key: cord-0943868-h3h7qtif
authors: Detopoulou, Paraskevi; Demopoulos, Constantinos A.; Antonopoulou, Smaragdi
title: Micronutrients, Phytochemicals and Mediterranean Diet: A Potential Protective Role against COVID-19 through Modulation of PAF Actions and Metabolism
date: 2021-01-30
journal: Nutrients
DOI: 10.3390/nu13020462
sha: ce9409fef96daf968331d77c7ed33e2bcf24b043
doc_id: 943868
cord_uid: h3h7qtif

The new coronavirus disease 2019 (COVID-19) pandemic is an emerging situation with high rates of morbidity and mortality, in the pathophysiology of which inflammation and thrombosis are implicated. The disease is directly connected to the nutritional status of patients and a well-balanced diet is recommended by official sources. Recently, the role of platelet activating factor (PAF) was suggested in the pathogenesis of COVID-19. In the present review several micronutrients (vitamin A, vitamin C, vitamin E, vitamin D, selenium, omega-3 fatty acids, and minerals), phytochemicals and Mediterranean diet compounds with potential anti-COVID activity are presented. We further underline that the well-known anti-inflammatory and anti-thrombotic actions of the investigated nutrients and/or holistic dietary schemes, such as the Mediterranean diet, are also mediated through PAF. In conclusion, there is no single food to prevent coronavirus Although the relationship between PAF and COVID-19 is not robust, a healthy diet containing PAF inhibitors may target both inflammation and thrombosis and prevent the deleterious effects of COVID-19. The next step is the experimental confirmation or not of the PAF-COVID-19 hypothesis.

The new coronavirus disease 2019 pandemic is an emerging situation with high rates of infectivity, morbidity and mortality [1] . The pathophysiology of the disease involves a cytokine storm and the activation of thrombotic pathways [2] . It was recently documented in Wuhan, China, that the disease is directly connected to the nutritional status of severely and critically ill patients [3] . Although "there is no diet to prevent coronavirus" [4] and there are limited applied clinical nutrition protocols for COVID-19 patients [5] [6] [7] , the focus of the international community shifts to recommending a healthy dietary pattern [8] , intended to control inflammation and thrombosis, which accompany the syndromes' complications [2] . Indeed, a well-balanced diet ensures the proper functioning of the immune system [4] and several micro-constituents alone or as part of a healthy dietary pattern, such as the Mediterranean diet, play a role in viral infections [9] , inflammation [10] and thrombosis [11, 12] . A key molecule implicated in COVID-19 pathology is platelet activating factor (PAF), as recently highlighted by our group [2, 13] . More particularly, PAF is a glyceryl-ether phospholipid (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) [14] , which is a potent mediator of inflammation and thrombosis [15, 16] . It is produced by various cells such as platelets, endothelial cells, macrophages, monocytes, neutrophils and other cells continuously or upon inflammatory stimuli [15] . It is noted that the main biosynthetic enzymes of PAF are lyso-PAF-acetyltransferases and dithiothreitol-insensitive CDP-choline: Figure 1 . Protective role of nutrition against COVID-19 through modulation of PAF action metabolism. Figure legend: Various agents activate cells (usually mast cells) and secrete p activating factor (PAF). The produced PAF then affects various target cells (tissue-organs vated target cells, coronavirus 19 binds to PAF receptors (PAFRs) exposed to their pericel membrane, enters these cells more easily and further induces PAF production. The action through inflammasomes, which is not mediated through PAFRs should not be ignored. O the virus can also enter and act on the initially activated cells (usually mast cells) causing known actions. Prolonged and replenished PAF production (feedback control) goes hand with a prolonged inflammatory and prothrombotic response and the characteristic pheno manifestations of COVID-19. PAF inhibitors can act (i) by inactivating PAFRs and (ii) by a PAF metabolism. PAF inhibitors have been found to typically reduce the activity of one o PAF key biosynthetic enzymes (regulatory enzymes) and/or increase the activity of the PA degrading enzyme. The role of antioxidants, micronutrients and phytochemicals that limi initial activation by reducing oxidative stress and/or the production of PAF-like activity c pounds in a non-enzymatic way is also pointed out..

Vitamin C acts as an antioxidant and can boost the immune system [47] . It is in the function and integrity of mucosal cells, the normal functioning of T cells also exerts antimicrobial effects [37] . Vitamin C and concentration is high in le and it is utilized in the case of infection [48] . Vitamin C reduces the risk, the seve the duration of different infectious diseases, its status has been associated with p nia [49] and the supplementation with vitamin C may prevent and treat respira systemic infections [47] . Therapeutic doses of vitamin C (24 gr/day intraveno seven days) are currently being tested in hospitalized COVID-19 patients [7] . H official sources indicate that there is no evidence yet to support intravenous sup of vitamin C in the management of COVID-19 [50] .

