The cookbook edition

In the "Nutrition series", I discuss the biochemical mechanisms underlying immunomodulatory, anti-inflammatory, cardiovasculoprotective and antithrombotic activities of nutrients. Metabolism of nutrients needs further investigation. The uptake and metabolism (after processing in the liver, kidneys and intestines) of some nutrients is seemingly poor (but not proven yet).  The point is to not believe in a prodigy nutrient or to rely on an unbalanced diet consisting of what people think are "super foods".

I will share some examples of foods that are abundant in antioxidants and that likely exert anti-inflammatory as well as immunomodulatory properties.

Antioxidants and quercetin: bell peppers, red cabbage, garlic, red and white onions, tomatoes and grapes

Citrus fruits, onions and cauliflower are sources of quercetin. Apple peels are a source of Ursolic Acid

 

Antioxidants naturally appear in colored legumes and fruits and color compounds protect vegetables against UV-radiation. Use it, don't overdo it. A varied diet is key

Cyanidin is a dominant flavylium in red cabbage, blueberries, red onion and blue grapes. Cyanidin exerts antioxidant and neuroprotective properties

Recipes for color-rich food

Home-made noodles with bell peppers and mushrooms
- 1,5 kg red (and/or white) onions;
- Red, green and orange bell peppers;
- 2 bulbs of garlic;
- 2 or 3 chili peppers;
- 2-3 trays of mushrooms;
- 1,5 inch of ginger;
- Season: curry, cumin, turmeric, pepper powder, cumin seed;
- Bean sprouts;
- Optional: chicken meat;
- Optional: linguine;
- Butter

Cut the onions and bell peppers in small pieces. It will take less time to extract water out of the vegetables. Peel 1 to 2 bulbs of garlic and cut them in very small slices or use a grater. Don't be afraid of the garlic: even these amounts will blend into your season and vegetable mix without getting too intense. Use latex gloves or a fork and a knive to part 2 chili peppers and cut them into small rings. The "pungent" part of a chili peppers is its skin, which contains capsaicin. Fatty substances absorb capsaicin. Adding butter during cooking will make the mix less pungent. Peel 1,5 inch or more of ginger root with the edge of a grapefruit spoon. The peel will come off surprisingly easy. You can grate the ginger root or julienne them. Some ginger roots can be very 'thready' when trying to julienne. This is when it's easier to use a handheld grater with small holes.

Make a season consisting of curry, cumin, turmeric, pepper powder and cumin seed. Slice the mushrooms. You can use a cast iron pan or a casserole. The benefit of a cast iron pan is that your legumes will not easily stick to the bottom. Stew the mushroom slices in a small amount of vegetable oil (1 spoon) until all the water has evaporated. Take the mushrooms out and store them on a heat-resistant plate. Stew the vegetables in one spoon of oil. Add the season during the process. If you opt to use a high temperature, keep stirring the mix with a ladle! If the water has evaporated, add the mushrooms to the legumes. Turn the lid on the pan and lower or minimize the temperature.

Take the chicken out of the fridge. Pat it dry with thick paper towel. Use a separate, heat-resistant plate for processing raw chicken meat; rinse the plate with boiling water immediately after storing raw chicken on it. Fry the chicken in a frying pan. Use sunflower oil or another vegetable oil. Chicken meat should always be well-done to avoid contamination with salmonella bacteria! Is the chicken well-done? Cut the meat into smaller pieces on a clean plate. Add the chicken to the vegetables. Lastly, add the bean sprouts. Never eat raw bean sprouts, as these might contain E.coli and salmonella, due to contamination of its sources.

You can now opt to add spaghettini, linguine, spaghetti or ramen noodles, depending on the favorable thickness.

Red cabbage salad
- 1/2 red cabbage (optional: a quarter white cabbage and a quarter red cabbage);
- Raisins;
- Mayonnaise or tartar sauce;
- Lemon;
- 1 yellow onion;
- 1 inch of grated ginger (optional)

Take off the outer layer of the cabbage and part the cabbage with a knife. Use a grater with medium holes to grate the cabbage. Peel the onion and grate. Add a few spoons of mayonnaise or tartar sauce. Add raisins to Squeeze half a lemon and pour the lemon juice over the mix. You can opt to add 1 inch of grated ginger, but do not overdo this combination, as ginger and lemon juice might taste like "dish water".

White/pointed cabbage curry
- 1 pointed cabbage or white cabbage;
- 3 leeks;
- 3 yellow or red onions;
- 2 chili peppers;
- 1 1/2 inch of ginger;
- 1 bulb of garlic;
- 1 teaspoon 5 spice mix;
- fennel seed;
- cayenne pepper, ground;
- cumin ground;
- cinnamon ground;
- optional: chicken, bacon or without meat

A biochemical perspective on nutrition, immunomodulation and counteracting of oxidative stress (1): quercetin, polysaccharides and curcumin compounds

"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).

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.

Zeaxanthin (a carotenoid found in the eye retina) and quercetin!

