key: cord-0696429-joyogk0u
authors: McCarty, Mark F.; Iloki Assanga, Simon Bernard; Lewis Luján, Lidianys; O’Keefe, James H.; DiNicolantonio, James J.
title: Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond
date: 2020-12-25
journal: Nutrients
DOI: 10.3390/nu13010047
sha: 690fc74984dd0e0f64981e0ab208af85eb91c511
doc_id: 696429
cord_uid: joyogk0u

Inflammasomes are intracellular protein complexes that form in response to a variety of stress signals and that serve to catalyze the proteolytic conversion of pro-interleukin-1β and pro-interleukin-18 to active interleukin-1β and interleukin-18, central mediators of the inflammatory response; inflammasomes can also promote a type of cell death known as pyroptosis. The NLRP3 inflammasome has received the most study and plays an important pathogenic role in a vast range of pathologies associated with inflammation—including atherosclerosis, myocardial infarction, the complications of diabetes, neurological and autoimmune disorders, dry macular degeneration, gout, and the cytokine storm phase of COVID-19. A consideration of the molecular biology underlying inflammasome priming and activation enables the prediction that a range of nutraceuticals may have clinical potential for suppressing inflammasome activity—antioxidants including phycocyanobilin, phase 2 inducers, melatonin, and N-acetylcysteine, the AMPK activator berberine, glucosamine, zinc, and various nutraceuticals that support generation of hydrogen sulfide. Complex nutraceuticals or functional foods featuring a number of these agents may find utility in the prevention and control of a wide range of medical disorders.

Inflammasomes are protein complexes that assemble in response to certain proinflammatory signals and induce the self-activation of caspase-1; this protease, in turn, cleaves pro-interleukin-1β and pro-interleukin-18 to generate the active forms of these mediators, which exert a crucial pro-inflammatory and pro-apoptotic effect in many pathologies [1, 2] . Inflammasomes can also induce a type of cell death known as pyroptosis; this results from caspase-1-mediated cleavage of the protein Gasdermin-D, which subsequently forms a pore in the plasma membrane that enables extracellular efflux of cytokines such as interleukin-1β, and that also can also induce cell swelling and death [3] . A range of different types of inflammasomes have been characterized; these include the NLR-subset (NLRP1, NLRP3, NAIP/NLRC4), as well as the AIM2 and IFI16 inflammasomes [4] . This review focuses on the NLRP3 inflammasome, which has received by far the most study.

Interleukin-1β plays a mediating role in atherosclerosis, myocardial infarction, and heart failure; a phase III study of the monoclonal antibody canakinumab that targets this cytokine found that, in patients who had previously experienced a myocardial infarct and had elevated plasma C-reactive protein, canakinumab administration significantly lowers risk for a subsequent Myocardial infarction (MI) [5, 6] . With respect to interleukin- 18, evidence suggests that this is a crucial driver of the retinal pigment cell apoptosis responsible for the untreatable dry form of age-related macular degeneration [7] [8] [9] . Inflammasomes are suspected to play a pathogenic role in the complications of diabetes, in a host of neurodegenerative disorders, in autoimmune disorders including rheumatoid arthritis, and in periodontal disease [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] . Inflammasomes contribute to the pathogenesis of chronic skin disorders such as psoriasis and acne [20] [21] [22] [23] . They have also been linked to asthma and allergic inflammation [24] [25] [26] [27] . And inflammasomes are mediators of certain acute inflammatory conditions, such as gout and the respiratory distress syndrome associated with the late stage of certain viral lung infections, including COVID-19 [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] . Hence, feasible measures that could prevent inflammasome activation-most particularly, safe nutraceutical measures-might be of considerable value in preventive and therapeutic medicine.

The NLRP3 inflammasome consists of the protein NLRP3 complexed with the proteins ASC and caspase-1, along with several accessory proteins, including NEK7 [39] . Formation of NLRP3 inflammasomes typically requires a priming step, in which the activated transcription factor Nuclear factor kappa beta (NF-kappaB) drives increased expression of NLRP3 and of pro-interleukin-1β and -18. Subsequent activation of NLRP3 inflammasomes, in which the NLRP3/ASC/caspase-1 complex assembles, is typically triggered by oxidative stress, a drop in intracellular potassium, and/or a disruption of lysosomes, which release cathepsins [40, 41] .

The role of oxidative stress in triggering NLRP3 inflammasome assembly is well characterized. This assembly requires an interaction between thioredoxin interacting protein (TXNIP) with NLRP3 [42, 43] . However, much of the cellular pool of TXNIP is tied up in covalent complexes with thioredoxin. When thioredoxin is in its usual reduced configuration, its C32 can nucleophilically attack a disulfide in TXNIP, forming a disulfide bond linking thioredoxin with TXNIP; in this configuration, TXNIP is incapable of interacting with NLRP3 [44, 45] . However, when cellular oxidant production accelerates, this disulfide bond is broken as thioredoxin assumes its oxidized configuration with a C32-C35 disulfide. Indeed, the cellular pool of thioredoxin is converted to this configuration as thioredoxin is employed to reduce other oxidized cellular proteins. Reconverting thioredoxin to its reduced form is the task of thioredoxin reductase, which employs NADPH as a reductant [46] . Hence, oxidative stress tends to free up TXNIP so that it can interact with NLRP3, whereas efficient thioredoxin reductase activity helps to maintain thioredoxin in a reduced state so that it can bind TXNIP, thereby preventing inflammasome activation.

The role of plummeting intracellular potassium in the assembly of NLRP3 inflammasomes is still poorly understood at the molecular level, but the phenomenon is well established [1, 47] . Potassium depletion is necessary for the kinase NEK7 to bind to NLRP3, an essential step in inflammasome formation [48] . A key mediator of cellular potassium depletion in many circumstances is the P2X7 receptor (P2X7R), whose natural agonist is extracellular ATP. During inflammation and cell damage, ATP is often released to the extracellular space, where it can interact with P2X7R. The activation of this receptor leads to the formation of a pore in the plasma membrane, which allows potassium to stream out, and calcium to stream in [49-51]. Activated P2X7R not only promotes the potassium depletion required for inflammasome formation, but also can stimulate generation of oxidative stress via NADPH oxidase activation and it has an adverse impact on mitochondrial function [52] [53] [54] [55] .

The role of lysosomal destabilization in inflammasome formation is likewise only sketchily understood. Exposure of cells to certain pathogenic crystals or particulatesincluding monosodium urate crystals and silica-can induce low-level permeabilization of lysosomes that somehow triggers potassium efflux [56] . In addition, extra-lysosomal cathepsin B physically interacts with NLPR3 on the endoplasmic reticulum membrane, prior to the association of NLPR3 with ASC; this interaction may be of mechanistic importance, as knockout of cathepsin B impairs inflammasome activation induced by a range of mediators [57] .

This concise sketch of inflammasome activation enables us to deduce that certain measures would tend to block inflammasome formation-among them: inhibition of NF-kappaB activation; up-regulated expression of thioredoxin and of thioredoxin reductase; down-regulated expression of TXNIP; inhibition of the generation of superoxide, most particularly that produced by NADPH oxidase complexes; and boosting the expression of enzymes that catabolize hydrogen peroxide. Fortuitously, certain nutraceuticals have the potential to accomplish these aims.