In addition, vitamin C decreased markers of thrombosis, such as tissue plas activator and von Willebrand factor in high risk patients with cardiovascular dis . The produced PAF then affects various target cells (tissue-organs). In activated target cells, coronavirus 19 binds to PAF receptors (PAFRs) exposed to their pericellular membrane, enters these cells more easily and further induces PAF production. The action of PAF through inflammasomes, which is not mediated through PAFRs should not be ignored. Of course, the virus can also enter and act on the initially activated cells (usually mast cells) causing its known actions. Prolonged and replenished PAF production (feedback control) goes hand in hand with a prolonged inflammatory and prothrombotic response and the characteristic phenotypic manifestations of COVID-19. PAF inhibitors can act (i) by inactivating PAFRs and (ii) by affecting PAF metabolism. PAF inhibitors have been found to typically reduce the activity of one or both PAF key biosynthetic enzymes (regulatory enzymes) and/or increase the activity of the PAF key degrading enzyme. The role of antioxidants, micronutrients and phytochemicals that limits the initial activation by reducing oxidative stress and/or the production of PAF-like activity compounds in a non-enzymatic way is also pointed out.

Vitamin C acts as an antioxidant and can boost the immune system [47] . It is involved in the function and integrity of mucosal cells, the normal functioning of T cells while it also exerts antimicrobial effects [37] . Vitamin C and concentration is high in leukocytes and it is utilized in the case of infection [48] . Vitamin C reduces the risk, the severity, and the duration of different infectious diseases, its status has been associated with pneumonia [49] and the supplementation with vitamin C may prevent and treat respiratory and systemic infections [47] . Therapeutic doses of vitamin C (24 gr/day intravenously, for seven days) are currently being tested in hospitalized COVID-19 patients [7] . However, official sources indicate that there is no evidence yet to support intravenous super doses of vitamin C in the management of COVID- 19 [50] .

In addition, vitamin C decreased markers of thrombosis, such as tissue plasminogen activator and von Willebrand factor in high risk patients with cardiovascular disease and [54] and its receptor [55] . It is also noted that in frailty, which worsens COVID-19 outcomes [56] the PAF catabolic enzyme Lp-PLA 2 is increased (suggesting its upregulation to counter-balance PAF levels) while anti-oxidant status is decreased (vitamin C, E, α-tocopherol, biological anti-oxidant potential, and total thiol levels) [57] . Vitamin C status could thus affect the inflammatory and micro-thrombotic environment including PAF and the morbidity of COVID-19.

Vitamin D exerts antimicrobial and anti-oxidant effects and supports the immune system against respiratory infection [58] . According to a meta-analysis vitamin D supplementation reduces the risk of acute respiratory infections [59] , has been inversely related to hepatitis viral load [60] and improves antibacterial immunity in HIV-1 patients [61] . An inverse association between mean levels of vitamin D and the number of COVID-19 cases/1 M was recently reported in a cross-sectional European study [62] whereas a UK study did not find an association between the vitamin's status and COVID-19 risk [63] . Moreover, low levels of vitamin D were found in COVID-19 positive patients [64] or hospitalized patients with COVID-19 [65] and have been connected to the severity of the disease. The hypothesis that vitamin D may explain susceptibility to COVID-19 infection in dark colored skin individuals does not seem to be valid [63] . It is noteworthy that several clinical trials are on the way regarding the role of vitamin D in the prevention and treatment of COVID-19, reviewed elsewhere [48] .

In vitro data suggest that 1,25-dihydroxyvitamin D3 reduces the secretion of the catabolic enzyme PAF-AH from placenta macrophages [66] , which implies an interrelation between PAF and the vitamin. Moreover, paricalcitol has an anti-inflammatory and anti-PAF action in hemodialysis patients inhibiting PAF/thrombin-induced platelet aggregation, reducing the activity of PAF biosynthetic enzymes and increasing the activity of the catabolic enzyme of PAF, i.e., PAF-AH [67] . The connection between vitamin D and PAF is further substantiated by the known anti-thrombotic effects of vitamin D [68] .

Vitamin E acts as an antioxidant and has a role in the proper functioning of the immune system [58] . Indeed, it protects cell membranes, including those of immune cells from lipid peroxidation [69] . In cases of influenza infection, the lung levels of vitamin E are reduced [70] , and supplementation with the vitamin reduces the severity and duration of the disease [71, 72] . In the same context, in a meta-analysis of randomized controlled trials vitamin E reduced C-reactive protein (CRP) levels [73] . A combination of vitamin E and C has been recently proposed for ameliorating cardiac injuries of critically ill COVID-19 patients, which furthers underline their role in the COVID-19 disease [74] .

Vitamin E deficiency is connected to increased PAF synthesis in rat polynuclear cells [75] . Moreover, vitamin E inhibits PAF induced platelet aggregation [76] [77] [78] and PAF synthesis [79] . In addition, lycopene alone or in combination with a-tocopherol reduces PAF synthesis in stimulated endothelial cells [80] , which can further blunt the inflammatory cataract. Vitamin E and increased Lp-PLA 2 have been associated with decreased asthma development [81] , and the vitamin may indirectly affect Lp-PLA 2 since it improves LDL quality, in which the enzyme is attached [82] . However, high levels of vitamin E ingested as a supplement (1500 IU for two weeks) seem not to influence the concentration of lyso-PAF [83] . In total, vitamin E can affect PAF levels, metabolism and its actions on platelets, i.e., the pro-thrombotic state.