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)₂D<sub>3.

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.</sub>

Bell pepper is a source of zeaxanthin, retinol (Vit A), ascorbic acid (Vit C) and flavonoids

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.

Extensive reading recommendations on SARS-CoV-2/COVID-19: all mechanisms involved (Part 6)

Factors involved in SARS-CoV-2/COVID-19

Activated endothelium as a source of Acute Lung Injury (ALI)/ARDS
Angiopoietin-2, permeability oedema, occurrence and severity of ALI/ARDS in septic and non-septic critically ill patients, BMJ Thorax Journal Vol 63, Issue 10, October 2008;
Endothelial biomarkers in human sepsis: pathogenesis and prognosis for ARDS, Pulmonary Circulation 2018 Apr-Jun; 8(2);

Acute Lung Injury (ALI)
A Perspective on Erythropoietin as a Potential Adjuvant Therapy for Acute Lung Injury (ALI)/ARDS in Patients with COVID-19, Archives of Medical Research 2020, Aug 11;

Coagulation
Thromboinflammation and the hypercoagulability of COVID-19, Journal of Thrombosis and Haemostasis, 13 April 2020;

Embolism
Pulmonary embolism in COVID-19 patients: a French multicentre cohort study, European Heart Journal Vol. 41, Issue 32, 21 August 2020, p3058-3068;

Hypoxia and HIF as a link between sepsis and thrombosis
Hypoxia and HIF activation as a possible link between sepsis and thrombosis, Thrombosis Journal 2019; 17: 16;
The stimulation of thrombosis by hypoxia, Thrombosis Research Vol. 181, p77-83, September 01, 2019;
Hypoxia response and acute lung and kidney injury: possible implications for therapy of COVID-19, Clinical Kidney Journal 2020 Aug; 13(4): 494-499;
Innate immunity during SARS-CoV-2: evasion strategies and activation trigger hypoxia and vascular damage, Clinical and Experimental Immunology, Journal of Translational Immunology, 26 September 2020;
COVID-19: hemoglobin, iron and hypoxia beyond inflammation: A narrative review, Clinics and Practice 2020 May 19; 10(2): 1271;
miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target, Angiogenesis 2018; 21(2): 183-202;

Hypoxia and Reactive Oxygen Species (ROS) (oxidative stress)
Keeping the engine primed: HIF factors as key regulators of cardiac metabolism and angiogenesis during ischemia, Journal of Molecular Medicine 2007 Dec;85(12):1309-15;
Role of oxidative stress and NFkB in hypoxia-induced pulmonary edema (curcumin as a NFkB blocker attenuates hypoxia-induced edema), Experimental Biology and Medicine Vol. 233, Issue 9, 2008;

Pathogenesis and structure of SARS-CoV-2
Does the pathogenesis of SARS-CoV-2 decrease at high-altitude?, Respiratory Physiology & Neurobiology Vol. 277, June 2020;
Mechanisms of Coronavirus Cell Entry Mediated by the Viral Spike Protein, MDPI Viruses 2012 Jun;4(6): 1011-1033;
Structure, Function and Evolution of Coronavirus Spike Proteins, Annual Reviews Virology 2016 Sep 29; 3(1): 237-261;
Cleavage of the SARS Coronavirus Spike Glycoprotein by Airway Proteases Enhances Virus Entry into Human Bronchial Epithelial Cells in Vitro, PLoS 2009; 4(11): e7870;

Pattern Recognition Receptors, Interferon pathways and cytokine cascades
Innate immunity during SARS-CoV-2: evasion strategies and activation trigger hypoxia and vascular damage, Clinical and Experimental Immunology, Journal of Translational Immunology, 26 September 2020;

Pulmonary vascular (right ventricular) consequences of COVID-19
Novel insights on the pulmonary vascular consequences of COVID-19, Lung Cellular and Molecular Physiology 2020 Aug 1; 319(2): L277-288;

Sepsis
Sepsis and septic shock: endothelial molecular pathogenesis associated with vascular thrombotic disease, Thrombosis Journal 2019; 17: 10;
Endothelial biomarkers in human sepsis: pathogenesis and prognosis for ARDS, Pulmonary Circulation 2018 Apr-Jun; 8(2);

Therapeutics and possible treatment options for COVID-19
Oxytocin as a Potential Adjuvant against COVID-19 Infection, Endocrine, Metabolic & Immune Disorders Drug Targets 2020, Sep 10;
Prophylactic efficacy of Quercetin in ameliorating the hypoxia induced vascular leakage in lungs of rats, PLoS One 2019; 14(6);
Nifedipine inhibits hypoxia induced transvascular leakage through downregulation of NFkB, Respiratory Physiology & Neurobiology Vol. 183, Issue 1, 31 July 2012, p26-34;

Extensive reading recommendations on SARS-CoV-2/ COVID-19: all mechanisms involved (Part 5)

So many factors involved! A non-exhaustive overview of factors involved in COVID-19

