Comparison of Vitamin D and Resveratrol Performances in COVID-19

Abstract

Over the last few years, we have experienced the infection generated by severe respiratory syndrome coronavirus 2 (SARS-CoV-2) often resulting in an exaggerated immune reaction and systemic inflammation. The preferred treatments against SARS-CoV-2 were those that mitigated immunological/inflammatory dysfunction. A variety of observational epidemiological studies have reported that vitamin D deficiency is often a crucial factor in many inflammatory diseases and autoimmune diseases, as well as the susceptibility to contract infectious diseases, including acute respiratory infections. Similarly, resveratrol regulates immunity, modifying the gene expression and the release of proinflammatory cytokines in the immune cells. Therefore, it plays an immunomodulatory role that can be beneficial in the prevention and development of non-communicable diseases associated with inflammation. Since both vitamin D and resveratrol also act as immunomodulators in inflammatory pathologies, many studies have paid particular attention to an integrated treatment of either vitamin D or resveratrol in the immune reaction against SARS-CoV-2 infections. This article offers a critical evaluation of published clinical trials that have examined the use of vitamin D or resveratrol as adjuncts in COVID-19 management. Furthermore, we aimed to compare the anti-inflammatory and antioxidant properties linked to the modulation of the immune system, along with antiviral properties of both vitamin D and resveratrol.

Keywords: COVID-19; anti-oxidant activity; anti-thrombotic activity; inflammation; resveratrol; vitamin D.

Figure 1

Anti-SARS-CoV-2 mechanisms of action of vitamin D and resveratrol. Vitamin D, by inhibiting the binding of ACE2 to the spike protein and by decreasing TMPRSS2 and Ctsl gene expression, prevents the transmission of SARS-CoV-2. As well as vitamin D, resveratrol affects the expression of ACE-2, suppresses the effects AT1R axis, improves AT2R axis and prevents SARS-CoV-2 entry, inhibiting Ctsl and TMPRSS2. Both vitamin D/VDR complex and resveratrol inhibit NF-κB activation and cytokine storm. Resveratrol, activating SIRT1 and SOD, decreases inflammation. Abbreviations: ACE2—angiotensin-converting enzyme 2; AT1R—angiotensin II type 1 receptor; AT2R—angiotensin II type 2 receptor; Ctsl—Cathepsin L; NF-κB—nuclear factor kappa B; ROS—reactive oxygen species; SARS-CoV-2—severe respiratory syndrome coronavirus 2; SIRT1—sirtuin 1; SOD—superoxide dismutase; TMPRSS2—transmembrane serine protease 2; VDR: vitamin D receptor.

Figure 2

Vitamin D and resveratrol immune response against SARS-CoV-2 infection. Vitamin D interacts with the cells of the innate immunity by activating TLRs and upregulating CYP27B1. The mechanism by which TLR binding improves CYP27B1 expression involves JAK-STAT, C/EBPβ, and p38 MAPK pathways. Following TLRs stimulation, vitamin D activates innate immunity, increasing cathelicidins and β-defensins. VDR is expressed in many immune cells. Once vitamin D is hydroxylated interacts with VDR, vitamin D/VDR complex negatively regulates STAT3. Vitamin D exerts its effects through genomic mechanisms modulated by VDR/RXR complex to bind to VDRE in target genes of immune cells such as neutrophils, macrophages, dendritic cells, and T and B lymphocytes. VDRE promotes the recruitment of nuclear proteins in transcriptional-complex-modulating inflammatory response. Resveratrol acts against COVID-19 inhibiting TRIF signaling in the TLRs pathway by RIP1/TANK in the TRIF complex. It inhibits STAT3 phosphorylation. Resveratrol reduces COX-2 expression by preventing TRIF signaling. Resveratrol also activates the SIRT1 pathway, which disrupts TLR4/NF-κB/STAT signal, decreasing cytokine storm. Resveratrol-inducing SIRT1 can mediate β-defensins induction. Both vitamin D and resveratrol inhibit NF-κB and consequently, NLRP3 inflammasome, avoiding CD4⁺ T cell activation and cytokine storm. Abbreviations: AP1—activator protein 1; C/EBPβ—CCAAT/enhancer binding protein β; CD4T—CYP27B1, cytochrome P450 family 27 subfamily B member 1; COX2—cyclooxygenase-2; JAK-STAT—Janus kinase/signal transducer and activator of transcription; NF-κB—nuclear factor kappa B; NLRP3—NLR family pyrin-domain-containing 3; p38 MAPK—p38 mitogen-activated protein kinase; RIP1—receptor-interacting protein; RXR—retinoid X receptor; SIRT1—sirtuin 1; STAT 3—signal transducer and activator of transcription 3; TANK—TRAF family member-associated NFKB activator; TLR—Toll-like receptor; TRIF—TIR-domain-containing, adapter-inducing interferon-β; VDR—vitamin D receptor; VDRE—vitamin D response elements.

Figure 3

Anti-oxidant and anti-thrombotic activity of Vitamin D and Resveratrol in COVID-19. Oxidative stress affects platelet function. Adhesion molecules, complements, and procoagulant factors trigger endothelial dysfunction, increased leukocyte and platelet reactivity, and activation of coagulation. Vitamin D/VDR prevents ROS-mediated activation of NLRP3 by Nrf2 translocation to the nucleus, inducing its transcriptional activity for antioxidant enzymes to inhibit oxidative stress. Vitamin D increases the levels of SERPINC1 transcripts and antithrombin. Resveratrol moderates ROS and NOS, inhibits arachidonic acid metabolism and hampers Ca²⁺ entry into platelets. Resveratrol exerts antithrombotic properties by increasing the activity of nitric oxide endothelial synthase (eNOS) and NO levels. Resveratrol-induced NO production results from its direct interaction with SIRT1 and Nrf2. Resveratrol exerts anti-inflammatory effects inhibiting HMGB1-mediated signaling pathway. Abbreviations: Ca²⁺—Calcium ion; eNOS—nitric oxide endothelial synthase; HMGB1—high-mobility group box 1; NET—neutrophil extracellular traps; NLRP3—NLR family pyrin-domain-containing 3; NOS—nitric oxide synthase; Nrf2—nuclear factor erythroid-2-related factor 2; ROS—reactive oxygen species; SERPINC1—serpin family C member 1; VDR—vitamin D receptor.

Figure 4

Schematic representation of the differences between vitamin D and resveratrol in the response to the inflammatory phenomena of COVID-19. Abbreviations: AMPs—adenosine monophosphate; c-maf—c-transcription factor Maf; COX-3—cyclooxygenase-3; GAPDH—glyceraldehyde-3-phosphate dehydrogenase; GATA-3—GATA binding protein 3; HMGB1—high-mobility group box 1; IL—interleukin; MCP—monocyte chemoattractant protein; NE—neutrophil; NET—neutrophil extracellular traps; NF-κB—nuclear factor kappa B; Nrf2—nuclear factor erythroid-2-related factor 2; PAD4—peptidyl arginine deiminase-4; SERPINC1—serpin family C member 1; SIRT1—sirtuin 1; STAT 3—signal transducer and activator of transcription 3; TGFβ1—transforming growth factor beta 1; Th-2—lymphocytes; TLR—Toll-like receptor.