, anti-oxidant, anti-inflammatory, and anti-angiogenic activities.106–109 EGCG can downregulate NF-κB activation by preventing the degradation of IκB.110,111 Additionally, it also inhibits the MAPK pathway and the proliferation of tumor cells.112,113 It works as an anti-apoptotic molecule by downregulating the expression of Bax and caspase 3.114–117 Its anti-inflammatory role is further demonstrated in proteolipid protein-induced experimental autoimmune encephalomyelitis mice. Treatment with EGCG effectively decreases TNF-α production and proteolipid protein-specific T cell proliferation ex vivo.118 It also inhibits delayed-type hypersensitivity skin responses and reduces serum IFN-γ, IL-17, IL-6, and IL-1β levels in mice by downregulating the expression of transcription factors such as Tbet and RORγt, which are crucial for Th1 and Th17 differentiation, respectively.119 The modification of T cell responses by EGCG is also observed in mouse models of diet-induced obesity-related inflammation as well as mice with collagen-induced arthritis.120 Mechanistically, EGCG treatment enhances STAT5 activation but attenuates STAT3 activation to promote regulatory T cell responses, thus mitigating Th17 responses in these obese models.120 It is possible that EGCG may regulate epigenetic modifications of FoxP3, enhancing regulatory T cell responses.121 The anti-inflammatory capacity of EGCG is able to ameliorate Porphyromonas gingivalis-induced atherosclerosis in apolipoprotein E-deficient mice by lowering the levels of serum monocyte chemoattractant protein-1 and acute phase C-reactive protein.122 Besides, EGCG treatment also decreases the relative levels of iNOS, matrix metalloproteinase-9, lectin-like oxidized low-density lipoprotein, CCL-2, ICAM-1, and NADPH oxidase-4 mRNA transcripts in the aorta of mice but increases heme oxygenase-1 expression.122 Interestingly, EGCG treatment can increase CD3, CD19, and Mac-3 expression, suggesting an increase in the numbers of T cells, B cells, and macrophages, respectively, and enhances the phagocytic activity of macrophages from peripheral circulation.123

Clinically, EGCG has been tested in a number of trials. While there was no significant change in the level of serum C-reactive protein, IL-1, IL-6, or adiponectin, EGCG was well tolerated in 35 obese subjects with metabolic syndrome.124 Topical administration of EGCG ameliorates inflammatory and noninflammatory acne lesions in an 8-week randomized clinical trial for acne vulgaris. Antimicrobial activity of EGCG against Propionibacterium acnes also has been demonstrated.125 Another study has shown that treatment with EGCG increases the apoptosis of circulating B cells in patients with chronic B cell lymphocytic leukemia by inhibiting vascular endothelial growth factor receptor signaling and downregulating the expression of anti-apoptotic Bcl2, X-linked inhibitor of apoptosis protein, and myeloid cell leukemia-1.126 The National Institute of Health, USA has initiated 91 interventional clinical trials for EGCG, highlighting the therapeutic potential of this polyphenol (https://www.clinicaltrials.gov/ct2/results?cond=&term=Epigallocatechin-3-gallate&cntry=&state=&city=&dist=%20 ).

Luteolin

Luteolin or 3′,4′,5,7-tetrahydroxyflavone is a flavonoid molecule with the backbone of 2-phenylchromone and can be extracted from the flowers of the marigold plant127 and other sources such as chamomile tea, oranges, celery, broccoli, honeysuckle, among others.128 Luteolin has neuroprotective, antineoplastic, anti-inflammatory, and anti-allergic activities. In-vitro studies have shown that luteolin reduces TNF-α and IL-6 release by LPS-treated RAW 264.7 cells, which is attributed to inhibition of the NF-κB- and MAPK-associated transcription factor ERK, p38, and AP-1 expression.13,129,130 Luteolin can help to inhibit T cell responses and IFN-γ production in both murine and human autoreactive T cells following challenge with alpha B-crystallin, which is an autoantigen-related to multiple sclerosis.131 Moreover, luteolin treatment reduces lymphocyte infiltration in the thyroid gland as well as downregulates IFN-γ, TNF-α, and COX-2 expression and the STAT1 and STAT3 signaling pathways during T cell activation in a mouse model of experimental autoimmune thyroiditis.132 Additionally, luteolin treatment ameliorates clinical symptoms and inhibits autoreactive T cell responses and IFN-γ production in an animal model of experimental autoimmune encephalomyelitis.133 Luteolin decreases leukocyte infiltrates and 6-keto-prostaglandin F1-alpha and COX-2 expression in mice with carrageenan-induced paw edema.14 Furthermore, luteolin inhibits the interaction of monocytes and endothelial cells by reducing the levels of ICAM-1 and vascular cell adhesion protein-1 (VCAM-1) expression in an animal model of TNF-α-induced atherosclerosis. It also reduces the levels of monocyte chemoattractant protein-1 expression and F4/80+ macrophage infiltrates in the aorta of mice, demonstrating its anti-inflammatory effect.134 A randomized double-blind controlled clinical trial has shown that topical application of luteolin reduces skin erythema post ultraviolet B-ray irradiation in 40 subjects.135 Finally, luteolin is reported to be much safer than quercetin as a dietary supplement.136

Colchicine

Colchicine is known as a tropolone derivative, and its chemical structure is N-[(7S)-1,2, 3,10-tetramethoxy-9-oxo-6,7-dihydro-5H-benzo(a)heptalen-7]-ylacetamide. This bioactive molecule is a major component of Colchicum autumnale. The mechanism of colchicine has been extensively studied with respect to damaging microtubule dynamics. Functionally, colchicine can inhibit T cell activation by downregulating the expression of IL-2 receptor and lymphocyte function-associated antigen 1 in human lymphocytes.137 In contrast, colchicine also has been used as an adjuvant to elicit ovalbumin-induced T cell responses, suggesting its dual roles in T cell immunity.138 Recently, colchicine derivatives have been shown to enhance the survival of allografts by inhibiting T cell differentiation and responses.139 Colchicine can activate nuclear factor erythroid 2-related factor 2 in hepatocytes to release hepatokines, such as growth differentiation factor 15, which inhibits the activation of myeloid cells, thus impairing their anti-inflammatory function.140 Colchicine has been approved by the Federal Drug Administration as a drug to treat Mediterranean fever and acute gout flares.141–143 Colchicine, along with other anti-inflammatory drugs, is used as a combinatorial therapy to reduce the recurrence or incessant pericarditis.144,145 Importantly, colchicine has been considered a potential drug candidate for the treatment of COVID-19 patients because of its diverse anti-inflammatory properties.146 A clinical study has further validated that colchicine treatment increases the discharge rate and decreases mortality in COVID-19 patients, accompanied by changes in lymphocyte numbers, lymphocyte-to-neutrophil ratios, and C-reactive protein amounts.147,148