Selenium has been proposed to potentially play a role in COVID-19 prevention, since in the form of sodium selenite it can oxidize thiol groups in the virus protein disulfide isomerase and thus inhibit the entrance viruses into the cell [84] . It also has an antioxidant role since it is a structural component of glutathione peroxidases, a family of antioxidant enzymes [85] . In parallel, selenoprotein H is involved in redox transcription while selenoprotein K found in the endoplasmic reticulum, is involved in calcium flux in immune cells which is a critical step in immune response [85] . Selenium deficiency is associated with an increase in inflammatory molecules [86] , and selenium supplementation has been found to improve the response against H1N1 virus [87] . In mouse models of asthma there seems to be a reverse-U relation with selenium concentration since too little or too much contributed to asthma attenuation [88] . The relationship selenium and the immune system is further corroborated in hospitalized patients with COVID-19, in which selenium levels were found to be sub-optimal [65] . Moreover, good selenium status, as assessed by the selenium hair content, has been connected to a higher recovery rate from COVID-19 [89] .

The relationship between selenium and PAF can be considered under the prism of the effects of selenium on oxidative stress and phospholipid metabolism. Firstly, the modulation of oxidative stress by selenium could affect PAF metabolism, as for example it deactivates Lp-PLA 2 [23] and increases PAF synthesis [54] . Secondly, selenoprotein I is implicated in phospholipid biosynthesis [85] . Moreover, PAF production is increased in the case of selenium deficiency in endothelial cells [90, 91] possibly through activation of its biosynthetic enzyme lyso-PAF-acetyltransferase [90] . It is noted that the content of diet in selenium did not alter Lp-PLA 2 in rats [92] , while selenium deficiency is associated with arterial thrombosis and selenium seems to decrease platelet aggregation [93] . It can be thus hypothesized that worse outcomes of COVID-19 on the grounds of selenium deficiency may be at least in part attributed to increased PAF and an associated pro-thrombotic state.

Omega-3 fatty acids have anti-inflammatory and anti-thrombotic effects [10] , and they may interfere with virus entry and replication through modulation of lipid rafts [94] . The results from animal studies show that mice with Klebsiella pneumoniae or Streptococcus pneumoniae had an upregulated immune defense and less bacterial burden when fed omega-3 fatty acids [95, 96] . However, it is noted that fish oil-fed mice display impaired resistance to influenza infection [97, 98] denoting a more complex immunomodulating effect of omega-3 fatty acids.

Omega-3 fatty acids also exert antithrombotic effects by various mechanisms including a reduction in thromboxane synthesis [99] and PAF [100, 101] . Omega-3 fatty acids are incorporated in the cell membrane and may regulate the activity of PLA 2 and thus lyso-PAF production, which is a prodrome molecule for PAF production [102] . DHA inhibits PAF increase in cell lines [103] . Moreover, omega-3 can reduce PAF production in Human Umbilical Vein Endothelial Cells (HUVEC) [101] . In cases of endotoxemia, which is also observed in seriously ill COVID-19 patients [104] , linolenic acid has been found to reduce PAF production in Sprague-Dawley rats [105] . In addition, a diet rich in fish oils (10%) has been found to reduce PAF and LTB 4 [106] . As far as PAF enzymes are concerned, a negative association has been documented between the PAF catabolic enzyme Lp-PLA 2 and adipose tissue omega-3 fatty acids [107] while the effects of supplementation did not change the enzyme's activity in healthy adults [108] but decreased the enzyme in volunteers with stable angina [109] and hypertriglyceridemia [110] . It is noted that Lp-PLA 2 , increases as a result of increased PAF in order to catabolize it, thus, the trend for an inverse association of Lp-PLA 2 with omega-3 fatty acids, implies a negative association with PAF. Moreover, results from a cross-sectional study of our group have shown that omega-6 fatty acids were positively correlated with PAF-CPT while no significant correlations were observed with omega-3 fatty acids and PAF or its enzymes [111] .

Zinc plays a role in maintaining the integrity of mucosal cells and antigen response [37] . It has antimicrobial, anti-inflammatory and antioxidant effects [37] . Moreover, it has been Nutrients 2021, 13, 462 6 of 25 found to inhibit the activity and replication of coronavirus (SARS-CoV-1) [112] , and it has a role in interferon-γ production [113] . Zinc deficiency can increase susceptibility to various infections, including those of the respiratory system [114] . Zinc supplementation in mechanically ventilated trauma patients was related to decreased risk of ventilatorassociated pneumonia [115] . Moreover, zinc may mediate the beneficial effects of the chloroquine, a drug which is widely used against COVID-19. Indeed, chloroquine is a zinc ionophore, which increases intracellular Zn 2+ levels [116] .

Copper can prevent oxidative DNA damage and decrease inflammatory markers [37], as it is a part of antioxidant enzymes such as Zn-Cu-superoxide dismutase and ceruloplasmin [117] . Its deficiency is connected with an increased rate of infections [118] , which may be related to its role in T-cell proliferation and Natural Killer (NK) activity [113] . On the other hand, macrophages can attack pathogens with high copper and as a result the concentration of copper may be found increased in lung infection [119] . However, no direct connection to COVID-19 has been identified to date.

Iron participates in the differentiation and growth of epithelial tissue and the production of reactive oxygen species, which combat pathogens [58] . Supplementary iron intake has been found to reduce respiratory infections [120] while pulmonary iron modulation represents a defensive mechanism against various respiratory pathogens [121] . Despite the important role of iron in the immune system, iron-containing enzymes are essential for the replication of coronavirus [122] and the chelation of iron compounds may prove beneficial [37] . Iron can also modulate interferon production [113] .