Phase 2 inducers are agents that trigger the increased expression of a wide range of antioxidant, detoxifying, and cytoprotective enzymes [58] . Many of them accomplish this by interacting covalently with cysteine groups of Keap1, a protein that binds to the transcription factor nrf2, retaining it in the cytoplasm and promoting its proteasomal degradation [59, 60] . When phase 2 inducers-or their electrophilic metabolites-bind to Keap1, nrf2 is freed up to migrate to the nucleus and promote the transcription of many cytoprotective enzymes, the promoters of whose genes contain antioxidant response elements capable of binding nrf2. Of key importance to our discussion is the fact that phase 2 induction boosts the expression of both thioredoxin and thioredoxin reductase, as well as that of glutathione peroxidase, capable of eliminating hydrogen peroxide [61-65]. Nutraceutical phase 2 inducers that have shown important clinical utility include lipoic acid, ferulic acid, melatonin, and sulforaphane [66] [67] [68] [69] [70] [71] [72] [73] [74] .

Whereas ferulic acid clearly stimulates nrf2-driven transcription, it is not clear that it interacts with Keap1; hence, its activity may be complementary to that of phase 2 inducers that do bind Keap1. Ferulic acid is of particular interest in light of the fact that, in addition to its phase 2 activity, it possesses a still poorly understood anti-inflammatory action that in many pro-inflammatory circumstances tends to suppress NF-kappaB activity [75] . In other words, it has potential for influencing both the NF-kappaB-dependent priming phase of inflammasome formation, as well as the activation phase. Ferulic acid's anti-inflammatory effect is still imperfectly understood, but may reflect reduced expression and/or diminished activity of the coupling factor MyD88, a key mediator in many pro-inflammatory signaling pathways that activate NF-kappaB and the stress-induced MAP kinases [75] [76] [77] . Not surprisingly, ferulic acid has been found to suppress NLRP3-dependent inflammasome formation in various cellular models and in rodents [78] [79] [80] [81] [82] [83] . Ferulic acid has good oral bioavailability and, as with sodium ferulate, has long been used in cardiovascular medicine in China [84] . Whereas its properties have been broadly explored in pre-clinical studies, its impacts as a nutraceutical have received minimal study to date. However, one recent controlled clinical study found that oral administration of ferulic acid (500 mg twice daily) decreased serum C-reactive protein by about a third in hyperlipidemic subjects-evidently indicative of significant systemic anti-inflammatory potential [85] . Ferulic acid, often in conjugated forms, is one of the most widely distributed of phytochemicals in foods; gut bacteria can convert anthocyanins to this compound, and ferulic acid may be the primary mediator of the health benefits associated with anthocyanin ingestion-as intact anthocyanins are barely absorbed [75] .

The tryptophan-derived hormone melatonin-often viewed as a nutraceutical insomuch as it can be administered orally and is sold in capsule form over-the-counterhas phase 2 activity that appears to reflect up-regulation of nrf2 at the transcriptional level [86] [87] [88] . This may reflect the fact that the promoter of the nrf2 gene contains E boxes that bind the "clock" transcription factor Bmal1, in conjunction with the protein Clock, and this drives nrf2 transcription [89, 90] . The expression of Bmal1 and other so-called clock genes varies with a diurnal rhythm in many types of cells; a nocturnal surge of melatonin produced by the pineal gland somehow functions to coordinate this diurnal variation with light/dark cycles [91, 92] . Bmal1 is the key driver of the diurnal cycles of clock genes, and melatonin appears to boost the amplitude of its cyclic expression, possibly by enhancing the activity of the RORα transcription factor that drives its transcription [93, 94] . Studies have found that melatonin loses its protective antioxidant/anti-inflammatory properties when RORα expression is blocked [95] [96] [97] . Nonetheless, the initial notion that melatonin acts as a direct agonist for RORα has been disproved. The molecular biology underlying melatonin's up-regulatory impact on RORα activity remains obscure, though this presumably reflects signaling transmitted by the melatonin membrane receptors MT1 and MT2, which are seven-pass receptors coupled to heterotrimeric G proteins [94, 98] . One intriguing study has provided evidence that melatonin boosts the nuclear importation of RORα, which would be expected to amplify its activity as a transcription factor [95] . The observation that melatonin concurrently boosts RORα mRNA could be explained by the fact that RORα promotes transcription of the gene encoding Bmal1, which in turn drives transcription of the RORα gene.

Like ferulic acid, melatonin has an effect independent of phase 2 induction that suppresses NF-kappa activation in many circumstances [99] [100] [101] . This may reflect the fact that Bmal1, whose expression melatonin boosts, binds to the promoter of the sirt1 gene and drives its transcription; sirt1 activity opposes NF-kappaB activity by de-acetylating p65 [95, 102, 103] . In combination with phase 2 induction, this makes melatonin particularly promising as an agent for down-regulating inflammasome activity, opposing both priming and activation steps. Indeed, a great many studies in cells cultures or rodents have shown that melatonin can suppress the activation of NLRP3 inflammasomes [104] [105] [106] .

Several phase 2-inducible enzymes required for disposing of hydrogen peroxide and maintaining thioredoxin in a reduced state-including glutathione peroxidase and thioredoxin reductase-are selenium-dependent [107] . Hence, assuring adequate selenium status may help prevent inflammasome overactivity in regions where soil selenium and dietary selenium intakes are low. Selenium status has been shown to modulate NLRP3dependent inflammasome activity in mice [108] .

The superoxide production that triggers inflammasome activation is often attributable in large part to NADPH oxidase complexes [109] [110] [111] [112] [113] [114] [115] [116] [117] [118] . Moreover, oxidants generated by these complexes often play a co-factor role in signaling pathways that activate NF-kappaB, possibly by expediting the assembly of certain protein signaling complexes [119, 120] . The enzyme heme oxygenase-1 (HO-1) exerts its antioxidant effects in large part by generating intracellular free bilirubin via degradation of free heme; bilirubin has been shown to inhibit certain NADPH oxidase complexes in physiological intracellular concentrations [121] [122] [123] [124] [125] [126] . Although the isoform specificity of this effect has not yet been adequately explored, NOX2 and NOX4 appear to be susceptible to bilirubin-mediated inhibition. A recent study reports that physiological levels of free bilirubin can inhibit activation of both inflammasomes and NF-kappaB in lipopolysaccharide (LPS)-treated macrophages [127] . Moreover, in a mouse model of LPS-induced septic shock, bilirubin injection reduces production of IL-1βand TNF-a, while enhancing survival [127] .

Although bilirubin is too insoluble for oral administration, and its more soluble precursor biliverdin is an extremely expensive fine chemical, cyanobacteria (such as spirulina) as well as certain blue-green algae are very rich sources of the biliverdin derivative phycocyanobilin (PhyCB), which within cells is rapidly reduced to the bilirubin homolog phycocyanorubin; the latter appears to share bilirubin's capacity to inhibit NADPH oxidase complexes [128] [129] [130] . This phenomenon likely explains the profound and versatile antioxidant and anti-inflammatory effects of orally administered spirulina (or of the spirulina protein phycocyanin, which contains PhyCB as a covalently-attached chromophore) observed in rodent models of numerous human disorders [129, 131, 132] . Hence, oral administration of spirulina-or of spirulina extracts enriched in PhyCB-may have clinical potential for suppressing both the priming and activation of inflammasomes. This proposition is supported by recent cell culture and rodent studies [133, 134] .