Capsaicin

Capsaicin is chemically known as (E)-N-[(4-hydroxy-3-methoxyphenyl) methyl]-8-methylnon-6-enamide and is a hydrophobic alkaloid present in chili peppers, Capsicum species, and the Solanaceae family. Historically, capsaicin has been used as a traditional medicine to combat pain. In fact, capsaicin is an agonist for transient receptor potential channel vanilloid subfamily member 1 (TRPV1),149,150 a Ca2+ channel that can be activated by various stimuli, such as pH, temperature, and others, to induce the sensation.151 Continuous stimulation by capsaicin, in turn, causes desensitization of these receptors, reducing the pain signals in neurons.152,153 Immunologically, capsaicin can reduce the levels of iNOS, NF-κB, and COX-2 expression in macrophages in a TRPV1-dependent manner.154 However, other studies report that capsaicin upregulates COX-2 expression in primary sensory neuronal cells, suggesting that capsaicin may have differential effects on COX-2 expression, based on the cell type.155 Actually, capsaicin blocks Jurkat cell activation by inhibiting the receptor-mediated Ca2+ entry.156 It also inhibits the proliferation of human T-cell leukemia virus type 1-associated chemoresistant adult T leukemia cells.157 Furthermore, the oral administration of capsaicin reduces T cell activation and proliferation in pancreatic lymph nodes, ameliorating the symptoms of type 1 diabetes in mice in an IL-10-dependent manner.158 In addition, capsaicin inhibits natural killer cell functions and TNF-α production. Capsaicin elicits its effects by binding to its receptor TRPV1.159 Capsaicin is also known to reduce paw inflammation in arthritic rats154,160 and attenuates the corticosterone-caused immune suppression in mice by reducing IL-10, IL-4, and transforming growth factor-β1 levels.161 One meta-analysis indicates that capsaicin is indeed efficient against osteoarthritis in a clinical setting.162 Finally, a cutaneous patch containing 8% capsaicin has been approved by the European Union for nondiabetic individuals to treat nephropathic pain.6

Terpenes and their derivatives

Terpenes belong to the largest class of secondary metabolites and are made of a backbone of five carbon isoprenoid units (C5H8).163 Terpenes can be classified based on the number of repeating isoprenoid units into hemiterpene, monoterpene, sesquiterpene, and diterpene with one, two, three, and four isoprenoid units, respectively. Terpenoids are modified terpenes, which may have different functional groups, rearrangements, or, more commonly, oxidized groups. These molecules have potent anti-inflammatory,164 anti-oxidant,165 and antibacterial activities.166

The sesquiterpenoids are a special class of terpenoids, and sesquiterpene lactones are primary examples of plant-based immunomodulators. Sesquiterpene lactones are major bioactive molecules that are derived from the plants belonging to the family Asteraceae.167 Sesquiterpene lactones can inhibit T cell receptor-mediated T cell activation in vitro. Similarly, the terpenoids, such as grosheimin, agracin, parthenolide, argablin, and estafiatin, by virtue of their α-methylene-γ-lactone backbone, can inhibit the CD3-mediated Ca2+ mobilization and signaling in T cells, which blocks ERK phosphorylation.168 On the contrary, other studies have reported that sesquiterpene lactones, such as 7-hydroxy frullanolide, inhibit both CD4+ T cell activation and peritoneal macrophage responses by opening up plasma membrane Ca2+ channels to increase intracellular Ca2+ levels.169 Parthenolide can reduce NF-κB signaling by preventing its binding to DNA and enhancing IκB-kinase activity.170 The sesquiterpene lactone fraction extracts from Artemissia khorassanica in vitro can inhibit the production of NO and PGE2 by downregulating COX and iNOS expression in macrophages. Moreover, treatment with sesquiterpene lactones shifts an IFN-γ-based Th1 response to an IL-4-producing Th2 response, highlighting their therapeutic potential.171 Artemisinin, thapsigargin, and parthenolide are the sesquiterpene lactones that have been approved for clinical trials as anticancer and anti-inflammatory drugs.172

Future perspectives

There is a plethora of traditional plant-based medicines with documented evidence of their beneficial effects, although the exact cellular and molecular mechanisms underlying their actions are still unknown. We have discussed the therapeutic potentials of some of the important plant-based immunomodulators and their pharmacological actions in regulating various immune responses (Fig. 3). However, the field of plant-based immunomodulation is still in its infancy as many plant-based extracts and compounds remain undiscovered and the mechanisms underlying their actions are still poorly understood. Therefore, further studies in this field are of utmost importance. Given the vastness of the recorded medicinal plants and their effects, plant-based immunomodulators are goldmines for future research and may be the alternative to combat dysregulated immune response-related diseases.

Schematic representation of plant-based immunomodulators (EGCG: epigallocatechin gallate) and their effects on different cell-signaling pathways.
Fig. 3  Schematic representation of plant-based immunomodulators (EGCG: epigallocatechin gallate) and their effects on different cell-signaling pathways.

The pathways include the mitogen-activated protein kinase (MAPK), nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor kappa-light-chain-enhancer of activated B cells, signal transducer and activator of transcription 1 (STAT1), and mammalian target of rapamycin (mTOR) pathways. The downstream immunomodulatory effects include downregulation of pro-inflammatory mediators and cytokines such as regulated on activation, normal T expressed and secreted (RANTES), interleukin-12 (IL-12), interleukin-6 (IL-6), prostaglandin E2 (PGE2), tissue necrosis factor alpha (TNFα). Additionally, they can also affect the mediators involved in the generation of oxidative and nitrosative stress such as cyclooxygenase (COX), nitric oxide (NO), inducible nitric oxide synthase (iNOS), lectin-like oxidized low-density lipoprotein (LOX1), and NADPH oxidase 4 (NOX4), which are all involved in immune cell responses. These cause an array of changes with respect to the immunomodulatory effects that the compounds modulate.

Conclusions

The immune system is an indispensable component for the host’s survival as it provides efficient protection via its diverse array of immune cells, protein components, and cell signaling cascades, functioning in complex networks to eradicate a myriad of different pathogens. However, the immune system is less than perfect and, depending on the types of extrinsic or intrinsic factors, immune responses may become dysfunctional to induce autoimmunity, hypersensitivity, and cancer. Autoimmune diseases are increasing the global health burden and are estimated to increase by 3.7% yearly for neurological diseases and 6% for endocrinal, gastrointestinal, and rheumatic diseases.173 Meanwhile, another major problem is the health burden due to cancer, and the World Health Organization has predicted that new cancer cases will increase at a rate of 15 million yearly by 2020.174 In 2018, the World Health Organization estimated that the annual emergence of cancer cases was about 18.1 million, which is approximately 3 million cases more than what was previously predicted.175 Furthermore, the COVID-19 pandemic has become the most recent problem, with most deaths in the Intensive Care Unit due to severe inflammation, which causes multiple organ dysfunction and failure.176 Immunomodulators modulate the dysfunctional immune responses during the pathogenic process of various diseases. Although there are a number of conventional immunomodulators available in the clinic, they may have varying adverse effects. Accordingly, alternative immunomodulators, such as plant-based immunomodulators, should be considered as a new option given their minimum side effects and cost effectiveness.

Abbreviations

COVID-19: 

coronavirus disease 2019

COX-2: 

cyclooxygenase-2

EGCG: 

epigallocatechin-3-gallate

ERK1/2: 

extracellular signal-regulated kinase 1/2

IκB: 

nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor

ICAM-1: 

intercellular adhesion molecule 1

IFN: 

interferon

IL: 

interleukin

iNOS: 

inducible nitric oxide synthase

LPS: 

lipopolysaccharide

MAPK: 

mitogen-activated protein kinase

NF-κB: 

nuclear factor kappa light chain enhancer of activated B cells

NO: 

nitric oxide

NOS2: 

nitric oxide synthase 2 (inducible)

PGE2: 

prostaglandin E2

PI3K: 

phosphoinositide 3-kinase

PMA: 

phorbol 12-myristate 13-acetate

RA: 

rheumatoid arthritis

ROS: 

reactive oxygen species

STAT1: 

signal transducer and activator of transcription 1

Th1: 

type 1 helper T cells

Th17: 

T helper 17 cells

Th2: 

type 2 helper T cells

TNF-α: 

tissue necrosis factor alpha

TRPV1: 

transient receptor potential cation channel subfamily V member 1

VCAM: 

vascular cell adhesion protein.

Declarations

Acknowledgement

We are thankful to the infrastructural support provided by the DBT-IISc partnership grant and DST-FIST.

Funding

This study was supported by a grant from SERB (EMR/2015/002486).

Conflict of interest

The authors have no conflicts of interest related to this publication.