The interrelation between PAF and zinc, copper and magnesium is not very clear. A low zinc diet reduces platelet aggregation suggesting a role of this nutrient in hemostasis [123] , while zinc and copper chelate complexes have a PAF inhibitory activity mainly attributed to stereochemical interactions [124, 125] . Chelating agents such as Mg 2+ , reduce the activity of PAF biosynthetic enzymes, such as Lyso-PAF-acetyltransferase [126] . The relationship between PAF and copper and iron with has been investigated under the prism of copper and iron induced oxidation of lipids and PAF-related enzymes [23] . It is noted that metal-induced oxidative stress in the presence of superoxide can inactivate PAF acetylhydrolase [127] and thus potentially increase PAF levels. In addition, macrophage responsiveness to PAF is altered by interferon [128] and provides protection against PAF induced injury [129] , which may reflect an indirect connection of some minerals with PAF through interferon.

Phytochemicals, such as polyphenols, act as antioxidants, modulate LDL oxidation [130] , and also exert anti-inflammatory, antiplatelet [131] and antiviral activity [132] . Resveratrol, is an inhibitor of SARS-CoV-1 [133] and curcumin was recently reported to bind to the target receptors of SARS-CoV-2 [134] . In addition, curcumin combined with vitamin C glycyrrhizic acid promotes interferons production and has immunomodulatory properties [135] . Luteolin binds to the surface spike protein of SARS-Cov-2 inhibiting in this way its entry into cells and it is a potential inhibitor of SARS-CoV-2's main protease (SARS-CoV 3CL) [136] . Moreover, lignans exhibit antiviral activity [137] .

With respect to PAF, resveratrol and tyrosol as well as their acetylated derivatives inhibit PAF induced platelet aggregation [138] while curcumin is a PAF inhibitor [139] and plays a role in thrombosis and coagulation [140, 141] . Moreover, curcumin and phenolic compounds acting as antioxidants can modulate LDL oxidation [130] and the subsequent production of PAF and PAF-like lipids [22] . Their effect could be also directly exerted on PAF biosynthetic enzymes as demonstrated by in vitro studies. Indeed, resveratrol and quercetin can inhibit both PAF's main biosynthetic enzymes in vitro [142, 143] , phenolic compounds reduce the activity of PAF biosynthetic enzymes in cell cultures stimulated with IL-1β [144] and flavonoids, have been documented to reduce lyso-PAF acetyltransferase activity [145] . More particularly, pro-anthocyanidins [146] , luteolin [145] , quercetin [80, 147] , hesperidin [147] and naringin [147] reduce the activity of lyso-PAF acetyltransferase in cell lines. Licoricidin and other components were also documented to inhibit lyso-PAF acetyltransferase [148] . Moreover, the antioxidant capacity of the diet, which is at least in part affected by phytochemical intake, was inversely related with PAF levels and the activity of lyso-PAF-acetyltransferase in healthy volunteers as evidenced by our group [34] . In parallel, PAF has been inversely related to antioxidant-rich foods (herbal drinks and coffee) [34] . Lignans, which have been proposed as an anti-COVID compound [137] are also PAF inhibitors [149] . Thus, the effects of flavonoids and other phytochemicals on PAF levels, actions, and its metabolic enzymes generate the hypothesis that their anti-inflammatory and anti-thrombotic actions are at least in part mediated by the PAF circuit.

Interestingly, certain natural flavonoids also have anti-PAF activity, in addition to their anti-inflammatory actions and ability to block coronavirus from binding to target cells [2, 13, 136] .

The Mediterranean diet including olive oil, fish, honey, fruits, vegetables and herbs is rich in polyphenols and other micro-constituents [35] and it has been inversely related to respiratory diseases [150] , inflammation [151] and thrombosis [11, 35] . It is possible that the combination of phytochemicals as those occurring in the Mediterranean diet have amplified actions in comparison to sole compounds [152] . In fact, complex natural product mixtures synergistically target multiple networks involved in inflammatory and thrombosis [152] . The adoption of Mediterranean diet as a whole reduces PAF induced platelet aggregation in patients with 2 diabetes [153, 154] . Moreover, it has been suggested to be a potentially protective diet against COVID-19 [10, 155] . It is noted that the adoption of the Mediterranean Diet decreases length of stay and mortality in hospitalized patients >65 y of age [156, 157] , which is of interest in the era of COVID-19 and the challenges of health systems.

Several natural products which are intrinsic characteristics of the Mediterranean diet such as garlic, salvia and olive oil have been proposed as additional measures for the prevention and treatment of COVID-19 [158] . These and additional Mediterranean foods will be briefly presented and a special reference will be provided on their relation with PAF and its enzymes. It is noted that PAF has been inversely related to a healthy dietary pattern including legumes, vegetables, poultry and fish [34].

Olive oil contains monounsaturated fatty acids and several microconstituents with antioxidant and anti-thrombotic action, such as polyphenols [159] and polar lipids [36]. Its anti-oxidant, anti-inflammatory and anti-thrombotic action render it a candidate food against COVID-19 [158] . It is noted that olive oil polar lipids act as PAF antagonists [36, 160] , and bioactive compounds have also been found in olive oil pomace and its byproducts [161] . From in vitro data it has been shown that olive oil polar lipids inhibit PAF-CPT which is a biosynthetic enzyme for PAF [142] . Moreover, lyso-PAF-AT has been negatively associated with a dietary pattern rich in olive oil and whole-wheat products as documented by our research team [34] . Lastly, the consumption of a yogurt enriched with PAF-inhibitors isolated from olive-oil by-products, led to attenuation of subclinical inflammation and platelet sensitivity to thrombotic stimuli in apparently healthy volunteers [162] .