PhyCB might also have potential for countering the downstream effects of inflammasome activation that are mediated by IL-1β, as endosomal activation of NOX2 has been reported to play a catalytic role in IL-1β signaling [120] . Whether this might be pertinent to IL-18 is not clear.

Expression of TXNIP is susceptible to suppression by AMP-activated kinase (AMPK) activity. A possible explanation for this is that AMPK can interfere with the activity of a transcription factor-the carbohydrate response element-binding protein (ChREBP)which is a key transcriptional activator of TXNIP expression. AMPK can phosphorylate this protein on serine-568; this impairs the ability of ChREBP to bind to DNA via its characteristic response elements. The contribution of ChREBP to transcription of the TXNIP gene is heightened in the context of hyperglycemia, which boosts ChREBP activity. There is also some evidence that, at least in certain contexts, AMPK can accelerate the proteasomal degradation of TXNIP. AMPK activation may also oppose inflammasome activation via activation of the deacetylase Sirt1, which has been shown to inhibit inflammasome assembly in several types of cells [135] [136] [137] [138] [139] [140] [141] . Sirt1 activity could be expected to inhibit inflammasome priming by suppressing the transcriptional activity of NF-kappaB, but additional mechanisms may be at play [142, 143] .

As is well known, the diabetes drug metformin exerts its metabolic benefits via AMPK activity. Also useful in this regard is the nutraceutical berberine, a compound found in many herbs used traditionally in Chinese medicine. Indeed, berberine is commonly employed in China for the management of type 2 diabetes. Unlike metformin, it also has the ability to lower elevated LDL cholesterol by prolonging the half-life of the mRNA coding for the hepatic LDL receptor [144] [145] [146] . In many cell culture and rodent models, berberine administration has been shown to suppress NLRP3 inflammasome formation [147] [148] [149] [150] [151] [152] .

Pre-incubation with millimolar concentrations of glucosamine has recently been reported to suppress inflammasome activation in human and mouse macrophages primed with LPS and then activated with either ATP or nigericin (a potassium ionophore) [55] . The inhibitory effect of glucosamine on activation was associated with a failure of the inflammasome accessory proteins PKR and NEK7 to bind to NLRP3, as well as suppression of an increase in mitochondrial superoxide generation. Whether or not the impact on PKR/NEK7 was mediated by the O-GlcNAcylation of these proteins has not been determined. Glucosamine also suppressed LPS-mediated priming by impeding NF-kappaB activation. Previous studies have shown that glucosamine has the potential to oppose NF-kappaB activation via O-GlcNAcylation of the anti-inflammatory protein A20 [153] . The latter is a deubiquitinase, which reverses certain ubiquitination reactions required for TRAF6-dependent activation of NF-kappaB; its O-GlcNAcylation appears to up-regulate its activity in this regard.

Although the millimolar concentrations of glucosamine employed in these cell culture studies are markedly higher than the plasma concentrations that can be achieved in vivo with oral administration of glucosamine, it is encouraging that, when administered orally for 3 days at 250 mg/kg daily in mice, glucosamine inhibited the influx of neutrophils into the peritoneal cavity induced by subsequent intraperitoneal injection of monosodium urate crystals, which are potent stimulants of inflammasome activation [55].

Although zinc is known to have anti-inflammatory properties, its impact on inflammasome activity has received little direct study. However, there is reason to suspect that improvement of suboptimal zinc status may down-regulate inflammasome activation by boosting expression of the de-ubiquitinase A20 [154] [155] [156] [157] [158] [159] [160] . A rise in plasma zinc levels can achieve this in macrophages, monocytes, smooth muscle cells, and likely other cell types via stimulation of the G protein-coupled membrane receptor GPR39; this leads to increased transcription of the A20 gene [157, 161, 162] . A20 opposes inflammation by removing ubiquitination chains that serve to promote inflammatory signaling. It is best known for opposing NF-kappaB activation by removing ubiquitin chains created by the TRAF6 ubiquitinase, which form a scaffolding that functions upstream from activation of NF-kappaB and the stress-activated MAP kinases JNK and p38 [163] [164] [165] [166] . Many agonists that promote inflammation, including those that stimulate TLR4, require TRAF6-mediated ubiquitination to exert their effects. This effect of A20 would be expected to oppose inflammasome priming that is TRAF6 dependent, and indeed there is considerable evidence that increases in A20 decrease inflammasome activity [167] [168] [169] . However, an additional effect is involved in this. In order to be an appropriate substrate for caspase-1, pro-IL-1β requires ubiquitination at K133 dependent on activity of the kinase RIPK3. A20 has been shown to reverse this ubiquitination, thereby reducing the ability of activated inflammasomes to generate active IL-1β [169, 170] .

When the mononuclear cells of healthy volunteers were stimulated ex vivo with LPS, their expression of IL1b was found to be significantly lower after the volunteers had been supplemented for 8 weeks with 45 mg zinc daily [154] . Analogously, TNF-α stimulation of NF-kappa B was found to be lower after zinc supplementation. Further study of the impact of zinc supplementation on inflammasome activity and IL-1β generation are evidently warranted. The impact of zinc supplementation on GPR activation, and hence inflammasome activity, would likely be greatest in the elderly, in whom mild zinc deficiency tends to be common [171] [172] [173] .

Fortuitously, for reasons that remain unclear, zinc supplementation tends to boost stimulated NF-kappaB activity in lymphocytes; this effect tends to aid the activation of T lymphocytes and support cell-mediated immunity [174, 175] . This likely explains why zinc supplementation can reduce the incidence of infections in the elderly [171] . Zinc thus manages to accomplish the needed trick of supporting antigen-specific immunity while curbing inflammation.

Physiological levels of the long-chain omega-3 fatty acids EPA and DHA can act as agonists for the GPR120 membrane receptor [176] . When this receptor is activated via omega-3 binding, it binds the cytoplasmic protein β-arrestin2 [177] . This interaction enables β-arrestin2 in turn to bind and sequester transforming growth factor-β activated kinase-1 (TAK1) binding protein-1 (TAB1), whose interaction with TAK1 is required for NF-kappaB activation triggered by a range of cytokines, bacterial products or DAMPs (damageassociated molecular patterns, such as high-mobility group box 1-HMGB1) that signal via TRAF2 or TRAF6; this includes toll-receptor 4 (TLR4) signaling [178] . Sequestration of TAB1 by the GPR120-β-arrestin2 complex prevents its interaction with TAK1, hence suppressing NF-kappaB activation via this type of signaling. Therefore, long-chain omega-3s have been shown to inhibit NLRP3 inflammasome activation via interaction with GPR120 [178] .