Authors’ contributions

Contributed to the study concept and design (SP and DPN), acquisition of the data (SP and JF), analysis and interpretation of the data (SP and DPN), writing and drafting of the manuscript (SP, JF, and DPN), critical revision of the manuscript (SP, JF, and DPN) and supervision (DPN).

References

  1. Lehman HK. Autoimmunity and Immune Dysregulation in Primary Immune Deficiency Disorders. Curr Allergy Asthma Rep 2015;15(9):53 View Article PubMed/NCBI
  2. Berglund A, Putney RM, Hamaidi I, Kim S. Epigenetic dysregulation of immune-related pathways in cancer: bioinformatics tools and visualization. Exp Mol Med 2021;53(5):761-771 View Article PubMed/NCBI
  3. Kumar S, Gupta P, Sharma S, Kumar D. A review on immunostimulatory plants. Zhong Xi Yi Jie He Xue Bao 2011;9(2):117-128 View Article PubMed/NCBI
  4. Wiseman AC. Immunosuppressive Medications. Clin J Am Soc Nephrol 2016;11(2):332-343 View Article PubMed/NCBI
  5. Bonilla FA. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. Pediatrics 2008;122(Supplement_4):S224-S225 View Article
  6. Jantan I, Ahmad W, Bukhari SN. Plant-derived immunomodulators: an insight on their preclinical evaluation and clinical trials. Front Plant Sci 2015;6:655 View Article PubMed/NCBI
  7. Patwardhan B, Warude D, Pushpangadan P, Bhatt N. Ayurveda and traditional Chinese medicine: a comparative overview. Evid Based Complement Alternat Med 2005;2(4):465-473 View Article PubMed/NCBI
  8. Elahee S, Mao H, Shen X. Traditional Indian medicine and traditional Chinese medicine: A comparative overview. Chinese Med Cult 2019;2(3):105 View Article
  9. Segneanu A, Velciov SM, Olariu S, FlorentinaCziple F, Damian D, Grozescu I. Amino Acid - New Insights and Roles in Plant and Animal [Internet]. London: IntechOpen; 2017 View Article
  10. Itokawa H, Morris-Natschke SL, Akiyama T, Lee KH. Plant-derived natural product research aimed at new drug discovery. J Nat Med 2008;62(3):263-280 View Article PubMed/NCBI
  11. Tripathi SK, Behera S, Panda M, Zengin G, Biswal BK. A comprehensive review on pharmacology and toxicology of bioactive compounds of Lagerstroemia Speciosa (L.) Pers. Current Traditional Medicine 2021;7(4):504-513 View Article
  12. Nair A, Chattopadhyay D, Saha B. New Look to Phytomedicine. Elsevier Inc; 2019, 435-499 View Article
  13. Chen CY, Peng WH, Tsai KD, Hsu SL. Luteolin suppresses inflammation-associated gene expression by blocking NF-kappaB and AP-1 activation pathway in mouse alveolar macrophages. Life Sci 2007;81(23-24):1602-1614 View Article PubMed/NCBI
  14. Ziyan L, Yongmei Z, Nan Z, Ning T, Baolin L. Evaluation of the anti-inflammatory activity of luteolin in experimental animal models. Planta Med 2007;73(3):221-226 View Article PubMed/NCBI
  15. Kang J, Zhang Y, Cao X, Fan J, Li G, Wang Q, et al. Lycorine inhibits lipopolysaccharide-induced iNOS and COX-2 up-regulation in RAW264.7 cells through suppressing P38 and STATs activation and increases the survival rate of mice after LPS challenge. Int Immunopharmacol 2012;12(1):249-256 View Article PubMed/NCBI
  16. Son DJ, Akiba S, Hong JT, Yun YP, Hwang SY, Park YH, et al. Piperine inhibits the activities of platelet cytosolic phospholipase A2 and thromboxane A2 synthase without affecting cyclooxygenase-1 activity: different mechanisms of action are involved in the inhibition of platelet aggregation and macrophage inflammatory response. Nutrients 2014;6(8):3336-3352 View Article PubMed/NCBI
  17. Vaibhav K, Shrivastava P, Javed H, Khan A, Ahmed ME, Tabassum R, et al. Piperine suppresses cerebral ischemia-reperfusion-induced inflammation through the repression of COX-2, NOS-2, and NF-κB in middle cerebral artery occlusion rat model. Mol Cell Biochem 2012;367(1-2):73-84 View Article PubMed/NCBI
  18. Sharma R, Amin H, Galib, Prajapti PK. Antidiabetic claims of Tinospora cordifolia (Willd.) Miers: critical appraisal and role in therapy. Asian Pac J Trop Biomed 2015;5(1):68-78 View Article
  19. Hu JZ, Huang JH, Xiao ZM, Li JH, Li XM, Lu HB. Tetramethylpyrazine accelerates the function recovery of traumatic spinal cord in rat model by attenuating inflammation. J Neurol Sci 2013;324(1-2):94-99 View Article PubMed/NCBI
  20. Liu HT, Du YG, He JL, Chen WJ, Li WM, Yang Z, et al. Tetramethylpyrazine inhibits production of nitric oxide and inducible nitric oxide synthase in lipopolysaccharide-induced N9 microglial cells through blockade of MAPK and PI3K/Akt signaling pathways, and suppression of intracellular reactive oxygen species. J Ethnopharmacol 2010;129(3):335-343 View Article PubMed/NCBI
  21. Chung JW, Choi RJ, Seo EK, Nam JW, Dong MS, Shin EM, et al. Anti-inflammatory effects of (Z)-ligustilide through suppression of mitogen-activated protein kinases and nuclear factor-κB activation pathways. Arch Pharm Res 2012;35(4):723-732 View Article PubMed/NCBI
  22. Wang Z, Lee Y, Eun JS, Bae EJ. Inhibition of adipocyte inflammation and macrophage chemotaxis by butein. Eur J Pharmacol 2014;738:40-48 View Article PubMed/NCBI
  23. Lee HN, Cho HJ, Lim DY, Kang YH, Lee KW, Park JH. Mechanisms by which licochalcone e exhibits potent anti-inflammatory properties: studies with phorbol ester-treated mouse skin and lipopolysaccharide-stimulated murine macrophages. Int J Mol Sci 2013;14(6):10926-10943 View Article PubMed/NCBI
  24. Yoo H, Ku SK, Baek YD, Bae JS. Anti-inflammatory effects of rutin on HMGB1-induced inflammatory responses in vitro and in vivo. Inflamm Res 2014;63(3):197-206 View Article PubMed/NCBI
  25. Choi SJ, Tai BH, Cuong NM, Kim YH, Jang HD. Antioxidative and anti-inflammatory effect of quercetin and its glycosides isolated from mampat (Cratoxylum formosum). Food Sci Biotechnol 2012;21:587-595 View Article
  26. Kleemann R, Verschuren L, Morrison M, Zadelaar S, van Erk MJ, Wielinga PY, et al. Anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models. Atherosclerosis 2011;218(1):44-52 View Article PubMed/NCBI
  27. Shaik YB, Castellani ML, Perrella A, Conti F, Salini V, Tete S, et al. Role of quercetin (a natural herbal compound) in allergy and inflammation. J Biol Regul Homeost Agents 2006;20(3-4):47-52 PubMed/NCBI
  28. Kang HK, Ecklund D, Liu M, Datta SK. Apigenin, a non-mutagenic dietary flavonoid, suppresses lupus by inhibiting autoantigen presentation for expansion of autoreactive Th1 and Th17 cells. Arthritis Res Ther 2009;11(2):R59 View Article PubMed/NCBI
