"Super foods" don't exist. There is no miracle drug, nutrient or other molecular substance, be it synthetic or biological, to prevent disease like a "one-size-fits-all" solution. One cannot claim a nutrient to prevent the occurrence of infections.
Of relevance is that certain nutrients can contribute to the targeting of mechanisms underlying diseases. Two major mechanisms underlying disease are failure of the innate and adaptive immunity to establish an adequate response to pathogens and reactive oxidative stress (ROS), a non-psychological, biomolecular phenomenon.
In this message, I will discuss a selection of research on biochemical substances found in nutritives. Note that questions regarding absorption and metabolism of nutrients remain to be answered.
1. Quercetin;
1.1. The flavonoid and flavonol group;
1.2. Quercetin inhibits the NF-kB pathway and LPS-induced STAT-1 macrophage activation;
1.3. Toxicity and carcinogenic risk of quercetin;
1.4. Antioxidant properties of quercetin to target Oxidative Stress and Reactive Nitrogen Species;
1.5 The bioavailability question: aglycones and glycosides;
2 Polysaccharides;
2.1. Antioxidant and immunomodulatory properties;
2.2. Antifibrotic activity of vegetable polysaccharides against BLM-fibrosis;
3 Curcumin compounds;
3.1. Curcumin analogs suppress IL1-β and COX-2 to attenuate hyperinflammation;
4 Warning: drug interactions with grapefruit flavonoids and non-flavonoids;
5 Next feature
1. Quercetin (3,3,4,5,7-pentahydroxyflavone, see: Quercetin, in: ScienceDirect, an overview)
1.1. The flavonoid and flavonol group
Quercetin is a flavonol, a polyphenolic benzene compound found in vegetables and fruits.
Quercetin concentrations are high in red onions and also found in capers, blackberries, cranberries, apples, buckwheat, citrus fruits, garlic, ginger, peppers, turmeric, grapes, elderberries, kale (cavolo nero), (green) tea and wine ("Flavonols and Kaempferols", in: Berries and Related Fruits, Encyclopedia of Fruit and Health 2016, P364-371). Catechin compounds in berries, wine and tea leaves are not actual flavonoids (Principles and Practice of Herbal Phytotherapy 2013, P17-82). While quercetin levels decrease with duration of storage and food procession, quercetin levels in strawberries increase when stored at -20C for 9 months (Chapter 2- Quercetin and Trypthanthrin: Two Broad Spectrum Anticancer Agents for Future Interventions, The Enzymes Vol. 37, 2015, P43-72). Quercetin rutinoside, found in citrus fruits, is mentioned to be irritating or allergenic to some people ("Quercetin", in: Polyphenols: Mechanisms of Action in Human Health and Disease, 2018, P403-413).
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| Strawberries: stored for 9 months at -20C increases its quercitin levels (courtesy of Mercedes Bouter LL.M.) |
1.2 Quercetin inhibits the NF-kB pathway and LPS-induced STAT-1 macrophage activation
Quercetin is associated with NF-kB inhibition, thereby reducing cytokine production. In vitro, quercetin was found to downregulate the inflammatory response of bone marrow-derived macrophages. Quercetin inhibits Lipopolysaccharide (LPS)-induced macrophage activation of STAT-1 and IFN-γ-induced STAT-1 activation ("Quercetin", in: Anti-inflammatory Properties of Cinnamon Polyphenols and Their Monomeric Precursors, Polyphenols in Human Health and Disease Vol. 1, 2014, P409-425; see also: Bioactive effects of quercetin in the central nervous system: Focusing on the mechanisms of actions, Biomedicine & Pharmacotherapy Vol. 84, December 2016, P892-908).
Quercetin suppresses anaphylactic responses in vitro by stabilization of mast cell membranes and inhibits enzymes responsible for production of leukotrienes (LTs), derived from arachidonic acid metabolism (literally: peanut butter acid) (see: Leukotrienes, in: Mast Cells, Basophils and Asthma; The Allergic Patient, in: Integrative Medicine (Fourth Edition) 2018, P300-309).