Fish have anti-inflammatory and anti-thrombotic properties, and they exert beneficial effects in the respiratory tract (see also omega-3 fatty acids) [159] . Indeed, fish has antiaggregatory effects mediated by PAF inhibition [153, 163, 164] attributed to polar lipids, neutral lipids [165] and other lipids, such as gangliosides [166] . Moreover, from in vitro data it has been shown that fish polar lipids inhibit PAF-CPT [142] . Fish polar lipids retard atherosclerosis in rabbits by down-regulating PAF biosynthesis and up-regulating PAF catabolism [167] . Interestingly, the antibacterial properties of fish go hand in hand with their anti-PAF activity, suggesting that PAF antagonists and agonists in fish may also have antibacterial activity [168] .

Detailed nutritional records of Cretan participants of the Seven Countries Study, highlight the presence of honey in their every-day diet [169] and Plato considered honey an essential component of a healthy diet [170] . Indeed, stingless bee honey has been found to inhibit TNF-α, IL-6 and interferon secretion from stimulated macrophages [171] and to reduce inflammation in animal models [172] . Honey has anti-bacterial properties due to its content of phenolic compounds, the production of hydrogen peroxide and other mechanisms such as osmosis [173] . Moreover, it has been suggested to have a role against COVID-19 epidemic [174, 175] , it has six compounds related to the receptor active site of COVID-19's main protease according to a in silico approach [176] and is currently being tested in a clinical trial (clinical trial NCT04323345) [176] . It is noted that honey displays anti-thrombotic activity [177] and it especially acts as a PAF inhibitor [178] . In total, the antibacterial, the anti-thrombotic and anti-PAF effects of honey render it a potentially useful food against the COVID epidemic.

Dairy products constitute a principal source of vitamin D, which has been proposed to play a role in the fight against the COVID-19 epidemic [179] [180] [181] . It is noted that milk, yogurt and fermented milk products also contain PAF inhibitors [182] [183] [184] , with goat yogurt presenting a more protective effect [185] .

Plant foods with antiviral properties have been recently reviewed as anti-COVID agents, as they prevent viral replication, enhance antibody production against influenza virus, and improve T-cell function [159] . A recent work reported the inhibition of COVID-19 with the use of molecular docking by plant terpenoids, such as Ginkgolide A [186] , which is also one of the most potent PAF inhibitors [187] . Garlic and onion which are also used in many recipes of the Mediterranean diet [188] also contain PAF inhibitors [189, 190] . Moreover, wild greens, which are rich in polyphenols have a postprandial anti-PAF effect [191] . Rice (Oryza sativa L.), traditionally used in several Mediterranean meals [188] may also be implicated in COVID-19, since rice bran policosanol extract has anti-aggregatory activity (although studies have researched only ADP-induced platelet aggregation and not PAF as an aggregatory agent) [192] . In addition, rice policosanol has been found to activate the nuclear factor erythroid 2-related factor 2 (Nrf-2) pathway [193] , a molecular pathway playing a role in combating COVID-19 [194] , which can also modulate PAF-acetylhydrolase transcription [195] .

Although wine is not recommended by national bodies as a means to fight coronavirus [8], the Mediterranean way of living and eating incorporates moderate wine consumption in its philosophy. A Mediterranean diet with moderate wine quantities could affect the pro-thrombotic status [196] and possibly the body's response to a virus. As it has been documented by our group wine consumption reduces PAF-induced platelet aggregation [197] and specific wine varieties affect PAF biosynthetic enzymes [198] in the postprandial state. Moreover, several bioactive lipids have been isolated from wines that exhibit anti-PAF biological activity [199] [200] [201] [202] and reduce the activity of its biosynthetic enzymes in monocytes [143] . Last but not least, bioactive compounds with anti-aggregatory have been also isolated from grape pomace extracts [203] , which may render winery by-products useful for the production of functional foods. [198] Wine (Robola, Cabernet Sauvignon) acute n = 10 31.3 ± 4.3 Healthy ↓ [197] Beer or alcohol-free 3 weeks n = 11 lean n = 9 overweight 19 ± 2 21 ± 2 Healthy no changes [227] Others Yogurt with bioactive ingredients from olive-oil by-products 8 weeks n = 92 35-65 Healthy ↓ [162] * Results from the same study (ANCHOR study). ↓: reduction; ↑: increase; EPA: Eicosapentaenoic acid; DHA: Docosahexaenoic acid; CRP: C-reactive protein; ALA: alpha-linolenic acid; AT:acetyltransferase, CPT: cholinephosphotransferase. 

The hypothesis of the protective effect of the Mediterranean Diet against COVID-19 should be regarded in parallel with epidemiological data. It can be argued that several Mediterranean countries, such as Italy and Spain had a high burden of the disease. It is difficult to make a safe assumption since the adherence of Southern European Mediterranean countries to the Mediterranean diet is generally considered rather moderate [228] . However, the adoption of the Mediterranean diet is lower in northern Italy than in the south of the country, which may in part explain the observed situation in Italy [229] .

Moreover, dietary changes in the quarantine may account for some differences, since limited access to fresh foods may be observed, in favor of packaged foods, which have a longer shelf life. Indeed, in Italy, 37.3% of respondents changed their diet and physical activity levels but only 16.7% of them improved their habits [230] . Italian adolescents increased their intake of legumes, fruit, sweets, and fast food during quarantine and had no change in vegetables intake, while Spanish adolescents and the general population displayed more healthy changes in their diet [231, 232] .