  29. Nicholas C, Batra S, Vargo MA, Voss OH, Gavrilin MA, Wewers MD, et al. Apigenin blocks lipopolysaccharide-induced lethality in vivo and proinflammatory cytokines expression by inactivating NF-kappaB through the suppression of p65 phosphorylation. J Immunol 2007;179(10):7121-7127 View Article PubMed/NCBI
  30. Lee IT, Lin CC, Lee CY, Hsieh PW, Yang CM. Protective effects of (-)-epigallocatechin-3-gallate against TNF-α-induced lung inflammation via ROS-dependent ICAM-1 inhibition. J Nutr Biochem 2013;24(1):124-136 View Article PubMed/NCBI
  31. Valles SL, Dolz-Gaiton P, Gambini J, Borras C, Lloret A, Pallardo FV, et al. Estradiol or genistein prevent Alzheimer’s disease-associated inflammation correlating with an increase PPAR gamma expression in cultured astrocytes. Brain Res 2010;1312:138-144 View Article PubMed/NCBI
  32. Liu X, Mei Z, Qian J, Zeng Y, Wang M. Puerarin partly counteracts the inflammatory response after cerebral ischemia/reperfusion via activating the cholinergic anti-inflammatory pathway. Neural Regen Res 2013;8(34):3203-3215 View Article PubMed/NCBI
  33. Andújar I, Recio MC, Bacelli T, Giner RM, Ríos JL. Shikonin reduces oedema induced by phorbol ester by interfering with IkappaBalpha degradation thus inhibiting translocation of NF-kappaB to the nucleus. Br J Pharmacol 2010;160(2):376-388 View Article PubMed/NCBI
  34. Vaillancourt F, Silva P, Shi Q, Fahmi H, Fernandes JC, Benderdour M. Elucidation of molecular mechanisms underlying the protective effects of thymoquinone against rheumatoid arthritis. J Cell Biochem 2011;112(1):107-117 View Article PubMed/NCBI
  35. Vang O, Ahmad N, Baile CA, Baur JA, Brown K, Csiszar A, et al. What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS One 2011;6(6):e19881 View Article PubMed/NCBI
  36. Youn J, Lee JS, Na HK, Kundu JK, Surh YJ. Resveratrol and piceatannol inhibit iNOS expression and NF-kappaB activation in dextran sulfate sodium-induced mouse colitis. Nutr Cancer 2009;61(6):847-854 View Article PubMed/NCBI
  37. Bauer J, Koeberle A, Dehm F, Pollastro F, Appendino G, Northoff H, et al. Arzanol, a prenylated heterodimeric phloroglucinyl pyrone, inhibits eicosanoid biosynthesis and exhibits anti-inflammatory efficacy in vivo. Biochem Pharmacol 2011;81(2):259-268 View Article PubMed/NCBI
  38. Koeberle A, Pollastro F, Northoff H, Werz O. Myrtucommulone, a natural acylphloroglucinol, inhibits microsomal prostaglandin E(2) synthase-1. Br J Pharmacol 2009;156(6):952-961 View Article PubMed/NCBI
  39. Cai B, Zhang Y, Wang Z, Xu D, Jia Y, Guan Y, et al. Therapeutic Potential of Diosgenin and Its Major Derivatives against Neurological Diseases: Recent Advances. Oxid Med Cell Longev 2020;2020:3153082 View Article PubMed/NCBI
  40. Zheng ZY, Yu XL, Dai TY, Yin LM, Zhao YN, Xu M, et al. Panaxdiol Saponins Component Promotes Hematopoiesis and Modulates T Lymphocyte Dysregulation in Aplastic Anemia Model Mice. Chin J Integr Med 2019;25(12):902-910 View Article PubMed/NCBI
  41. Shen YC, Chen CF, Chiou WF. Andrographolide prevents oxygen radical production by human neutrophils: possible mechanism(s) involved in its anti-inflammatory effect. Br J Pharmacol 2002;135(2):399-406 View Article PubMed/NCBI
  42. Song JY, Han SK, Son EH, Pyo SN, Yun YS, Yi SY. Induction of secretory and tumoricidal activities in peritoneal macrophages by ginsan. Int Immunopharmacol 2002;2(7):857-865 View Article PubMed/NCBI
  43. Brinker AM, Ma J, Lipsky PE, Raskin I. Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae). Phytochemistry 2007;68(6):732-766 View Article PubMed/NCBI
  44. Li LW, Na C, Tian SY, Chen J, Ma R, Gao Y, Lou G. Ellagic acid induces HeLa cell apoptosis via regulating signal transducer and activator of transcription 3 signaling. Exp Ther Med 2018;16(1):29-36 View Article PubMed/NCBI
  45. Chen HS, Bai MH, Zhang T, Li GD, Liu M. Ellagic acid induces cell cycle arrest and apoptosis through TGF-β/Smad3 signaling pathway in human breast cancer MCF-7 cells. Int J Oncol 2015;46(4):1730-1738 View Article PubMed/NCBI
  46. Shah D, Gandhi M, Kumar A, Cruz-Martins N, Sharma R, Nair S. Current insights into epigenetics, noncoding RNA interactome and clinical pharmacokinetics of dietary polyphenols in cancer chemoprevention. Crit Rev Food Sci Nutr 2021:1-37 View Article PubMed/NCBI
  47. Stefanska J, Pawliczak R. Apocynin: molecular aptitudes. Mediators Inflamm 2008;2008:106507 View Article PubMed/NCBI
  48. Bhaumik S, Jyothi MD, Khar A. Differential modulation of nitric oxide production by curcumin in host macrophages and NK cells. FEBS Lett 2000;483(1):78-82 View Article PubMed/NCBI
  49. Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, et al. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res 2001;480–481:243-268 View Article
  50. Singh S, Aggarwal BB. Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected]. J Biol Chem 1995;270(42):24995-25000 View Article PubMed/NCBI
  51. Dhandapani KM, Mahesh VB, Brann DW. Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and NFkappaB transcription factors. J Neurochem 2007;102(2):522-538 View Article PubMed/NCBI
  52. Ghasemi F, Shafiee M, Banikazemi Z, Pourhanifeh MH, Khanbabaei H, Shamshirian A, et al. Curcumin inhibits NF-kB and Wnt/β-catenin pathways in cervical cancer cells. Pathol Res Pract 2019;215(10):152556 View Article PubMed/NCBI
  53. Kumar S, Ahuja V, Sankar MJ, Kumar A, Moss AC. Curcumin for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2012;10:CD008424 View Article PubMed/NCBI
  54. da Silva JLG, Passos DF, Bernardes VM, Cabral FL, Schimites PG, Manzoni AG, et al. Co-Nanoencapsulation of Vitamin D3 and Curcumin Regulates Inflammation and Purine Metabolism in a Model of Arthritis. Inflammation 2019;42(5):1595-1610 View Article PubMed/NCBI
  55. Makuch S, Więcek K, Woźniak M. The Immunomodulatory and Anti-Inflammatory Effect of Curcumin on Immune Cell Populations, Cytokines, and In Vivo Models of Rheumatoid Arthritis. Pharmaceuticals (Basel) 2021;14(4):309 View Article PubMed/NCBI
  56. Lu L, Qi S, Chen Y, Luo H, Huang S, Yu X, et al. Targeted immunomodulation of inflammatory monocytes across the blood-brain barrier by curcumin-loaded nanoparticles delays the progression of experimental autoimmune encephalomyelitis. Biomaterials 2020;245:119987 View Article PubMed/NCBI
  57. Wu T, Marakkath B, Ye Y, Khobahy E, Yan M, Hutcheson J, et al. Curcumin Attenuates Both Acute and Chronic Immune Nephritis. Int J Mol Sci 2020;21(5):E1745 View Article PubMed/NCBI
  58. Roep BO. The role of T-cells in the pathogenesis of Type 1 diabetes: from cause to cure. Diabetologia 2003;46(3):305-321 View Article PubMed/NCBI