Curiously, other receptors-the kappa opioid receptor, and beta2 adrenergic receptorswhen activated by their agonists, have been shown to bind β-arrestin2 and thereby impede NF-kappaB activation in certain circumstances [179, 180] . The activated melatonin receptors MT1 and MT2 likewise bind to β-arrestins, and it would be of interest to determine whether melatonin might reduce NF-kappaB activation by a similar mechanism [181] .

Physiological concentrations of the endogenously generated gas hydrogen sulfide (H 2 S) have been found to inhibit inflammasome activity in preclinical studies [182] [183] [184] [185] . This may reflect, at least in part, its ability to act both as a phase 2 inducer, and as an activator of AMPK [186] [187] [188] [189] [190] . The latter effect is contingent on boosted activity of calmodulin-dependent kinase kinase-β, which confers an activating phosphorylation on AMPK [191] [192] [193] . Nutraceutical modulation of endogenous H 2 S production has so far received little study. Since cysteine is the rate-limiting substrate for H 2 S production via both cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CES), and since intracellular cysteine availability tends to decline with advancing age, supplementation with N-acetylcysteine, a nutraceutical that functions as a delivery form for cysteine, may be useful for boosting H 2 S production, particularly in the elderly [194, 195] . In addition, in rodent studies, taurine supplementation has been shown amplify expression of CBS in the vascular system and of CES in the brain; the mechanistic basis of this effect remains obscure, but it is likely to account, at least in part, for the favorable impact of taurine on cardiovascular health and CNS protection observed in rodent studies [196, 197] .

CES is allosterically activated by S-adenosylmethionine; such activation logically would be expected to boost endogenous H 2 S expression in the brain and retina, where CES is the predominant source of H 2 S production [198] [199] [200] . Nutraceuticals that promote methyl group donation-folate, vitamin B12, and betaine-can be expected to help maintain an effective cellular pool of S-adenosylmethionine, and thereby promote H 2 S generation via CES.

Cell culture and rodent studies suggest that the commonly discussed phytochemicals curcumin and resveratrol have potential for suppression of inflammasome activation [201] [202] [203] [204] [205] [206] [207] [208] . However, the clinical pertinence of these observations can be doubted, owing to rapid intestinal conjugation and, in the case of curcumin, poor absorption and rapid intestinal reduction in humans [209] [210] [211] [212] . Nonetheless, efforts to develop delivery systems that might surmount these obstacles are ongoing [213, 214] . Although the curcumin metabolite tetrahydrocurcumin has some anti-inflammatory properties, it does not appear to inhibit inflammasome activation [208] .

These considerations suggest that nutraceutical regimens providing some or all of lipoic acid, ferulic acid, PhyCB, berberine, N-acetylcysteine, glucosamine, taurine, folate, vitamin B12, and betaine may have clinical potential for suppressing the contribution of NLRP3 inflammasomes to a number of inflammation-linked pathologies in which such inflammasomes play a key mediating role.

As an illustrative example, consider the dry form of age-related macular degeneration (geographic atrophy), for which there is still no clinically established therapy aside from lutein/zeaxanthin support for the macular pigment. Inflammasome-mediated production of interleukin-18 within retinal pigment epithelial cells is now strongly suspected to play a key role in driving this disorder [215] [216] [217] [218] [219] [220] [221] [222] . The utility of supplemental zinc (80 mg daily + 2 mg copper) for slowing progression of early age-related macular degeneration (AMD) has been demonstrated in the AREDS1 trial [223, 224] . Recent epidemiology has established that diabetics treated with the drug metformin are at notably lower risk for AMD than other diabetics that are comparably controlled; this could reflect a protective role for AMPK in this syndrome [225, 226] . Urinary levels of the melatonin metabolite 6-sulfatoxymelatonin have been reported to be low in patients with AMD, and melatonin administration is protective in a mouse model of dry AMD [227] [228] [229] [230] . Although the decreased risk for AMD associated with frequent spinach ingestion has been attributed to lutein, little attention has been paid to the fact that spinach is extraordinarily rich in betaine, and also a fine source of folate. In the first epidemiological study associating lutein ingestion with AMD risk, Seddon and colleagues reported that subjects who claimed to consume spinach or collard greens almost every day were at 80% lower risk for AMD [231] . Whether this magnitude of protection could be confirmed in further studies remains to be seen, but this might be an intriguing hint that the betaine content of spinach also contributes to the protection it affords. Indeed, a study in identical twins discordant for AMD found that diets high in betaine were associated with protection from this disorder [232] . Moreover, in a placebocontrolled clinical trial, which so far has received insufficient attention, supplementation with folic acid (2.5 mg) and vitamins B12 and B6 was associated with a reduction in risk for new-onset AMD of about one-third after 7 years of follow-up [233] . Conversely, elevated homocysteine, a marker for poor methyl group availability, is an established risk factor for AMD [234] . Conceivably, these findings reflect a modulatory effect of methyl donors on CES activity in the retina, though the possibility that modulation of DNA methylation plays some role in this phenomenon might be considered.

It is notable that PhyCB, phase 2 inducers, melatonin, N-acetylcysteine, berberine, glucosamine, and zinc have already been suggested for use in the management of COVID-19 [235] [236] [237] [238] [239] [240] [241] [242] [243] [244] [245] . The NADPH oxidase-inhibitory activity PhyCB may have potential for upregulating the type 1 interferon response to SARS-CoV-2 and other RNA viruses, and may also act to suppress the induction of tissue factor, a likely trigger for the thrombotic complications of COVID-19 [235, 236] . Phase 2 inducers and N-acetylcysteine could be expected to play a complementary role with respect to these effects [235, 236] . Glucosamine may likewise up-regulate the type 1 interferon response to viruses [236, 246] . Whereas the impact of berberine on COVID- 19 has not yet been assessed, use of metformin-like berberine, an activator of AMPK-has been associated with lower risk for mortality in diabetic patients hospitalized with COVID-19 [247, 248] . A lower blood zinc level has been correlated with a poorer clinical outcome in early-stage COVID-19 patients treated with hydroxychloroquine and azithromycin [249] . However, whether short-term zinc supplementation can importantly influence zinc status in COVID-19 patients is questionable, and the utility of supplemental zinc in this context is the subject of conflicting reports [250] [251] [252] . Long-term supplementation prior to infection may be the best protective strategy. The possibility that treatment with zinc ionophores (such as chloroquine) might enable zinc to act intracellularly to inhibit replications of coronaviruses has been suggested; while this phenomenon has been demonstrated in vitro, its relevance in vivo remains to be established [253, 254] . A fall in serum levels of H 2 S has been associated with increased mortality in hospitalized COVID-19 patients, whereas these serum levels correlate inversely with the inflammation markers interleukin-6 (IL-6) and C-reactive protein, known markers for an adverse outcome; hence, nutraceuticals that support H 2 S production may have a protective anti-inflammatory impact in this syndrome [255] . It is of possible relevance that taurine administration has been shown to exert anti-inflammatory activity when the lungs of rodents have been challenged with endotoxin or various other pro-inflammatory agents [256] [257] [258] . Similar effects have been reported with phycocyanin, glucosamine, berberine, lipoic and ferulic acids, melatonin, and N-acetylcysteine [259] [260] [261] [262] [263] [264] [265] .