In contrast, preliminary results from the COVIdiet in Greece, presented at the Webinar held by the Hellenic Dietetic Association have shown that participants improved their eating habits and reduced their consumption of fast food, especially those who were already more aware of the importance of a healthy diet. However, cooking increased, and the preparation and consumption of homemade sweets and pastries also increased increased [233] .

In conclusion, there is no single food to prevent, heal, or treat coronavirus. Although the relationship between PAF and COVID-19 is not robust, a healthy diet containing PAF inhibitors may target both inflammation and thrombosis and prevent the deleterious effects of COVID-19. After completing our theoretical new approach on PAF and COVID-19, the next step is the experimental confirmation or not of the PAF-COVID-19 hypothesis. 

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Association between regional selenium status and reported outcome of COVID-19 cases in China

Selenium modulates 1-O-Alkyl-2-Acetyl-sn-Glycero-3-Phosphocholine (PAF) Biosynthesis in bovine aortic endothelial cells

Selenium deficiency inhibits prostacyclin release and enhances production of platelet activating factor by human endothelial cells

Studies on HDL associated enzymes under experimental hypercholesterolemia: Possible modulation on selenium supplementation

Effects of sodium selenite on in vitro interactions between platelets and endothelial cells

May omega-3 fatty acid dietary supplementation help reduce severe complications in Covid-19 patients?

Dietary supplementation with omega-3 polyunsaturated fatty acids ameliorates acute pneumonia induced by Klebsiella pneumoniaein BALB/c mice

Omega-3 fatty acids in contrast to omega-6 protect against pneumococcal pneumonia

Fish oil-fed mice have impaired resistance to influenza infection

Fish Oil feeding delays influenza virus clearance and impairs production of interferon-γ and virus-specific Immunoglobulin A in the Lungs of mice

Fatty acids and TxA2 generation, in the absence of platelet-COX-1 activity

Possible mechanisms for the differential effects of high linoleate safflower oil and high α-linolenate perilla oil diets on platelet-activating factor production by rat polymorphonuclear leukocytes

ω-3 Fatty acids suppress monocyte adhesion to human endothelial cells: Role of endothelial PAF generation

Effect of docosahexaenoic acid on the generation of platelet-activating factor by eosinophilic leukemia cells, Eol-1

Docosahexaenoic acid inhibits PAF and LTD4 stimulated [Ca2+]iincrease in differentiated monocytic U937 cells

Endotoxemia and circulating bacteriome in severe COVID-19 patients

Dietary α-linolenate suppresses endotoxin-induced platelet-activating factor production in rat kidney

The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the generation of platelet-activating factor and leukotriene B4 in hypoxic-ischemic brain in young mice

Lipoprotein-associated phospholipase A2 concentrations in plasma are associated with the extent of coronary artery disease and correlate to adipose tissue levels of marine n-3 fatty acids

The effect of marine n-3 fatty acids in different doses on plasma concentrations of Lp-PLA2 in healthy adults

Polyunsaturated omega-3 fatty acids reduce lipoprotein-associated phospholipase A2 in patients with stable angina

Dose-response effects of marine omega-3 fatty acids on apolipoproteins, apolipoprotein-defined lipoprotein subclasses, and Lp-PLA2 in individuals with moderate hypertriglyceridemia

Associations between red blood cells fatty acids, desaturases and metabolism of Platelet Activating Factor in healthy volunteers

Zn2+ Inhibits coronavirus and arterivirus RNA Polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture

A review of micronutrients and the immune system-working in harmony to reduce the risk of infection

Zinc and the risk for infectious disease

Zinc supplementation in adult mechanically ventilated trauma patients is associated with decreased occurrence of ventilator-associated pneumonia: A secondary analysis of a prospective, observational study

Chloroquine is a zinc ionophore

Is copper an antioxidant nutrient?

The immune system as a physiological indicator of marginal copper status?

The Yin and Yang of copper during infection

Iron supplementation improves iron status and reduces morbidity in children with or without upper respiratory tract infections: A randomized controlled study in Colombo, Sri Lanka

Iron homeostasis in the lungs-a balance between health and disease

Depriving Iron supply to the virus represents a promising adjuvant therapeutic against viral survival

Zinc homeostasis in platelet-related diseases

Structurally diverse metal coordination compounds, bearing imidodiphosphinate and diphosphinoamine ligands, as potential inhibitors of the platelet activating factor

A Review on platelet activating factor inhibitors: Could a new class of potent metal-based anti-inflammatory drugs induce anticancer properties?