  59. Barnes PJ. Th2 cytokines and asthma: an introduction. Respir Res 2001;2(2):64-65 View Article PubMed/NCBI
  60. Ravikumar N, Kavitha CN. Therapeutic potential of curcumin on immune dysregulation in comorbid diabetic asthma in Mice. Biomed Pharmacol J 2020;13(2):821-831 View Article
  61. Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, et al. Immune evasion in cancer: Mechanistic basis and therapeutic strategies. Semin Cancer Biol 2015;35(Suppl):S185-S198 View Article PubMed/NCBI
  62. Seliger B. Strategies of tumor immune evasion. BioDrugs 2005;19(6):347-354 View Article PubMed/NCBI
  63. Wang Y, Lu J, Jiang B, Guo J. The roles of curcumin in regulating the tumor immunosuppressive microenvironment. Oncol Lett 2020;19(4):3059-3070 View Article PubMed/NCBI
  64. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm 2007;4(6):807-818 View Article PubMed/NCBI
  65. Nehra S, Bhardwaj V, Kar S, Saraswat D. Chronic Hypobaric Hypoxia Induces Right Ventricular Hypertrophy and Apoptosis in Rats: Therapeutic Potential of Nanocurcumin in Improving Adaptation. High Alt Med Biol 2016;17(4):342-352 View Article PubMed/NCBI
  66. Tahmasebi S, El-Esawi MA, Mahmoud ZH, Timoshin A, Valizadeh H, Roshangar L, et al. Immunomodulatory effects of nanocurcumin on Th17 cell responses in mild and severe COVID-19 patients. J Cell Physiol 2021;236(7):5325-5338 View Article PubMed/NCBI
  67. Burns J, Yokota T, Ashihara H, Lean ME, Crozier A. Plant foods and herbal sources of resveratrol. J Agric Food Chem 2002;50(11):3337-3340 View Article PubMed/NCBI
  68. Gao X, Xu YX, Janakiraman N, Chapman RA, Gautam SC. Immunomodulatory activity of resveratrol: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production. Biochem Pharmacol 2001;62(9):1299-1308 View Article PubMed/NCBI
  69. Holmes-McNary M, Baldwin AS. Chemopreventive properties of trans-resveratrol are associated with inhibition of activation of the IkappaB kinase. Cancer Res 2000;60(13):3477-3483 PubMed/NCBI
  70. Manna SK, Mukhopadhyay A, Aggarwal BB. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-kappa B, activator protein-1, and apoptosis: potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol 2000;164(12):6509-6519 View Article PubMed/NCBI
  71. Silva AM, Oliveira MI, Sette L, Almeida CR, Oliveira MJ, Barbosa MA, et al. Resveratrol as a natural anti-tumor necrosis factor-α molecule: implications to dendritic cells and their crosstalk with mesenchymal stromal cells. PLoS One 2014;9(3):e91406 View Article PubMed/NCBI
  72. Donnelly LE, Newton R, Kennedy GE, Fenwick PS, Leung RH, Ito K, et al. Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms. Am J Physiol Lung Cell Mol Physiol 2004;287(4):L774-L783 View Article PubMed/NCBI
  73. Eo SH, Kim SJ. Resveratrol-mediated inhibition of cyclooxygenase-2 in melanocytes suppresses melanogenesis through extracellular signal-regulated kinase 1/2 and phosphoinositide 3-kinase/Akt signalling. Eur J Pharmacol 2019;860:172586 View Article PubMed/NCBI
  74. Kowalski J, Samojedny A, Paul M, Pietsz G, Wilczok T. Effect of apigenin, kaempferol and resveratrol on the expression of interleukin-1beta and tumor necrosis factor-alpha genes in J774.2 macrophages. Pharmacol Rep 2005;57(3):390-394 PubMed/NCBI
  75. Ma C, Wang Y, Shen A, Cai W. Resveratrol upregulates SOCS1 production by lipopolysaccharide-stimulated RAW264.7 macrophages by inhibiting miR-155. Int J Mol Med 2017;39(1):231-237 View Article PubMed/NCBI
  76. Wung BS, Hsu MC, Wu CC, Hsieh CW. Resveratrol suppresses IL-6-induced ICAM-1 gene expression in endothelial cells: effects on the inhibition of STAT3 phosphorylation. Life Sci 2005;78(4):389-397 View Article PubMed/NCBI
  77. Euba B, López-López N, Rodríguez-Arce I, Fernández-Calvet A, Barberán M, Caturla N, et al. Resveratrol therapeutics combines both antimicrobial and immunomodulatory properties against respiratory infection by nontypeable Haemophilus influenzae. Sci Rep 2017;7(1):12860 View Article PubMed/NCBI
  78. Corrêa MG, Pires PR, Ribeiro FV, Pimentel SP, Cirano FR, Napimoga MH, et al. Systemic treatment with resveratrol reduces the progression of experimental periodontitis and arthritis in rats. PLoS One 2018;13(10):e0204414 View Article PubMed/NCBI
  79. Xian Y, Gao Y, Lv W, Ma X, Hu J, Chi J, et al. Resveratrol prevents diabetic nephropathy by reducing chronic inflammation and improving the blood glucose memory effect in non-obese diabetic mice. Naunyn Schmiedebergs Arch Pharmacol 2020;393(10):2009-2017 View Article PubMed/NCBI
  80. Farkhondeh T, Folgado SL, Pourbagher-Shahri AM, Ashrafizadeh M, Samarghandian S. The therapeutic effect of resveratrol: Focusing on the Nrf2 signaling pathway. Biomed Pharmacother 2020;127:110234 View Article PubMed/NCBI
  81. Lai X, Pei Q, Song X, Zhou X, Yin Z, Jia R, et al. The enhancement of immune function and activation of NF-κB by resveratrol-treatment in immunosuppressive mice. Int Immunopharmacol 2016;33:42-47 View Article PubMed/NCBI
  82. Lai X, Cao M, Song X, Jia R, Zou Y, Li L, et al. Resveratrol promotes recovery of immune function of immunosuppressive mice by activating JNK/NF-κB pathway in splenic lymphocytes. Can J Physiol Pharmacol 2017;95(6):763-767 View Article PubMed/NCBI
  83. Bakker GC, van Erk MJ, Pellis L, Wopereis S, Rubingh CM, Cnubben NH, et al. An antiinflammatory dietary mix modulates inflammation and oxidative and metabolic stress in overweight men: a nutrigenomics approach. Am J Clin Nutr 2010;91(4):1044-1059 View Article PubMed/NCBI
  84. Tomé-Carneiro J, Larrosa M, Yáñez-Gascón MJ, Dávalos A, Gil-Zamorano J, Gonzálvez M, et al. One-year supplementation with a grape extract containing resveratrol modulates inflammatory-related microRNAs and cytokines expression in peripheral blood mononuclear cells of type 2 diabetes and hypertensive patients with coronary artery disease. Pharmacol Res 2013;72:69-82 View Article PubMed/NCBI
  85. Parlar A, Muñoz-Acevedo A, Üçkardeş F, Jaimes L, Aneva I, Morales B, et al. Resveratrol as an anti-asthmatic agent: Could this stilbenoid help against COVID-19 in any way? A meta-analysis. Bol Latinoam y Del Caribe Plantas Med y Aromat 2021;20(5):463-481 View Article
  86. Middleton E, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 2000;52(4):673-751 PubMed/NCBI
  87. Ito T, Warnken SP, May WS. Protein synthesis inhibition by flavonoids: roles of eukaryotic initiation factor 2alpha kinases. Biochem Biophys Res Commun 1999;265(2):589-594 View Article PubMed/NCBI
