# Honey as an Adjuvant in the Treatment of COVID-19 Infection: A Review
## 4 Honey as a Co-Adjuvant of SARS-CoV-2 Infection Treatment
### Regulation/Boosting of Host Immune Signaling Pathways  
Oxidative stress has a role in several pathological conditions, including neurological disorders, cancer, aging, endocrine illness, and pathogen infection. During virus invasion, oxidative stress induces inflammatory damage, with a consequently exacerbated immune response, the so-called cytokine storm [120]. Most SARS-CoV-2 patients showed elevated serum levels of C reactive protein (CRP), a marker of systemic inflammation [128]. The production of ROS and reactive nitrogen species (RNS) is generally counterbalanced by the action of antioxidant molecules or enzymes. The antioxidant effect of honey [101; 104; 129] is mainly correlated with the content of phenolic acids and flavonoids, sugars, proteins, amino acids, caroten, organic acids, and water-soluble vitamins (vitamin B1, B2, B3, B9, B12, and vitamin C) [120; 129]. Nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant gene expression is noticeably reduced in COVID-19 patients. Nrf2 stimulators may inhibit the replication of SARS-CoV-2 as well as related inflammatory gene expression, as demonstrated for honey [100; 130]. As stated above, inflammatory processes are also a hallmark of SARS-CoV-2 infection. The inflammatory markers mitogen-activated protein kinase (MAPK) and the nuclear factor kappa B (NF-\(\kappa\)B) induce the production of several other inflammatory factors, such as enzymes, cytokines, proteins, and cyclooxygenase-2 (COX-2), lipoxygenase 2 (LOX-2), CRP, interleukins (IL-18, IL-6, and IL-10), tumor necrosis factor \(\alpha\) (TNF-\(\alpha\)), granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), macrophage inflammatory protein (MIP1), MIP1A, MIP1B, platelet-derived growth factor (PDGF), and interferon-inducible protein 10 (IP-10) [118; 122; 128]. Recent in vitro and in vivo studies have demonstrated the anti-inflammatory mechanisms of honey. [PERSON] et al. [120] stated that honey decreases carrageenan-induced rat paw inflammation by attenuating NF-\(\kappa\)B translocation to the nucleus, and by inhibition of the NF-\(\kappa\)B degradation, with subsequent decrease of pro-inflammatory mediators COX-2 and TNF-\(\alpha\). Moreover, the same authors reported that honey also inhibited the production of the proinflammatory mediators nitric oxide (NO), prostaglandin E2 (PGE(2)), TNF-\(\alpha\), and IL-6, using the same animal model [112]. The attachment of SARS-CoV-2 to the cell surface occurs via interaction with the ACE-2 receptor, which is present in several cell surfaces, including lungs, heart, kidney, and arteries. Upon virus entrance, viral particles are recognizable by pattern recognition receptors (e.g., TLR3, TLR4, and TLR7). Inside human cells, the immune system is activated, including macrophages, natural killer cells, CD4+ and CD8+ T-cells, B-cells, neutrophils, and dendritic cells, aimed at the destruction of SARS-CoV-2 [120]. It has been reported that honey stimulates B-lymphocytes and T-lymphocytes in cell culture to multiply and activate neutrophils, which induce cytokine production, such as, IL-1, IL-6, and TNF-\(\alpha\) and apalbumin 1 (AP-1) [131]. A variety of honeys have been associated with the increase of immune responses mediators [132; 133]. [PERSON] et al. [134] discovered a 5.8 kDA component of Manuka honey that stimulates the production of TNF-\(\alpha\) in macrophages via TLR4, such as blockade suppress honey-mediated immunomodulatory effects. Besides all these phenomena, honey active phagocytosis and autophagy for pathogen clearance. Phagocytes are the first line of defense of the innate immune system, it being demonstrated that honey provides a supply of glucose essential for the \"respiratory burst\" of phagocytes (such as, polymorphonuclear neutrophils (PMNs) and peripheral blood mononuclear cells (MNCs)) [135].