Quercetin is also associated with suppression of anti-inflammatory M2 macrophage and the anti-inflammatory cytokine IL-10 in vitro in obese models. However, overall quercetin was found to reduce chronic inflammation by suppression of NF-kB, TNF-alpha and oxidative stress (Quercetin suppresses immune cell accumulation and improves mitochondrial gene expression in adipose tissue of diet-induced obese mice, Molecular Nutrition and Food Research Vol. 60, Issue 2, February 2016, P300-312).
1.3 Toxicity and carcinogenic risk of quercetin
Quercetin supplementation might enhance nephrotoxic effects in predamaged kidneys and promote tumor development in estrogen-dependent cancers (Safety Aspects of the Use of Quercetin as a Dietary Supplement, Molecular Nutrition and Food Research Vol. 61, Issue 1, January 2018). Phytoestrogens could also induce estrogen-dependent cancers: phytoestrogens mimic estrogen 17β-estradiol (E2). Quercetin does not decrease E2-induced oxidant stress. Inhibition of Cathegol-O-Methyltransferase (COMT) by quercetin prolongs exposure to 17β-estradiol and cathegol estrogens, thus inducing the risk of carcinogenic activity and chronic exposure to metabolic oxidative stress (Dietary quercetin exacerbates the development of estrogen-induced breast tumors in female ACI rats, Toxicology and Applied Pharmacology Vol. 247, Issue 2, 1 September 2010, P83-90).
1.4 Antioxidant properties of quercetin to target Oxidative Stress and Reactive Nitrogen Species
Quercetin may stimulate cell defenses against oxidative stress (Reactive Oxygen Species and Reactive Nitrogen Species) by induction of Nrf2-ARE and Paraoxonase-2 (PON2). However, the neuroprotective effect on astrocytes depends on whether quercetin metabolites are able to pass the Blood-Brain Barrier, which requires coadministation of alpha-tocopherol to enhance transport (Mechanisms of Neuroprotection by Quercetin: Counteracting Oxidative Stress and More, Oxidative Medicine and Cellular Longevity 2016; 2016: 2986796; see also: Potential for Brain Accessibility and Analysis of Stability of Selected Flavonoids in Relation to Neuroprotection in Vitro, Brain Research Vol. 1651, 15 November 2016, P17-26). Another counterinflammatory mechanism of quercetin is the blocking of poly-unsaturated fatty acid (PUFA) through inhibition of lipoxygenase.
Seemingly paradoxical, quercetin can increase NF-kB activation through phosphorylation of Thr23 and Ser22. Activation of the NF-kB pathway might be the defense mechanism by tumor cells in response to quercetin, but NF-kB activity through nuclear factor IKK-alpha and IKK-beta phosphorylation has probable anti-carcinogenic properties. Whether patients would benefit from quercetin supplementation, is gene-dependent (Quercetin inhibits prostate cancer by attenuating cell survival and inhibiting anti-apoptotic pathways, World Journal of Surgical Oncology 2018; 16: 108). In vivo, Cisplatin and Quercetin, (CP and QC) act synergistically with hyperthermia (43 °C) to inhibit tumor growth; however, caution is warranted with regards to anti-oxidative effects of quercetin on cisplatin, which might impair cisplatin therapy (Interactions between Cisplatin and Quercetin at Physiological and Hyperthermic Conditions on Cancer Cells in Vitro and in Vivo, Molecules 2020 Jul; 25(14): 3271).
1.5 The bioavailability question: aglycones and glycosides
The reported optimal dose for quercetin and kaempferol to have cardiovasculoprotective effects is 500 mg of the aglycone form. Flavonols are divided into aglycones and glycosides. Aglycones are fat-soluble (lipophilic), while glycosides, sugar structures, are water-soluble (lipophobic). Dietary fat intake was shown to increase the absorption of quercetin glycones from the intestines. While kaempferol (found in cichorei endive and broccoli) is the most stabile compound, the bioavailability of quercetin flavonols is higher. Of quercetin sources, the 24-hour urinary excretion is highest for red onions; red wine and tea perform poorer (Dietary Quercetin and Kaempferol: Bioavailability and Potential Cardiovascular-Related Bioactivity in Humans, MDPI Nutrients 2019, 11(10), 2288).