  88. Ruiz PA, Braune A, Hölzlwimmer G, Quintanilla-Fend L, Haller D. Quercetin inhibits TNF-induced NF-kappaB transcription factor recruitment to proinflammatory gene promoters in murine intestinal epithelial cells. J Nutr 2007;137(5):1208-1215 View Article PubMed/NCBI
  89. Boots AW, Haenen GR, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol 2008;585(2-3):325-337 View Article PubMed/NCBI
  90. Min Z, Yangchun L, Yuquan W, Changying Z. Quercetin inhibition of myocardial fibrosis through regulating MAPK signaling pathway via ROS. Pak J Pharm Sci 2019;32(3 Special):1355-1359 PubMed/NCBI
  91. Igbe I, Shen XF, Jiao W, Qiang Z, Deng T, Li S, et al. Dietary quercetin potentiates the antiproliferative effect of interferon-α in hepatocellular carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase. Oncotarget 2017;8(69):113734-113748 View Article PubMed/NCBI
  92. Hämäläinen M, Nieminen R, Vuorela P, Heinonen M, Moilanen E. Anti-inflammatory effects of flavonoids: genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-kappaB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-kappaB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages. Mediators Inflamm 2007;2007:45673 View Article PubMed/NCBI
  93. Kobuchi H, Roy S, Sen CK, Nguyen HG, Packer L. Quercetin inhibits inducible ICAM-1 expression in human endothelial cells through the JNK pathway. Am J Physiol 1999;277(3):C403-C411 View Article PubMed/NCBI
  94. Ying B, Yang T, Song X, Hu X, Fan H, Lu X, et al. Quercetin inhibits IL-1 beta-induced ICAM-1 expression in pulmonary epithelial cell line A549 through the MAPK pathways. Mol Biol Rep 2009;36(7):1825-1832 View Article PubMed/NCBI
  95. Morikawa K, Nonaka M, Narahara M, Torii I, Kawaguchi K, Yoshikawa T, et al. Inhibitory effect of quercetin on carrageenan-induced inflammation in rats. Life Sci 2003;74(6):709-721 View Article PubMed/NCBI
  96. Stewart LK, Soileau JL, Ribnicky D, Wang ZQ, Raskin I, Poulev A, et al. Quercetin transiently increases energy expenditure but persistently decreases circulating markers of inflammation in C57BL/6J mice fed a high-fat diet. Metabolism 2008;57(7 Suppl 1):S39-S46 View Article PubMed/NCBI
  97. Rogerio AP, Dora CL, Andrade EL, Chaves JS, Silva LF, Lemos-Senna E, et al. Anti-inflammatory effect of quercetin-loaded microemulsion in the airways allergic inflammatory model in mice. Pharmacol Res 2010;61(4):288-297 View Article PubMed/NCBI
  98. Bungsu I, Kifli N, Ahmad SR, Ghani H, Cunningham AC. Herbal Plants: The Role of AhR in Mediating Immunomodulation. Front Immunol 2021;12:697663 View Article PubMed/NCBI
  99. Michalski J, Deinzer A, Stich L, Zinser E, Steinkasserer A, Knippertz I. Quercetin induces an immunoregulatory phenotype in maturing human dendritic cells. Immunobiology 2020;225(4):151929 View Article PubMed/NCBI
  100. Yu W, Zhu Y, Li H, He Y. Injectable Quercetin-Loaded Hydrogel with Cartilage-Protection and Immunomodulatory Properties for Articular Cartilage Repair. ACS Appl Bio Mater 2020;3(2):761-771 View Article PubMed/NCBI
  101. Hu Y, Gui Z, Zhou Y, Xia L, Lin K, Xu Y. Quercetin alleviates rat osteoarthritis by inhibiting inflammation and apoptosis of chondrocytes, modulating synovial macrophages polarization to M2 macrophages. Free Radic Biol Med 2019;145:146-160 View Article PubMed/NCBI
  102. Karimi A, Naeini F, Asghari Azar V, Hasanzadeh M, Ostadrahimi A, Niazkar HR, et al. A comprehensive systematic review of the therapeutic effects and mechanisms of action of quercetin in sepsis. Phytomedicine 2021;86:153567 View Article PubMed/NCBI
  103. Colunga Biancatelli RML, Berrill M, Catravas JD, Marik PE. Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19). Front Immunol 2020;11:1451 View Article PubMed/NCBI
  104. Boots AW, Drent M, de Boer VC, Bast A, Haenen GR. Quercetin reduces markers of oxidative stress and inflammation in sarcoidosis. Clin Nutr 2011;30(4):506-512 View Article PubMed/NCBI
  105. Pfeuffer M, Auinger A, Bley U, Kraus-Stojanowic I, Laue C, Winkler P, et al. Effect of quercetin on traits of the metabolic syndrome, endothelial function and inflammation in men with different APOE isoforms. Nutr Metab Cardiovasc Dis 2013;23(5):403-409 View Article PubMed/NCBI
  106. Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol 2011;82(12):1807-1821 View Article PubMed/NCBI
  107. Yang H, Landis-Piwowar K, Chan TH, Dou QP. Green tea polyphenols as proteasome inhibitors: implication in chemoprevention. Curr Cancer Drug Targets 2011;11(3):296-306 View Article PubMed/NCBI
  108. Zhou Y, Tang J, Du Y, Ding J, Liu JY. The green tea polyphenol EGCG potentiates the antiproliferative activity of sunitinib in human cancer cells. Tumour Biol 2016;37(7):8555-8566 View Article PubMed/NCBI
  109. Chen BH, Hsieh CH, Tsai SY, Wang CY, Wang CC. Anticancer effects of epigallocatechin-3-gallate nanoemulsion on lung cancer cells through the activation of AMP-activated protein kinase signaling pathway. Sci Rep 2020;10(1):5163 View Article PubMed/NCBI
  110. Muraoka K, Shimizu K, Sun X, Tani T, Izumi R, Miwa K, et al. Flavonoids exert diverse inhibitory effects on the activation of NF-kappaB. Transplant Proc 2002;34(4):1335-1340 View Article PubMed/NCBI
  111. Joo SY, Song YA, Park YL, Myung E, Chung CY, Park KJ, et al. Epigallocatechin-3-gallate Inhibits LPS-Induced NF-κB and MAPK Signaling Pathways in Bone Marrow-Derived Macrophages. Gut Liver 2012;6(2):188-196 View Article PubMed/NCBI
  112. Chung JY, Park JO, Phyu H, Dong Z, Yang CS. Mechanisms of inhibition of the Ras-MAP kinase signaling pathway in 30.7b Ras 12 cells by tea polyphenols (-)-epigallocatechin-3-gallate and theaflavin-3,3′-digallate. FASEB J 2001;15(11):2022-2024 View Article PubMed/NCBI
  113. Shih LJ, Lin YR, Lin CK, Liu HS, Kao YH. Green tea (-)-epigallocatechin gallate induced growth inhibition of human placental choriocarcinoma cells. Placenta 2016;41:1-9 View Article PubMed/NCBI
  114. Hara Y, Fujino M, Adachi K, Li XK. The reduction of hypoxia-induced and reoxygenation-induced apoptosis in rat islets by epigallocatechin gallate. Transplant Proc 2006;38(8):2722-2725 View Article PubMed/NCBI
  115. Park HJ, Shin DH, Chung WJ, Leem K, Yoon SH, Hong MS, et al. Epigallocatechin gallate reduces hypoxia-induced apoptosis in human hepatoma cells. Life Sci 2006;78(24):2826-2832 View Article PubMed/NCBI
  116. Yu HN, Ma XL, Yang JG, Shi CC, Shen SR, He GQ. Comparison of effects of epigallocatechin-3-gallate on hypoxia injury to human umbilical vein, RF/6A, and ECV304 cells induced by Na(2)S(2)O(4). Endothelium 2007;14(4-5):227-231 View Article PubMed/NCBI