Clinical studies suggest that the drug colchicine may be useful in the cytokine storm phase of COVID-19 [266] [267] [268] . It is therefore intriguing to consider the fact that colchicine can suppress activation of NLRP3-dependent inflammasome activation by disrupting microtubules required for achieving the apposition of mitochondrially-bound ASC with endoplasmic reticulum-bound NLRP3 necessary for inflammasome formation [269, 270] . Colchicine's activity in gout may be partially rooted in this anti-inflammasome mechanism, as IL-1β is a key mediator of gouty arthritis [29] . Unfortunately, colchicine's narrow therapeutic index lessens the feasibility of its use in preventive medicine [271] .

The lethality of COVID-19 is notably greater in patients with metabolic syndrome: visceral obesity, hypertension, diabetes [272] [273] [274] [275] . Arguably, this may reflect greater exposure of lung tissue to saturated fatty acids such as palmitic acid, that can exert pro-inflammatory effects [276] . One such effect of palmitic acid is an up-regulation of inflammasome activation [277] [278] [279] . Hence, nutraceutical measures that oppose inflammasome activation may offset to some degree the greater mortality risk imposed by metabolic syndrome in COVID-19 patients.

NLRP3-dependent inflammasomes play a mediating role in a vast range of inflammationlinked pathologies, by catalyzing the formation and extracellular export of interleukins-1β and -18, and by inducing pyroptotic cell death. A consideration of the molecular biology underlying inflammasome priming and activation, and of pertinent scientific literature, suggests that a number of nutraceuticals may have potential for blunting inflammasome activity. A range of antioxidant measures may oppose the oxidant-catalyzed association of TXNIP with NLRP3, including PhyCB, phase 2 inducers (e.g., lipoic acid, ferulic acid, melatonin), and N-acetylcysteine. AMPK activators such as berberine oppose the expression of TXNIP at the transcriptional level. Glucosamine can work to oppose the NF-kappaB activation required for inflammasome priming, and also by inhibiting the association of NLRP3 with the accessory proteins PKR and NEK7, likely by promoting O-GlcNAcylation of key proteins. Zinc can oppose inflammasome priming and IL-1β generation via induction of the A20 de-ubiquitinase. Since H 2 S inhibits inflammasome activity, nutraceuticals that support H 2 S synthesis-N-acetylcysteine, and, in at least certain circumstances, taurine and catalysts of methyl donation-may aid this effect. These relationships are summarized in the Figure 1 . Complex nutraceutical programs or functional foods featuring these agents may have preventive and therapeutic utility in the diverse range of pathologies in which inflammasome activity plays a mediating role.

Nutrients 2020, 12, x FOR PEER REVIEW 9 of 21

NLRP3-dependent inflammasomes play a mediating role in a vast range of inflammation-linked pathologies, by catalyzing the formation and extracellular export of interleukins-1β and -18, and by inducing pyroptotic cell death. A consideration of the molecular biology underlying inflammasome priming and activation, and of pertinent scientific literature, suggests that a number of nutraceuticals may have potential for blunting inflammasome activity. A range of antioxidant measures may oppose the oxidant-catalyzed association of TXNIP with NLRP3, including PhyCB, phase 2 inducers (e.g., lipoic acid, ferulic acid, melatonin), and N-acetylcysteine. AMPK activators such as berberine oppose the expression of TXNIP at the transcriptional level. Glucosamine can work to oppose the NF-kappaB activation required for inflammasome priming, and also by inhibiting the association of NLRP3 with the accessory proteins PKR and NEK7, likely by promoting O-GlcNAcylation of key proteins. Zinc can oppose inflammasome priming and IL-1β generation via induction of the A20 de-ubiquitinase. Since H2S inhibits inflammasome activity, nutraceuticals that support H2S synthesis-N-acetylcysteine, and, in at least certain circumstances, taurine and catalysts of methyl donation-may aid this effect. These relationships are summarized in the Figure 1 . Complex nutraceutical programs or functional foods featuring these agents may have preventive and therapeutic utility in the diverse range of pathologies in which inflammasome activity plays a mediating role. As a final comment, it has recently been reported that NLRP3-knockout mice enjoy a considerable enhancement of both mean (34%) and maximal (29%) lifespan [280] . This makes the possibility of safe nutraceutical and dietary measures for down-regulating inflammasome activity all the more intriguing.

Since the writing of the original draft of this manuscript, a comprehensive review has appeared citing literature on a vast range of phytochemicals that have modulated inflammasome activity in vitro or in vivo [281] . This review may be considered complementary to ours. Our focus is on nutraceuticals that are currently commercially available, can be presumed to be adequately absorbed and physiologically active in defined oral dose schedules, and have reasonably well-defined mechanisms of action. Hence, it lends itself to current development of functional foods and supplementation programs, which may have some clinical utility for controlling inflammasome activation. As a final comment, it has recently been reported that NLRP3-knockout mice enjoy a considerable enhancement of both mean (34%) and maximal (29%) lifespan [280] . This makes the possibility of safe nutraceutical and dietary measures for down-regulating inflammasome activity all the more intriguing.

Since the writing of the original draft of this manuscript, a comprehensive review has appeared citing literature on a vast range of phytochemicals that have modulated inflammasome activity in vitro or in vivo [281] . This review may be considered complementary to ours. Our focus is on nutraceuticals that are currently commercially available, can be presumed to be adequately absorbed and physiologically active in defined oral dose schedules, and have reasonably well-defined mechanisms of action. Hence, it lends itself to current development of functional foods and supplementation programs, which may have some clinical utility for controlling inflammasome activation. 

The inflammasome: an integrated view

Inflammasome: activation mechanisms

Emerging Activators and Regulators of Inflammasomes and Pyroptosis

Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Interleukin-18 Induces Retinal Pigment Epithelium Degeneration in Mice

RNA dysmetabolism induces Caspase-8-mediated cell death in age-related macular degeneration

cGAS drives noncanonical-inflammasome activation in age-related macular degeneration

Inflammasomes contributing to inflammation in arthritis

A new research hot spot: The role of NLRP3 inflammasome activation, a key step in pyroptosis, in diabetes and diabetic complications

The Roles of the NLRP3 Inflammasome in Neurodegenerative and Metabolic Diseases and in Relevant Advanced Therapeutic Interventions

The pathogenic role of the inflammasome in neurodegenerative diseases

NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice

The mechanisms of NLRP3 inflammasome/pyroptosis activation and their role in Parkinson's disease

Inhibition of the hepatic Nlrp3 protects dopaminergic neurons via attenuating systemic inflammation in a MPTP/p mouse model of Parkinson's disease

MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration

Upregulation of proteins of the NLRP3 inflammasome in patients with periodontitis and uncontrolled type 2 diabetes

Metformin inhibits IL-1Î 2 secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis

Genetic support for the role of the NLRP3 inflammasome in psoriasis susceptibility

The role of NLRP3 inflammasome in infection-related, immune-mediated and autoimmune skin diseases

Ferulic acid exerts neuroprotective effects against cerebral ischemia/reperfusioninduced injury via antioxidant and anti-apoptotic mechanisms in vitro and in vivo

Ferulic Acid Rescues LPS-Induced Neurotoxicity via Modulation of the TLR4 Receptor in the Mouse Hippocampus

