| Vitamin D3 (Cholecalciferol) |
Regulates production of antimicrobial peptides (cathelicidin and defensin); ↑ expression of antimicrobial peptides [56] ↑ expression of proteins involved in intercellular connections (connexin-43, tight junctions, and E-cadherin) in epithelial barriers [56] Vitamin D receptor (VDR) expressed in almost all leukocytes (i.e., activated CD4+ and CD8+ T cells, B cells, and antigen-presenting cells, such as macrophages and dendritic cells); receptor-ligand pair (Vit D3 and VDR) acts as a strong immunosuppressor [56,57] Enhances mobility and phagocytosis of macrophages, and ↑ generation of tumor necrosis factor (TNF)-∝ by macrophages [58] Causes neutrophils to traffic to sites of inflammation and stimulates them to kill microbes [56] Controls interferon (IFN) production [56] Inhibits the proliferation, differentiation, and production of antibodies by B cells [56] Inhibits differentiation and maturation of dendritic cells, ↓ expression of major histocompatibility complex (MHC)-II and auxiliary stimulative molecules such as B7 and CD40 on dendritic cells, and thus, ↓ cytotoxicity of CD8+ T cells [56] Reduces T lymphocyte proliferation and regulates skewing towards particular CD4+ T cell subsets [57] Shifts cytokine patterns from a Th-1 to a Th-2 milieu by inhibiting cytokines required for Th1 differentiation (e.g., IL-12) or produced by differentiated Th1 cells (e.g., IL-2 and IFN-γ), and augmenting Th2 cell development to promote self-tolerance [57,59] Activates renin-angiotensin system (RAS) pathway by inducing transforming growth factor (TGF)-β-1 [56] Reduces risk of developing autoimmune diseases (e.g., Type 1 diabetes mellitus, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Crohn’s disease, thyroiditis, psoriasis, polymyalgia rheumatic, autoimmune gastritis, and systemic sclerosis) [60,61]
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| Coriolus versicolor extract (polysaccharide krestin (PSK), polysaccharide peptide (PSP)) |
PSP induces expression of TNF-∝; pro-inflammatory cytokine with potent tumoricidal activity and capable of inducing apoptosis [62]
PSP increases production of IL-12; Th1-related cytokine that enhances the cytotoxic activities of natural killer and CD8+ T cells and their expression of TNF-∝ [62] PSP induces interleukin (IL)-1β; a pleiotropic cytokine and pro-inflammatory signal to enhance lymphocyte proliferation and differentiation [63,62] Coriolus versicolor (CV) extract activates T lymphocytes, B lymphocytes, monocytes/macrophages, bone marrow cells, natural killer cells and lymphocyte activated killer cells in vitro [64] Promotes the proliferation and/or production of antibodies and various cytokines (i.e., IL-2 and IL-6, IFNs, and TNF-∝) [64]
CV extracts shown to restore certain depressed immunological responses caused by tumor burden or chemotherapy treatment to normal levels [65,66,67]
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| Quercetin |
Neutralizes free radicals through the donation of hydrogen atoms; antioxidant activity increases cell survival rate [68] Strong reducing agent; provides protection against oxidative stress [69] Inhibits production of cyclooxygenase (COX) and lipoxygenase (LOX) inflammatory enzymes [70] Induces gene expression and production of Th-1 derived IFN-γ, and down-regulates Th-2-derived IL-4 by blood mononuclear cells [70]
Direct regulatory effect on basic functional properties of leukocytes via the extracellular regulated kinase 2 (Erk2) mitogen-activated protein kinase (MAPK) signaling pathway in human mitogen-activated blood mononuclear cells and purified T lymphocytes [70]
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| Carotenoids |
Strong antioxidant agents to combat oxidative stress caused by cytokine storm induced by the innate immune system in response to viral infections [71] Vitamin C improves pulmonary function and decreases risk of acute respiratory distress syndrome [71] Vitamin E alleviates oxidative damage and inflammation induced by SARS-CoV-2 [71] β-carotene and lycopene possess anti-inflammatory properties due to their reactive oxygen species (ROS)-scavenging activities [71]
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| Probiotics |
Activates naïve T and B cells: probiotics and their antigenic metabolites can be phagocytosed by microfold cells forming endosomes that can be released and acquired by dendritic cells, which then transports them to local lymph nodes [72] Induces the release of antimicrobial defensins from epithelial cells [72] Modulates innate and adaptive immune responses, and facilitates the development and maturation of the immune system [72] Regulates host-pathogen interactions by initiating innate immune responses; composed of Toll-like receptors, nuclear factor kappa B (NF-κB), MAPK, and c-Jun NH2-terminal kinase (JNK) pathways [72] Enhances viability of natural killer cells and macrophages [72] Stimulates release of secretory IgA [72]
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| Omega-3 fatty acids |
Upregulates the activation status of macrophages, neutrophils, T-cells, B-cells, dendritic cells, natural killer cells, mast cells, basophils, and eosinophils [73] Modulates neutrophil function via neutrophil migration, phagocytic capacity, and production of ROS and cytokines [74] Activates function of T cells by promoting antigen-presenting cells (APC) [73] Improves function of macrophages by secreting cytokines and chemokines, promoting phagocytosis, and activating macrophages via polarization [73] Downregulates NF-κB [73] Anti-inflammatory due to production of different prostaglandins, lipoxins, and peroxisome proliferator-activated receptor gamma (PPARγ) [73]
Affects cell signaling by affecting lipid raft formation and functions [73]
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| Melatonin |
Potent free radical scavenger and antioxidant; detoxifies various ROS and reactive nitrogen species [75] Stimulates the activities of several antioxidant enzymes and/or upregulates their gene expression [75] Suppresses activity or downregulates gene expressions of several proinflammatory enzymes (e.g., COX2, inducible nitric oxide synthase (iNOS), eosinophilic peroxidase, and matrix metallopeptidase 2 and 9 (MMP2,9)) [75] Suppresses NLRP3 inflammasome progression [75] Inhibition of IκBα phosphorylation suppresses the cytokine storm [75] Downregulates the overreaction of the innate immune response and promotes adaptive immunity [75] Inhibits migration of neutrophils to inflammatory sites by blocking ERK phosphorylation [75] Downregulates mast cell activation, ↓ production of TNF-∝ and IL-6, and inhibits IKK/NF- κB signal transduction pathway in activated mast cells [75]
Balances ratio of T lymphocyte subpopulations and ↑ numbers of B lymphocyte and antibody titer following vaccination [75]
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