Enzymatic synthesis of 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine, a hypotensive and platelet-aggregating lipid

Oxygen radicals inhibit human plasma acetylhydrolase, the enzyme that catabolizes platelet-activating factor

Alteration of Macrophage responsiveness to platelet-activating factor by interferon-γ and lipopolysaccharide

Protection against platelet-activating factor-induced injury by interferon inducer in perfused rabbit lung

Effects of postprandial hydroxytyrosol and derivates on oxidation of LDL, cardiometabolic state and gene expression

Role of polyphenols and other phytochemicals on molecular signaling

Antiviral properties of the natural polyphenols delphinidin and epigallocatechin gallate against the flaviviruses west nile virus, zika virus, and dengue virus

Effective inhibition of MERS-CoV infection by resveratrol

Revealing the Potency of Citrus and Galangal Constituents to Halt SARS-CoV-2 Infection

A Novel combination of vitamin c, curcumin and glycyrrhizic acid potentially regulates immune and inflammatory response associated with coronavirus infections: A Perspective from system biology analysis

COVID-19, pulmonary mast cells, cytokine storms, and beneficial actions of luteolin

Challenges at the Time of COVID-19: Opportunities and Innovations in antivirals from nature

Biological activity of acetylated phenolic compounds

Inhibitory effect of curcumin, a food spice from turmeric, on platelet-activating factor-and arachidonic acid-mediated platelet aggregation through inhibition of thromboxane formation and Ca2+ signaling

Curcumin, hemostasis, thrombosis, and coagulation

Role and application of curcumin as an alternative therapeutic agent

Characterization of the de novo biosynthetic enzyme of platelet activating factor, ddt-insensitive cholinephosphotransferase, of human mesangial cells

Effect of robola and cabernet sauvignon extracts on platelet activating factor enzymes activity on U937 cells

Platelet activating factor (PAF) biosynthesis is inhibited by phenolic compounds in U-937 cells under inflammatory conditions

Inhibition of lyso PAF acetyltransferase activity by flavonoids

Dual Inhibitory activities of tannins from Hamamelis virginiana and related polyphenols on 5-Lipoxygenase and Lyso-PAF: Acetyl-CoA acetyltransferase1

Modulation by flavonoids of PAF and related phospholipids in endothelial cells during oxidative stress

Inhibition of LysoPAF Acetyltransferase activity by components of licorice root

Chemical and biochemical characterization of lignan analogs as novel PAF receptor antagonists

Diet and asthma: Is it time to adapt our message? Nutrients

Adherence to Mediterranean diet and 10-year incidence (2002-2012) of diabetes: Correlations with inflammatory and oxidative stress biomarkers in the ATTICA cohort study

The role of adaptogens in prophylaxis and treatment of viral respiratory infections

Effect of Traditional greek mediterranean meals on platelet aggregation in normal subjects and in patients with type 2 diabetes mellitus

Effect of fast-food Mediterranean-type diet on type 2 diabetics and healthy human subjects' platelet aggregation

Mediterranean Diet and COVID-19: Hypothesizing Potential benefits in people with diabetes. Front. Endocrinol. 2020, 11

Effects of Mediterranean diet on hospital length of stay, medical expenses, and mortality in elderly, hospitalized patients: A 2-year observational study

Adherence to Mediterranean diet, malnutrition, length of stay and mortality in elderly patients hospitalized in internal medicine wards

Exploitation of some natural products for prevention and/or nutritional treatment of SARS-CoV2 infection

Antiviral functional foods and exercise lifestyle prevention of coronavirus

Antithrombotic lipid minor constituents from vegetable oils. comparison between olive oils and others

Bioactive polar lipids in olive oil, pomace and waste byproducts

Lipid fractions with aggregatory and antiaggregatory activity toward platelets in fresh and fried cod (Gadus morhua): Correlation with platelet-activating factor and atherogenesis

Zabetakis, I. Comparison of antiatherogenic properties of lipids obtained from wild and cultured sea bass (Dicentrarchus labrax) and gilthead sea bream (Sparus aurata)

Antiatherogenic properties of lipid fractions of raw and fried fish

Identification and Study of gangliosides from Scomber scombrus muscle

Zabetakis, I. Fish polar lipids retard atherosclerosis in rabbits by down-regulating PAF biosynthesis and up-regulating PAF catabolism

Zabetakis, I. Antibacterial and anti-PAF activity of lipid extracts from sea bass (Dicentrarchus labrax) and gilthead sea bream (Sparus aurata)

Mediterranean Diet of Crete

Dietetics in ancient Greek philosophy: Plato's concepts of healthy diet

Investigation of phenolic compounds, antioxidant and anti-inflammatory activities in stingless bee honey (Meliponinae)

Stingless bee honey protects against lipopolysaccharide induced-chronic subclinical systemic inflammation and oxidative stress by modulating Nrf2, NF-κB and p38 MAPK

Antimicrobial activity and rutin identification of honey produced by the stingless bee Melipona compressipes manaosensis and commercial honey

Anti-inflammatory properties of stingless bee honey may reduce the severity of pulmonary manifestations in COVID-19 Infections. Malays

Prospects of honey in fighting against COVID-19: Pharmacological insights and therapeutic promises

Silico approach of some selected honey constituents as sars-cov-2 main protease (COVID-19) inhibitors

Effect of natural honey on human platelets and blood coagulation proteins

PAF antagonists in food: Isolation and identification of PAF antagonists in honey and wax

Association of vitamin D with the modulation of the disease severity in COVID-19

Vitamin D Insufficiency is prevalent in severe Covid-19

Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID-19 are associated with greater disease severity

Platelet-Activating factor (PAF) Antagonists in foods: A study of lipids with paf or anti-paf-like activity in cow's milk and yogurt

Zabetakis, I. Yoghurt fermentation alters the composition and antiplatelet properties of milk polar lipids

Zabetakis, I. The effect of ovine milk fermentation on the antithrombotic properties of polar lipids

Evaluation of sensory and in vitro antithrombotic properties of traditional Greek yogurts derived from different types of milk

Molecular Docking Study of Novel COVID-19 Protease with Low Risk Terpenoides Compounds of Plants