Sodium Ferulate Attenuates Oxidative Stress Induced Inflammation via Suppressing NALP3 and NF-κB Signal Pathway. Sichuan Da Xue Xue Bao Yi Xue Bao

Targeting inflammatory mediators with ferulic acid, a dietary polyphenol, for the suppression of monosodium urate crystal-induced inflammation in rats

Ferulic acid inhibits neuro-inflammation in mice exposed to chronic unpredictable mild stress

Sodium Ferulate Attenuates Oxidative Stressvia Suppressing NALP3 Inflammasome and ERK Signal Pathway

Ferulic acid protects against methotrexate nephrotoxicity via activation of Nrf2/ARE/HO-1 signaling and PPARΠ3 , and suppression of NF-κB/NLRP3 inflammasome axis

Pharmacological Actions of Sodium Ferulate in Cardiovascular System

Ferulic Acid Supplementation Improves Lipid Profiles, Oxidative Stress, and Inflammatory Status in Hyperlipidemic Subjects: A Randomized, Double-Blind

The Keap1-Nrf2-antioxidant response element pathway: A review of its regulation by melatonin and the proteasome

Melatonin: an ancient molecule that makes oxygen metabolically tolerable

The Protective Effects of Melatonin on Aluminum-Induced Hepatotoxicity and Nephrotoxicity in Rats

Circadian clock protein BMAL1 regulates IL-1Î 2 in macrophages via NRF2

Clock Protein Bmal1 and Nrf2 Cooperatively Control Aging or Oxidative Response and Redox Homeostasis by Regulating Rhythmic Expression of Prdx6

Molecular Architecture of the Circadian Clock in Mammals

Circadian modification network of a core clock driver BMAL1 to harmonize physiology from brain to peripheral tissues

The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1

RORα is not a receptor for melatonin

Disruption of the NF-κB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-α and blocks the septic response in mice

The circadian nuclear receptor RORα negatively regulates cerebral ischemia-reperfusion injury and mediates the neuroprotective effects of melatonin

Melatonin prevents endothelial dysfunction in SLE by activating the nuclear receptor retinoic acid-related orphan receptor-α

Melatonin Target Proteins: Too Many or Not Enough? Front. Endocrinol

Melatonin suppresses proinflammatory mediators in lipopolysaccharide-stimulated CRL1999 cells via targeting MAPK, NF-κB, c/EBPβ, and p300 signaling

Melatonin modulates TLR4-mediated inflammatory genes through MyD88-and TRIF-dependent signaling pathways in lipopolysaccharide-stimulated RAW264.7 cells

Melatonin protects against blood-brain barrier damage by inhibiting the TLR4/ NF-κB signaling pathway after LPS treatment in neonatal rats

CLOCK/BMAL1 regulates circadian change of mouse hepatic insulin sensitivity by SIRT1

Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase

Melatonin attenuated early brain injury induced by subarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling

Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome

Melatonin alleviates cadmium-induced liver injury by inhibiting the TXNIP-NLRP3 inflammasome

Responsiveness of Selenoproteins to Dietary Selenium

Selenium Attenuates Staphylococcus aureus Mastitis in Mice by Inhibiting the Activation of the NALP3 Inflammasome and NF-κB/MAPK Pathway

NADPH Oxidase-Induced NALP3 Inflammasome Activation Is Driven by Thioredoxin-Interacting Protein Which Contributes to Podocyte Injury in Hyperglycemia

Cofactorindependent antiphospholipid antibodies activate the NLRP3-inflammasome via endosomal NADPH-oxidase: implications for the antiphospholipid syndrome

NADPH Oxidase-Dependent NLRP3 Inflammasome Activation and its Important Role in Lung Fibrosis by Multiwalled Carbon Nanotubes

Angiotensin(1-7) attenuated Angiotensin II-induced hepatocyte EMT by inhibiting NOX-derived H2O2-activated NLRP3 inflammasome/IL-1Î 2 /Smad circuit. Free Radic

Amyloid Î 2 induces NLRP3 inflammasome activation in retinal pigment epithelial cells via NADPH oxidase-and mitochondria-dependent ROS production

NADPH Oxidase 2 Regulates NLRP3 Inflammasome Activation in the Brain after Traumatic Brain Injury

Apocynin alleviates lung injury by suppressing NLRP3 inflammasome activation and NF-κB signaling in acute pancreatitis

Through Reducing ROS Production, IL-10 Suppresses Caspase-1-Dependent IL-1β Maturation, thereby Preventing Chronic Neuroinflammation and Neurodegeneration

Apocynin inhibited NLRP3/XIAP signalling to alleviate renal fibrotic injury in rat diabetic nephropathy

Periodontal ligament fibroblasts migration injury via ROS/TXNIP/Nlrp3 inflammasome pathway with Porphyromonas gingivalis lipopolysaccharide

Nox2 and Rac1 Regulate H2O2-Dependent Recruitment of TRAF6 to Endosomal Interleukin-1 Receptor Complexes

Endosomal Nox2 facilitates redox-dependent induction of NF-kappaB by TNF-alpha

Bilirubin decreases NOS2 expression via inhibition of NAD(P)H oxidase: implications for protection against endotoxic shock in rats

Carbon monoxide and bilirubin from heme oxygenase-1 suppresses reactive oxygen species generation and plasminogen activator inhibitor-1 induction

NO Modulates NADPH Oxidase Function Via Heme Oxygenase-1 in Human Endothelial Cells

Induction of heme oxygenase-1 in vivo suppresses NADPH oxidase derived oxidative stress

Nox4 NADPH oxidase mediates oxidative stress and apoptosis caused by TNF-α in cerebral vascular endothelial cells

Nitric oxide protected against NADPH oxidase-derived superoxide generation in vascular endothelium: Critical role for heme oxygenase-1

Physiological concentrations of bilirubin control inflammatory response by inhibiting NF-κB and inflammasome activation

Inactivation of phytochrome-and phycobiliprotein-chromophore precursors by rat liver biliverdin reductase

Clinical Potential of Spirulina as a Source of Phycocyanobilin

Phycocyanin and phycocyanobilin from Spirulina platensis protect against diabetic nephropathy by inhibiting oxidative stress

A Biliprotein with Antioxidant, Anti-Inflammatory and Neuroprotective Effects

Spirulina maxima extract prevents activation of the NLRP3 inflammasome by inhibiting ERK signaling

A. C-phycocyanin protects against ethanol-induced gastric ulcers in rats: Role of HMGB1/NLRP3/NF-κB pathway

AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity

Negative regulation of NLRP3 inflammasome by SIRT1 in vascular endothelial cells

SIRT1 Alleviates LPS-Induced IL-1Î 2 Production by Suppressing NLRP3 Inflammasome Activation and ROS Production in Trophoblasts

Aloin suppresses lipopolysaccharide-induced acute lung injury by inhibiting NLRP3/NF-κB via activation of SIRT1 in mice

SIRT1 agonism modulates cardiac NLRP3 inflammasome through pyruvate dehydrogenase during ischemia and reperfusion

An Acetylation Switch of the NLRP3 Inflammasome Regulates Aging-Associated Chronic Inflammation and Insulin Resistance

Resveratrol pretreatment attenuates traumatic brain injury in rats by suppressing NLRP3 inflammasome activation via SIRT1

SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling

SIRT1 longevity factor suppresses NF-kappaB -driven immune responses: regulation of aging via NF-kappaB acetylation?