Recommended literature
Therapeutic potential of quercetin as a cardiovascular agent, European Journal of Medicinal Chemistry Vol. 155, 15 July 2018, P889-904.
In this study, quercetin was found to inhibit LDL (Low Density Lipoprotein) oxidation, to reduce adhesion molecules and to protect against platelet aggregation.
Prophylactic efficacy of Quercetin in ameliorating the hypoxia induced vascular leakage in lungs of rats, PLoS One 2019; 14(6);
Pleiotropic beneficial effects of epigallocatechin gallate, quercetin and delphinidin on cardiovascular diseases associated with endothelial dysfunction, Cardiovascular and hematological agents in medicinal chemistry 2013 December;11(4):249-64;
Quercetin in Hypoxia-Induced Oxidative Stress: Novel Target for Neuroprotection, International Review of Neurobiology Vol. 102, 2012, P107-146;
2. Polysaccharides
2.1 Antioxidant and immunomodulatory properties
In Paragraph 1 I discussed the pharamcological and prophylactic potential of quercetin, as well as risks of dietary or supplementary intake of quercetin. Quercetin is known for its immunomodulatory and antioxidant properties: it is associated with NF-kB inhibition, suppression of Lipopolysaccharide (LPS)-induced macrophage activation of STAT-1 and TNF-alpha and reduction of Oxidative Stress. Oxidative Stress, NF-kB, elevated levels of IL-1, IL-6, TNF-alpha, cell adhesion molecules ICAM-I, VCAM-I and P-selectin are associated with hypoxia. In addition, vegetable polysaccharides are associated with specific antifibrotic properties.
2.2 Antifibrotic activity of vegetable polysaccharides against BLM-fibrosis
In BLM-fibrosis (bleomycin-stimulated fibrosis), plant polysaccharides are shown to alleviate inflammation of pulmonary alveoli, reduction of hyaluronic acid and deposition of collagen fibrils. Seaweed sargassum hemiphyllum attenuates the increased expression of TIMP-1, CXCL1, MCP-1, MIP-2, and interleukin-1 receptor antagonist (IL-1RA). Seaweed, administered in therapeutic doses, is able to arrest TGF-β1-induced human embryonic pulmonary fibroblast (HEPF)
cell proliferation, collagen deposition and matrix metalloproteinase
activity. Ginsen has a high binding affinity for TGF-β1. Basil suppresses TGF-β1-induced fibrotic activity and marine algae inhibit heparin/heparan sulfate-TGF-β1-interaction (A review for natural polysaccharides with anti-pulmonary fibrosis properties, which may benefit to patients infected by 2019-nCoV, Carbohydrate Polymers 2020 Nov 1; 247: 116740).
Ophiocordyceps lanpingensis (OLP) funghi polysaccharides suppress expression levels of TNF-α, IL-1β, IL-6 (Macrophage M1-secreted), OSM, IL-10 and IL-13 (Macrophage M2-secreted) genes in lung tissues. OLP decreases MCP-1 and decreases Reactive Oxygen Species/Oxidative Stress though counteracting lipid peroxidation activity. These mechanisms show the potential of OLP to inhibit pulmonary fibrosis through reduction of macrophages and through antioxidant activity targeting lipid peroxidation (Ophiocordyceps lanpingensis polysaccharides attenuate pulmonary fibrosis in mice, Biomedicine & Pharmacotherapy Vol. 126, June 2020).
3. Curcumin compounds
3.1 Curcumin analogs suppress IL1-β and COX-2 to attenuate hyperinflammation
Curcumin analogs are shown to inhibit the expression of TNF-alpha and IL-6 by downregulation of the Extracellular signal-regulated kinase (ERK) and to suppress IL1-β in epithelial cells and Cyclooxygenase 2 (COX-2) (Anti-inflammatory effects of novel curcumin analogs in experimental acute lung injury, Respiratory Research 2015; 16(1): 43). The function of COX-2 is to synthesize prostaglandins involved in the "inflammatory soup". A 2008 study found curcumin, adjusted as a NF-kB blocker, to attenuate hypoxia-induced lung leakage (Role of Oxidative Stress and NF-kB in Hypoxia-Induced Pulmonary Edema, Journal of Experimental Biology and Medicine Vol. 233, Issue 9, 2008).