  117. Gu JJ, Qiao KS, Sun P, Chen P, Li Q. Study of EGCG induced apoptosis in lung cancer cells by inhibiting PI3K/Akt signaling pathway. Eur Rev Med Pharmacol Sci 2018;22(14):4557-4563 View Article PubMed/NCBI
  118. Aktas O, Prozorovski T, Smorodchenko A, Savaskan NE, Lauster R, Kloetzel PM, et al. Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J Immunol 2004;173(9):5794-5800 View Article PubMed/NCBI
  119. Wang J, Ren Z, Xu Y, Xiao S, Meydani SN, Wu D. Epigallocatechin-3-gallate ameliorates experimental autoimmune encephalomyelitis by altering balance among CD4+ T-cell subsets. Am J Pathol 2012;180(1):221-234 View Article PubMed/NCBI
  120. Byun JK, Yoon BY, Jhun JY, Oh HJ, Kim EK, Min JK, et al. Epigallocatechin-3-gallate ameliorates both obesity and autoinflammatory arthritis aggravated by obesity by altering the balance among CD4+ T-cell subsets. Immunol Lett 2014;157(1-2):51-59 View Article PubMed/NCBI
  121. Wong CP, Nguyen LP, Noh SK, Bray TM, Bruno RS, Ho E. Induction of regulatory T cells by green tea polyphenol EGCG. Immunol Lett 2011;139(1-2):7-13 View Article PubMed/NCBI
  122. Cai Y, Kurita-Ochiai T, Hashizume T, Yamamoto M. Green tea epigallocatechin-3-gallate attenuates Porphyromonas gingivalis-induced atherosclerosis. Pathog Dis 2013;67(1):76-83 View Article PubMed/NCBI
  123. Huang AC, Cheng HY, Lin TS, Chen WH, Lin JH, Lin JJ, et al. Epigallocatechin gallate (EGCG), influences a murine WEHI-3 leukemia model in vivo through enhancing phagocytosis of macrophages and populations of T- and B-cells. In Vivo 2013;27(5):627-634 PubMed/NCBI
  124. Basu A, Du M, Sanchez K, Leyva MJ, Betts NM, Blevins S, et al. Green tea minimally affects biomarkers of inflammation in obese subjects with metabolic syndrome. Nutrition 2011;27(2):206-213 View Article PubMed/NCBI
  125. Yoon JY, Kwon HH, Min SU, Thiboutot DM, Suh DH. Epigallocatechin-3-gallate improves acne in humans by modulating intracellular molecular targets and inhibiting P. acnes. J Invest Dermatol 2013;133(2):429-440 View Article PubMed/NCBI
  126. Lee YK, Bone ND, Strege AK, Shanafelt TD, Jelinek DF, Kay NE. VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG), in B-cell chronic lymphocytic leukemia. Blood 2004;104(3):788-794 View Article PubMed/NCBI
  127. Wolniak M, Tomczykowa M, Tomczyk M, Gudej J, Wawer I. Antioxidant activity of extracts and flavonoids from Bidens tripartita. Acta Pol Pharm 2007;64(5):441-447 PubMed/NCBI
  128. Hosseinzade A, Sadeghi O, Naghdipour Biregani A, Soukhtehzari S, Brandt GS, Esmaillzadeh A. Immunomodulatory Effects of Flavonoids: Possible Induction of T CD4+ Regulatory Cells Through Suppression of mTOR Pathway Signaling Activity. Front Immunol 2019;10:51 View Article PubMed/NCBI
  129. Xagorari A, Papapetropoulos A, Mauromatis A, Economou M, Fotsis T, Roussos C. Luteolin inhibits an endotoxin-stimulated phosphorylation cascade and proinflammatory cytokine production in macrophages. J Pharmacol Exp Ther 2001;296(1):181-187 PubMed/NCBI
  130. Xagorari A, Roussos C, Papapetropoulos A. Inhibition of LPS-stimulated pathways in macrophages by the flavonoid luteolin. Br J Pharmacol 2002;136(7):1058-1064 View Article PubMed/NCBI
  131. Verbeek R, Plomp AC, van Tol EA, van Noort JM. The flavones luteolin and apigenin inhibit in vitro antigen-specific proliferation and interferon-gamma production by murine and human autoimmune T cells. Biochem Pharmacol 2004;68(4):621-629 View Article PubMed/NCBI
  132. Xia N, Chen G, Liu M, Ye X, Pan Y, Ge J, et al. Anti-inflammatory effects of luteolin on experimental autoimmune thyroiditis in mice. Exp Ther Med 2016;12(6):4049-4054 View Article PubMed/NCBI
  133. Verbeek R, van Tol EA, van Noort JM. Oral flavonoids delay recovery from experimental autoimmune encephalomyelitis in SJL mice. Biochem Pharmacol 2005;70(2):220-228 View Article PubMed/NCBI
  134. Jia Z, Nallasamy P, Liu D, Shah H, Li JZ, Chitrakar R, et al. Luteolin protects against vascular inflammation in mice and TNF-alpha-induced monocyte adhesion to endothelial cells via suppressing IΚBα/NF-κB signaling pathway. J Nutr Biochem 2015;26(3):293-302 View Article PubMed/NCBI
  135. Casetti F, Jung W, Wölfle U, Reuter J, Neumann K, Gilb B, et al. Topical application of solubilized Reseda luteola extract reduces ultraviolet B-induced inflammation in vivo. J Photochem Photobiol B 2009;96(3):260-265 View Article PubMed/NCBI
  136. Seelinger G, Merfort I, Wölfle U, Schempp CM. Anti-carcinogenic effects of the flavonoid luteolin. Molecules 2008;13(10):2628-2651 View Article PubMed/NCBI
  137. Perico N, Ostermann D, Bontempeill M, Morigi M, Amuchastegui CS, Zoja C, et al. Colchicine interferes with L-selectin and leukocyte function-associated antigen-1 expression on human T lymphocytes and inhibits T cell activation. J Am Soc Nephrol 1996;7(4):594-601 View Article PubMed/NCBI
  138. Titus RG. Colchicine is a potent adjuvant for eliciting T cell responses. J Immunol 1991;146(12):4115-4119 PubMed/NCBI
  139. Choi MY, Wee YM, Kim YH, Shin S, Yoo SE, Han DJ. Novel colchicine derivatives enhance graft survival after transplantation via suppression of T-cell differentiation and activity. J Cell Biochem 2019;120(8):12436-12449 View Article PubMed/NCBI
  140. Weng JH, Koch PD, Luan HH, Tu HC, Shimada K, Ngan I, et al. Colchicine acts selectively in the liver to induce hepatokines that inhibit myeloid cell activation. Nat Metab 2021;3(4):513-522 View Article PubMed/NCBI
  141. Bhattacharyya B, Panda D, Gupta S, Banerjee M. Anti-mitotic activity of colchicine and the structural basis for its interaction with tubulin. Med Res Rev 2008;28(1):155-183 View Article PubMed/NCBI
  142. Nuki G. Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr Rheumatol Rep 2008;10(3):218-227 View Article PubMed/NCBI
  143. Stanton RA, Gernert KM, Nettles JH, Aneja R. Drugs that target dynamic microtubules: a new molecular perspective. Med Res Rev 2011;31(3):443-481 View Article PubMed/NCBI
  144. Imazio M, Bobbio M, Cecchi E, Demarie D, Demichelis B, Pomari F, et al. Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial. Circulation 2005;112(13):2012-2016 View Article PubMed/NCBI
  145. Imazio M, Brucato A, Cemin R, Ferrua S, Belli R, Maestroni S, et al. Colchicine for recurrent pericarditis (CORP): a randomized trial. Ann Intern Med 2011;155(7):409-414 View Article PubMed/NCBI
  146. Tardif JC, Bouabdallaoui N, L’Allier PL, Gaudet D, Shah B, Pillinger MH, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. The Lancet Respiratory Medicine 2021;9(8):924-932 View Article