Effects of ginkgolide A, B and K on platelet aggregation

Macronutrient content and food exchanges for 48 Greek Mediterranean dishes

Inhibition of platelet aggregation by onion extracts

Inhibitory effect of sulfur-containing compounds in Scorodocarpus borneensis Becc. on the Aggregation of rabbit platelets

Mediterranean wild plants reduce postprandial platelet aggregation in patients with metabolic syndrome

Modulation of platelet functions by crude rice (Oryza sativa) bran policosanol extract

γ-Oryzanol improves cognitive function and modulates hippocampal proteome in mice

Nrf2-interacting nutrients and COVID-19: Time for research to develop adaptation strategies

The Nrf2/ARE Pathway: A Promising target to counteract mitochondrial dysfunction in parkinson's disease. Park

The French paradox three decades later: Role of inflammation and thrombosis

Wine consumption reduced postprandial platelet sensitivity against platelet activating factor in healthy men

Postprandial effects of wine consumption on platelet activating factor metabolic enzymes

Biologically active lipids with antiatherogenic properties from white wine and must

Separation of biologically active lipids from red wine

Biological activity of total lipids from red and white wine/must

Structure elucidation of phenolic compounds from red/white wine with antiatherogenic properties

Evaluation of anti-platelet activity of grape pomace extracts

Interactions between dietary fat, fish, and fish oils and their effects on platelet function in men at risk of cardiovascular disease

A double-blind, randomized, placebo-controlled trial of n-3 fatty acid based lipid infusion in acute, extended guttate psoriasis

Consumption of plant extract supplement reduces platelet activating factor-induced platelet aggregation and increases platelet activating factor catabolism: A randomised, doubleblind and placebo-controlled trial

Effect of a ginkgolide mixture (bn 52063) in antagonising skin and platelet responses to platelet activating factor in man

Icosapent ethyl reduces atherogenic markers in high-risk statin-treated patients with stage 3 chronic kidney disease and high triglycerides

Effects of icosapent ethyl on lipid and inflammatory parameters in patients with diabetes mellitus-2, residual elevated triglycerides (200-500 mg/dL), and on statin therapy at LDL-C goal: The ANCHOR study

Effects of purified eicosapentaenoic acid and docosahexaenoic acid on platelet, fibrinolytic and vascular function in hypertensive type 2 diabetic patients

Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: The Epanova for lowering very high triglycerides (EVOLVE) trial

Usefulness of icosapent ethyl (eicosapentaenoic acid ethyl ester) in women to lower triglyceride levels (results from the marine and anchor trials)

Effects of omega-3 fatty acids on arterial stiffness in patients with hypertension: A randomized pilot study

intensive lifestyle modification reduces Lp-PLA2 in dyslipidemic HIV/HAART patients

Replacing with whole grains and legumes reduces Lp-PLA2 activities in plasma and PBMCs in patients with prediabetes or T2D

Effects of garlic extract on platelet aggregation: A randomized placebo-controlled double-blind study

Effects of eicosapentaenoic acid and docosahexaenoic acid on cardiovascular disease risk factors: A randomized clinical trial

Effects of prescription omega-3-acid ethyl esters, coadministered with atorvastatin, on circulating levels of lipoprotein particles, apolipoprotein CIII, and lipoprotein-associated phospholipase A2 mass in men and women with mixed dyslipidemia

Eicosapentaenoic acid ethyl ester (amr101) therapy in patients with very high triglyceride levels (from the multi-center, placebo-controlled, randomized, double-blind, 12-week study with an open-label extension [marine] trial)

Effects of omega-3 carboxylic acids on lipoprotein particles and other cardiovascular risk markers in high-risk statin-treated patients with residual hypertriglyceridemia: A randomized, controlled, double-blind trial

N-3 PUFA Esterified to glycerol or as ethyl esters reduce non-fasting plasma triacylglycerol in subjects with hypertriglyceridemia: A randomized trial

Seeger, W. ω-3 vs. ω-6 lipid emulsions exert differential influence on neutrophils in septic shock patients: Impact on plasma fatty acids and lipid mediator generation

Vitamin D Improves selected metabolic parameters but not neuropsychological or quality of life indices in osa: A Pilot Study

Plasma lipid levels and platelet and neutrophil function in patients with vascular disease following fish oil and olive oil supplementation

Efficacy and safety of eicosapentaenoic acid ethyl ester (amr101) therapy in statin-treated patients with persistent high triglycerides (from the anchor study)

Effects of icosapent ethyl (eicosapentaenoic acid ethyl ester) on atherogenic lipid/lipoprotein, apolipoprotein, and inflammatory parameters in patients with elevated high-sensitivity c-reactive protein (from the anchor study)

Moderate alcohol consumption and lipoprotein-associated phospholipase A2 activity

Exploring the Validity of the 14-Item Mediterranean Diet Adherence Screener (MEDAS): A Cross-National Study in Seven European Countries around the Mediterranean Region

Trends in adherence to the Mediterranean diet in an Italian population between 1991 and 2006

Eating habits and lifestyle changes during COVID-19 lockdown: An Italian survey

Covid-19 Confinement and Changes of Adolescent's Dietary Trends in Italy

Changes in dietary behaviours during the COVID-19 Outbreak Confinement in the Spanish COVIDiet Study

PRESS RELEASE-The Role of Nutrition in the COVID-19 Era