In vivo studies have shown that curcumin inhibits inflammatory cytokines IL-1, IL-6, IL-8, Tumor Necrosis Factor-alpha (TNF-α), IKKβ and IL-1β. Curcumin decreases expression of inflammatory and profibrotic factors such as MCP1, CXCL1, CXCL10, MMP-2, Interferon-gamma (IFN-γ) and MMP-9.
Curcumin is mentioned to act on p65 to block the NF-κB pathway. Inhibition of Toll-like receptor 2, 4 and 7 (TLR 2, 4 and 7) expression and TRAF6 genes reduces viral inflammation. Curcumin compounds regulate IL-10, which in its turn is a regulator of TNF-alpha, Reactive Oxidative Stress and Treg cells (IL-10 plays an important role as an immune-modulator in the pathogenesis of atopic diseases, Molecular Medicine Reports 2008;1(6):837-42). IL-10 is an anti-inflammatory cytokine that suppresses the expression of Intercellular Adhesion Molecule-1 (ICAM-1) in the vasculature, thereby reducing tissue damage. Notably, curcumin activates the Nrf2-hemeoxygenase-1 (Nrf2-HO-1)-axis, an antiviral and immunomodulating mechanism to protect the pulmonary alveoli (The Inhibitory Effects of Curcumin on Virus-Induced Cytokine Storm and its Potential Use in the Associated Severe Pneumonia, Frontiers in Cell and Developmental Biology, 12 June 2020).
Curcumin has also been shown to upregulate ACE2 and Angiotensin II Type II receptor and downregulate Angiotensin II type I receptor, in order to restore balance in the Renin-Angiotensin-Aldosterone System (RAS/RAAS) (Potential effects of curcumin in the treatment of COVID-19 infection, Phytotherapy Research, 19 May 2020).
Beside anti-Reactive Oxidative Stress (ROS) properties, curcumin compounds carry out mechanisms to protect lung tissue:
1. Curcumin compounds regulate anti-inflammatory IL-10;
2. Curcumin activates antiviral activity and immunomodulation via the Nrf2-OH-1-axis.
A major downside is that turmeric curcumin is not a stable compound. The properties of curcumin, however, offer pharmaceutical options.
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| Zeaxanthin (a carotenoid found in the eye retina) and quercetin! |
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| Bell peppers in green, red and orange; chili peppers, garlic, red onions, curcuma, ginger |
4. Warning: drug interactions with grapefruit flavonoids and non-flavonoids
Grapefruit: Although grapefruits offer a rich source of flavonoids (naringenin, naringin, quercetin and kaempferol) and non-flavonoids (bergamottin), naringin and the furinocoumarin bergamottin are able to inhibit CYP3A4 in the small intestines. CYP3A4 enzymes break down drugs. Inhibition of CYP3A4 creates the risk of an actual overdose. Immunosuppressants, calcium antagonists (cardiovascular medication) and muscle relaxants such as benzodiazepines interact with grapefruit furanocoumarins (Grapefruit and drug interactions, Prescrire International 2012 Dec;21(133):294; Interaction of Grapefruit Juice and Calcium Channel Blockers, American Journal of Hypertension Vol. 19, Issue 7, July 2006).
5 Next feature
Next feature, I will discuss immunomodulatory properties of nutrition. Among one of the prominent compounds is the steroid hormone commonly known as Vitamin D3, calcitriol, in its active form 1,25-dihydroxyvitamin D3 = 1,25(OH)2D3.
Also worth mentioning in a next feature is a compound with presumed anti-inflammatory properties: bromelain, found in pineapples. Bromelain compounds in synergy with acteylcysteine is hypothesized to exert antiviral activity.
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| Bell pepper is a source of zeaxanthin, retinol (Vit A), ascorbic acid (Vit C) and flavonoids |
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| Do not overdo it! While only large amounts of chili peppers/capsicum annuum will contain significant nutritional values of Vitamin A and C, its main ingredient capsaicin (found in the glands of the membranes) is highly irritant when ingested at even lower amounts. |