Efficacy and safety of berberine for dyslipidaemias: A systematic review and meta-analysis of randomized clinical trials

Efficacy and Safety of Berberine Alone or Combined with Statins for the Treatment of Hyperlipidemia: A Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials

Berberine is a novel cholesterollowering drug working through a unique mechanism distinct from statins

NLRP3 inflammasome as a target of berberine in experimental murine liver injury: interference with P2X7 signalling

Effects of Berberine on NLRP3 and IL-1Î 2 Expressions in Monocytic THP-1 Cells with Monosodium Urate Crystals-Induced Inflammation

Berberine Attenuates NLRP3 Inflammasome Activation in Macrophages to Reduce the Secretion of Interleukin-1Î 2

Berberine inhibits NLRP3 Inflammasome pathway in human triple-negative breast cancer MDA-MB-231 cell

Berberine Inhibits Nod-Like Receptor Family Pyrin Domain Containing 3 Inflammasome Activation and Pyroptosis in Nonalcoholic Steatohepatitis via the ROS/TXNIP Axis

Berberine suppresses influenza virus-triggered NLRP3 inflammasome activation in macrophages by inducing mitophagy and decreasing mitochondrial ROS

O-Linked Π2 -N-Acetylglucosamine Modification of A20 Enhances the Inhibition of NF-κB (Nuclear Factor-κB) Activation and Elicits Vascular Protection After Acute Endoluminal Arterial Injury

Antioxidant effect of zinc in humans. Free Radic

Zinc is an Antioxidant and Anti-Inflammatory Agent: Its Role in Human Health

Molecular Mechanisms of Zinc as a Pro-Antioxidant Mediator: Clinical Therapeutic Implications

Zinc Inhibits Phosphate-Induced Vascular Calcification through TNFAIP3-Mediated Suppression of NF-κB

Zinc Prevents Abdominal Aortic Aneurysm Formation by Induction of A20-Mediated Suppression of NF-κB Pathway

Association of zinc administration with growth suppression of intracranial aneurysms via induction of A20

Zinc inhibited LPS-induced inflammatory responses by upregulating A20 expression in microglia BV2 cells

The Zinc Sensing Receptor, ZnR/GPR39, in Health and Disease

Maternal high-zinc diet attenuates intestinal inflammation by reducing DNA methylation and elevating H3K9 acetylation in the A20 promoter of offspring chicks

The cytokine-inducible zinc finger protein A20 inhibits IL-1-induced NF-kappaB activation at the level of TRAF6

Molecular basis for the unique deubiquitinating activity of the NF-kappaB inhibitor A20

The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses

Inhibition of NF-kappaB signaling by A20 through disruption of ubiquitin enzyme complexes

A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation

Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis

A20 restricts ubiquitination of pro-interleukin-1Î 2 protein complexes and suppresses NLRP3 inflammasome activity

Control of the inflammasome by the ubiquitin system

Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress

An antioxidant and anti-inflammatory agent: Role of zinc in degenerative disorders of aging

Effect of zinc supplementation on serum zinc concentration and T cell proliferation in nursing home elderly: a randomized, double-blind, placebo-controlled trial

Zinc enhances the expression of interleukin-2 and interleukin-2 receptors in HUT-78 cells by way of NF-kappaB activation

Zinc in Human Health: Effect of Zinc on Immune Cells

GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects

Discovery of novel FFA4 (GPR120) receptor agonists with Î 2 -arrestin2-biased characteristics

Inhibitory effects of omega-3 fatty acids on early brain injury after subarachnoid hemorrhage in rats: Possible involvement of G protein-coupled receptor 120/Î 2 -arrestin2/TGF-Î 2 activated kinase-1 binding protein-1 signaling pathway

Î 2 -arrestin protects neurons by mediating endogenous opioid arrest of inflammatory microglia

Î 2 -arrestin2 regulates the anti-inflammatory effects of Salmeterol in lipopolysaccharide-stimulated BV2 cells

Assessments of cellular melatonin receptor signaling pathways: Î 2 -arrestin recruitment, receptor internalization, and impedance variations

Hydrogen sulfide inhibits NLRP3 inflammasome activation and reduces cytokine production both in vitro and in a mouse model of inflammation

Evaluation on the effect of hydrogen sulfide on the NLRP3 signaling pathway and its involvement in the pathogenesis of atherosclerosis

Hydrogen sulfide protects against DSS-induced colitis by inhibiting NLRP3 inflammasome. Free Radic

Endogenous hydrogen sulphide attenuates NLRP3 inflammasome-mediated neuroinflammation by suppressing the P2X7 receptor after intracerebral haemorrhage in rats

Hydrogen Sulfide Induces Keap1 S-sulfhydration and Suppresses Diabetes-Accelerated Atherosclerosis via Nrf2 Activation

Hydrogen sulfide attenuates calcification of vascular smooth muscle cells via KEAP1/NRF2/NQO1 activation

Hydrogen sulfide alleviates liver injury via S-sulfhydrated-Keap1/Nrf2/LRP1 pathway

Hydrogen Sulfide Inhibits High Glucose-induced Matrix Protein Synthesis by Activating AMP-activated Protein Kinase in Renal Epithelial Cells

Hydrogen Sulfide Lowers Proliferation and Induces Protective Autophagy in Colon Epithelial Cells

CaMKKÎ 2 -dependent activation of AMP-activated protein kinase is critical to suppressive effects of hydrogen sulfide on neuroinflammation

The role of sodium hydrosulfide in attenuating the aging process via PI3K/AKT and CaMKKÎ 2 /AMPK pathways

Hydrogen Sulphide Treatment Increases Insulin Sensitivity and Improves Oxidant Metabolism through the CaMKKbeta-AMPK Pathway in PA-Induced IR C2C12 Cells

Boosting endogenous production of vasoprotective hydrogen sulfide via supplementation with taurine and N-acetylcysteine: a novel way to promote cardiovascular health

The Deficit in Low Molecular Weight Thiols as a Target for Antiageing Therapy

Taurine Supplementation Lowers Blood Pressure and Improves Vascular Function in Prehypertension: Randomized, Double-Blind, Placebo-Controlled Study

Taurine supplementation reduces neuroinflammation and protects against white matter injury after intracerebral hemorrhage in rats

Structural insight into the molecular mechanism of allosteric activation of human cystathionine Î 2 -synthase by S-adenosylmethionine

A diet rich in taurine, cysteine, folate, B12 and betaine may lessen risk for Alzheimer's disease by boosting brain synthesis of hydrogen sulfide

Comparative localization of cystathionine beta synthases and cystathionine gamma lyase in canine, non-human primate and human retina

Resveratrol ameliorates hepatic metaflammation and inhibits NLRP3 inflammasome activation

Resveratrol inhibits NLRP3 inflammasome activation by preserving mitochondrial integrity and augmenting autophagy