  147. Brunetti L, Diawara O, Tsai A, Firestein BL, Nahass RG, Poiani G, et al. Colchicine to Weather the Cytokine Storm in Hospitalized Patients with COVID-19. J Clin Med 2020;9(9):E2961 View Article PubMed/NCBI
  148. Manenti L, Maggiore U, Fiaccadori E, Meschi T, Antoni AD, Nouvenne A, et al. Reduced mortality in COVID-19 patients treated with colchicine: Results from a retrospective, observational study. PLoS One 2021;16(3):e0248276 View Article PubMed/NCBI
  149. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997;389(6653):816-824 View Article PubMed/NCBI
  150. Yang F, Zheng J. Understand spiciness: mechanism of TRPV1 channel activation by capsaicin. Protein Cell 2017;8(3):169-177 View Article PubMed/NCBI
  151. O’Neill J, Brock C, Olesen AE, Andresen T, Nilsson M, Dickenson AH. Unravelling the mystery of capsaicin: a tool to understand and treat pain. Pharmacol Rev 2012;64(4):939-971 View Article PubMed/NCBI
  152. Haanpää M, Treede RD. Capsaicin for neuropathic pain: linking traditional medicine and molecular biology. Eur Neurol 2012;68(5):264-275 View Article PubMed/NCBI
  153. Sanz-Salvador L, Andrés-Borderia A, Ferrer-Montiel A, Planells-Cases R. Agonist- and Ca2+-dependent desensitization of TRPV1 channel targets the receptor to lysosomes for degradation. J Biol Chem 2012;287(23):19462-19471 View Article PubMed/NCBI
  154. Kim CS, Kawada T, Kim BS, Han IS, Choe SY, Kurata T, et al. Capsaicin exhibits anti-inflammatory property by inhibiting IkB-a degradation in LPS-stimulated peritoneal macrophages. Cell Signal 2003;15(3):299-306 View Article PubMed/NCBI
  155. Li T, Wang G, Hui VCC, Saad D, de Sousa Valente J, La Montanara P, et al. TRPV1 feed-forward sensitisation depends on COX2 upregulation in primary sensory neurons. Sci Rep 2021;11(1):3514 View Article PubMed/NCBI
  156. Fischer BS, Qin D, Kim K, McDonald TV. Capsaicin inhibits Jurkat T-cell activation by blocking calcium entry current I(CRAC). J Pharmacol Exp Ther 2001;299(1):238-246 PubMed/NCBI
  157. Zhang J, Nagasaki M, Tanaka Y, Morikawa S. Capsaicin inhibits growth of adult T-cell leukemia cells. Leuk Res 2003;27(3):275-283 View Article PubMed/NCBI
  158. Nevius E, Srivastava PK, Basu S. Oral ingestion of Capsaicin, the pungent component of chili pepper, enhances a discreet population of macrophages and confers protection from autoimmune diabetes. Mucosal Immunol 2012;5(1):76-86 View Article PubMed/NCBI
  159. Kim HS, Kwon HJ, Kim GE, Cho MH, Yoon SY, Davies AJ, et al. Attenuation of natural killer cell functions by capsaicin through a direct and TRPV1-independent mechanism. Carcinogenesis 2014;35(7):1652-1660 View Article PubMed/NCBI
  160. Joe B, Rao UJ, Lokesh BR. Presence of an acidic glycoprotein in the serum of arthritic rats: modulation by capsaicin and curcumin. Mol Cell Biochem 1997;169(1-2):125-134 View Article PubMed/NCBI
  161. Viveros-Paredes JM, Puebla-Pérez AM, Gutiérrez-Coronado O, Macías-Lamas AM, Hernández-Flores G, Ortiz-Lazareno PC, et al. Capsaicin attenuates immunosuppression induced by chronic stress in BALB/C mice. Int Immunopharmacol 2021;93:107341 View Article PubMed/NCBI
  162. De Silva V, El-Metwally A, Ernst E, Lewith G, Macfarlane GJ, Arthritis Research UK Working Group on Complementary and Alternative Medicines. Evidence for the efficacy of complementary and alternative medicines in the management of osteoarthritis: a systematic review. Rheumatology (Oxford) 2011;50(5):911-920 View Article PubMed/NCBI
  163. RUZICKA L. The isoprene rule and the biogenesis of terpenic compounds. Experientia 1953;9(10):357-367 View Article PubMed/NCBI
  164. Gallily R, Yekhtin Z, Hanuš LO. The Anti-Inflammatory Properties of Terpenoids from Cannabis. Cannabis Cannabinoid Res 2018;3(1):282-290 View Article PubMed/NCBI
  165. González-Burgos E, Gómez-Serranillos MP. Terpene compounds in nature: a review of their potential antioxidant activity. Curr Med Chem 2012;19(31):5319-5341 View Article PubMed/NCBI
  166. Guimarães AC, Meireles LM, Lemos MF, Guimarães MCC, Endringer DC, Fronza M, et al. Antibacterial Activity of Terpenes and Terpenoids Present in Essential Oils. Molecules 2019;24(13):E2471 View Article PubMed/NCBI
  167. Salapovic H, Geier J, Reznicek G. Quantification of Sesquiterpene Lactones in Asteraceae Plant Extracts: Evaluation of their Allergenic Potential. Sci Pharm 2013;81(3):807-818 View Article PubMed/NCBI
  168. Schepetkin IA, Kirpotina LN, Mitchell PT, Kishkentaeva АS, Shaimerdenova ZR, Atazhanova GA, et al. The natural sesquiterpene lactones arglabin, grosheimin, agracin, parthenolide, and estafiatin inhibit T cell receptor (TCR) activation. Phytochemistry 2018;146:36-46 View Article PubMed/NCBI
  169. Pathak S, Gokhroo A, Kumar Dubey A, Majumdar S, Gupta S, Almeida A, et al. 7-Hydroxy Frullanolide, a sesquiterpene lactone, increases intracellular calcium amounts, lowers CD4+ T cell and macrophage responses, and ameliorates DSS-induced colitis. Int Immunopharmacol 2021;97:107655 View Article PubMed/NCBI
  170. García-Piñeres AJ, Lindenmeyer MT, Merfort I. Role of cysteine residues of p65/NF-kappaB on the inhibition by the sesquiterpene lactone parthenolide and N-ethyl maleimide, and on its transactivating potential. Life Sci 2004;75(7):841-856 View Article PubMed/NCBI
  171. Zamanai Taghizadeh Rabe S, Iranshahi M, Rastin M, Tabasi N, Mahmoudi M. In vitro immunomodulatory properties of a sesquiterpene lactone-bearing fraction from Artemisia khorassanica. J Immunotoxicol 2015;12(3):223-230 View Article PubMed/NCBI
  172. Ghantous A, Gali-Muhtasib H, Vuorela H, Saliba NA, Darwiche N. What made sesquiterpene lactones reach cancer clinical trials?. Drug Discov Today 2010;15(15-16):668-678 View Article PubMed/NCBI
  173. Wraith DC. The Future of Immunotherapy: A 20-Year Perspective. Front Immunol 2017;8:1668 View Article PubMed/NCBI
  174. Frankish H. 15 million new cancer cases per year by 2020, says WHO. Lancet 2003;361(9365):1278 View Article PubMed/NCBI
  175. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68(6):394-424 View Article
  176. Ragab D, Salah Eldin H, Taeimah M, Khattab R, Salem R. The COVID-19 Cytokine Storm; What We Know So Far. Front Immunol 2020;11:1446 View Article PubMed/NCBI
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Plant-based Immunomodulators and Their Potential Therapeutic Actions

Sanmoy Pathak, Joshuah Fialho, Dipankar Nandi
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