Resveratrol inhibits the acetylated α-tubulin-mediated assembly of the NLRP3-inflammasome

Resveratrol Protects against Sepsis-Associated Encephalopathy and Inhibits the NLRP3/IL-1Î 2 Axis in Microglia

Curcumin suppresses NLRP3 inflammasome activation and protects against LPS-induced septic shock

Curcumin Represses NLRP3 Inflammasome Activation via TLR4/MyD88/NF-κB and P2X7R Signaling in PMA-Induced Macrophages

Curcumin Ameliorates Diabetic Nephropathy by Suppressing NLRP3 Inflammasome Signaling

Curcumin Suppresses IL-1Î 2 Secretion and Prevents Inflammation through Inhibition of the NLRP3 Inflammasome

Curcumin uptake and metabolism

Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine

Metabolism and bioavailability of trans-resveratrol

Bioavailability of resveratrol

Dietary Curcumin: Correlation between Bioavailability and Health Potential

Recent Strategies in Resveratrol Delivery Systems

DICER1 Loss and Alu RNA Induce Age-Related Macular Degeneration via the NLRP3 Inflammasome and MyD88

Oxidative stress activates NLRP3 inflammasomes in ARPE-19 cells-Implications for age-related macular degeneration (AMD)

NLRP3 Inflammasome Activation in Retinal Pigment Epithelial Cells by Lysosomal Destabilization: Implications for Age-Related Macular Degeneration

TLR-Independent and P2X7-Dependent Signaling MediateAluRNA-Induced NLRP3 Inflammasome Activation in Geographic Atrophy

The NLRP3 Inflammasome and its Role in Age-Related Macular Degeneration

Complement Component C5a Primes Retinal Pigment Epithelial Cells for Inflammasome Activation by Lipofuscin-mediated Photooxidative Damage

NLRP3 Upregulation in Retinal Pigment Epithelium in Age-Related Macular Degeneration

Retinal Pigment Epithelium Cell Death Is Associated With NLRP3 Inflammasome Activation by All-trans

A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no

A Systematic Review on Zinc for the Prevention and Treatment of Age-Related Macular Degeneration

The Common Antidiabetic Drug Metformin Reduces Odds of Developing Age-Related Macular Degeneration

Association between Metformin and a Lower Risk of Age-Related Macular Degeneration in Patients with Type 2 Diabetes

Melatonin protects the retina from experimental nonexudative age-related macular degeneration in mice

Urinary 6-sulfatoxymelatonin level in age-related macular degeneration patients

Effects of Melatonin in Age-Related Macular Degeneration

Melatonin in Retinal Physiology and Pathology: The Case of Age-Related Macular Degeneration

Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. Eye Disease Case-Control Study Group

Smoking, dietary betaine, methionine, and vitamin D in monozygotic twins with discordant macular degeneration: epigenetic implications

Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women's Antioxidant and Folic Acid Cardiovascular Study

Homocysteine and the risk of age-related macular degeneration: a systematic review and meta-analysis

Thrombotic complications of COVID-19 may reflect an upregulation of endothelial tissue factor expression that is contingent on activation of endosomal NADPH oxidase

Nutraceuticals have potential for boosting the type 1 interferon response to RNA viruses including influenza and coronavirus

N-acetylcysteine as a potential treatment for novel coronavirus disease

Reactive oxygen species as an initiator of toxic innate immune responses in retort to SARS-CoV-2 in an ageing population, consider N-acetylcysteine as early therapeutic intervention

A potential therapeutic agent for SARS-CoV-2. Med. Hypotheses. 2020, 143, 109862

Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases

Identification of potential inhibitors against SARS-CoV-2 by targeting proteins responsible for envelope formation and virion assembly using docking based virtual screening, and pharmacokinetics approaches

Targeting the Heme-Heme Oxygenase System to Prevent Severe Complications Following COVID-19 Infections

COVID-19 and heme oxygenase: novel insight into the disease and potential therapies

Goździcka-Jà 3 zefiak, A. Antiviral activity of berberine

Melatonin is significantly associated with survival of intubated COVID-19 patients

MAVS O-GlcNAcylation Is Essential for Host Antiviral Immunity against Lethal RNA Viruses

Observational Study of Metformin and Risk of Mortality in Patients Hospitalized with Covid-19

Metformin Treatment Was Associated with Decreased Mortality in COVID-19 Patients with Diabetes in a Retrospective Analysis

Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis

Treatment of SARS-CoV-2 with high dose oral zinc salts: A report on four patients

The Minimal Effect of Zinc on the Survival of Hospitalized Patients With COVID-19: An Observational Study

Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone

Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture

Zinc and respiratory tract infections: Perspectives for COVIDâ€'19 (Review)

Serum Hydrogen Sulfide and Outcome Association in Pneumonia by the SARS-CoV-2 Corona virus

Protective action of taurine, given as a pretreatment or as a posttreatment, against endotoxin-induced acute lung inflammation in hamsters

Taurine Reduces Lung Inflammation and Fibrosis Caused By Bleomycin

Taurine Protects Rat Bronchioles from Acute Ozone-Induced Lung Inflammation and Hyperplasia

Therapeutic Effect of C-Phycocyanin Extracted from Blue Green Algae in a Rat Model of Acute Lung Injury Induced by Lipopolysaccharide

The effects of phycocyanin on bleomycin-induced pulmonary fibrosis and the intestinal microbiota in C57BL/6 mice

Glucosamine regulation of LPS-mediated inflammation in human bronchial epithelial cells

Glucosamine improves survival in a mouse model of sepsis and attenuates sepsis-induced lung injury and inflammation

Berberine ameliorates lipopolysaccharide-induced acute lung injury via the PERK-mediated Nrf2/HO-1 signaling axis

Beneficial effect of alpha-lipoic acid on lipopolysaccharide-induced oxidative stress in bronchoalveolar lavage fluid

Protective effects of early treatment with lipoic acid in LPS-induced lung injury in rats

Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial

Association between treatment with colchicine and improved survival in a single-centre cohort of adult hospitalised patients with COVID-19 pneumonia and acute respiratory distress syndrome

Successful Treatment of Covid-19 Associated Cytokine Release Syndrome with Colchicine. A Case Report and Review of Literature

Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome

Colchicine to decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation

The development of a targeted and more potent, anti-Inflammatory derivative of colchicine: Implications for gout

Visceral Adiposity and High Intramuscular Fat Deposition Independently Predict Critical Illness in Patients with Sars-COV-2

The role of visceral adiposity in the severity of COVID-19: Highlights from a unicenter cross-sectional pilot study in Germany

Aging, Male Sex, Obesity, and Metabolic Inflammation Create the Perfect Storm for COVID-19

COVID-19 and the role of chronic inflammation in patients with obesity

The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms

Palmitic acid induces interleukin-1Î 2 secretion via NLRP3 inflammasomes and inflammatory responses through ROS production in human placental cells

Saturated fatty acids, obesity, and the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in asthmatic patients

Saturated Fatty Acids Undergo Intracellular Crystallization and Activate the NLRP3 Inflammasome in Macrophages

NLRP3 inflammasome activation in inflammaging

Nutraceutical Compounds Targeting Inflammasomes in Human Diseases