ADAMTS-13

All complications of COVID-19
Overview of lethal human coronaviruses, Signal Transduction and Targeted Therapy 2020; 5: 89;

B cell profiles
Illuminating vitamin D effects on B cells- the Multiple Sclerosis perspective, Immunology 2016 Mar; 147(3): 275-284;

Cardiovascular complications of COVID-19
Anticipating the long-term cardiovascular effects of COVID-19, Journal of Thrombosis and Thrombolysis 2020 Sep 3: 1-13;
COVID-19 and Heart Failure With Preserved Ejaction Fraction, JAMA September 30, 2020;

Coagulation
Unique transcriptional changes in coagulation cascade genes in SARS-CoV-2 infected lung epithelial cells: A potential factor in COVID-19 coagulopathies, NIH MedRvix Preprint, 2020 Jul 7;
COVID-19 and Coagulopathy:  FAQ, ASH 24 September 2020;

Development of therapeutics for COVID-19
Challenging pathway towards the identification of SARS-CoV-2/COVID-19 therapeutics, Journal of Antimicrobial Chemotherapy Vol. 75, Issue 9, September 2020, p2381-2383;
COVID-19/SARS-CoV-2 Infection: Lysosomes and Lysosomotropism Implicate New Treatment Strategies and Personal Risks, International Journal of Molecular Sciences 2020 Jul; 21(14): 4953;
SARS-CoV-2/COVID-19 and advances in developing potential therapeutics and vaccines to counter this emerging pandemic, Annals of Clinical Microbiology and Antimicrobials 2020; 19: 40;
Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing, Nature 586, 113-119(2020);

Embolism
COVID-19 and Pulmonary Embolism: FAQ, 22 September 2020;

Immunology
T-helper type I cytokine release is enhanced by in vitro zinc supplementation due to increased natural killer cells, Nutrition Vol. 23, Issue 2, February 2007, p157-163;
Zinc signals and immune function (NK-, T- and B-cells), BioFactors Vol. 40, Issue 1, January/February 2014, p27-40;

Inflammatory response to SARS-CoV-2 in COVID-19
Understanding COVID-19: From Origin to Potential Therapeutics, International Journal of Environmental Research and Public Health 2020 Aug;17(16): 5904;

Inhibitors to explore
Coronaviruses and Nature's Pharmacy for the Relief of COVID-19 (inhibitory properties of natural compounds), Revista Brasileira de Farmacognosia 2020 Oct 6: 1-19;

Interferon
Attenuated Interferon and Proinflammatory Response in SARS-CoV-2-Infected Human Dendritic Cells is Associated with Viral Antagonism of STAT1 Phosphorylation, The Journal of Infectious Diseases Vol. 222, Issue 5, 1 September 2020;
Auto-antibodies against type I IFNs in patients with life-threatening COVID-19, AAAS Science, 24 Sep 2020 (treatment with injected or nebulized IFN-β may have beneficial effects);

Macrophages
Attenuated Interferon and Proinflammatory Response in SARS-CoV-2-Infected Human Dendritic Cells is Associated with Viral Antagonism of STAT1 Phosphorylation, The Journal of Infectious Diseases Vol. 222, Issue 5, 1 September 2020;

Nsp3 and STAT1 in cytokine storm syndrome
A Putative Role of de-Mono-ADP-Ribosylation of STAT1 by the SARS-CoV-2 Nsp3 Protein in the Cytokine Storm Syndrome of COVID-19, Viruses 2020 Jun; 12(6): 646;

Oxidative Stress
Zinc status is associated with inflammation, oxidative stress, lipid and glucose metabolism, The Journal of Physiological Sciences 2018; 68(1): 19-31;
Relations between metabolic syndrome, oxidative stress and inflammation and cardiovascular disease, Verhandelingen van de Koninklijke Academie voor Geneeskunde van België 2008;70(3):193-219;

Pathogenesis, evolution and structure of SARS-CoV-2
Rampant C > U Hypermutation in the Genomes of SARS-CoV-2 and Other Coronaviruses: Causes and Consequences for their Short- and Long-Term Evolutionary Trajectories, mSphere 2020 May-Jun; 5(3);
Mutation Patterns of Human SARS-CoV-2 and Bat RATG13 Coronavirus Genomes are Strongly Biased Towards C > U Transitions, Indicating Rapid Evolution in Their Hosts, Genes (Basel.) 2020 Jul; 11(7):761;
Molecular epidemiology, evolution and phylogeny of SARS coronavirus, Infection, Genetics and Evolution 2019 Jul; 71: 21-30;
Overview of lethal human coronaviruses, Signal Transduction and Targeted Therapy 2020; 5: 89;
2017 Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus, PLoS Pathogens 2017 Nov;13(11);
Signal hotspot mutations in SARS-CoV-2 evolve as the virus spreads and actively replicates in different parts of the world, Virus Research 2020 Nov; 289: 198170;

Possible treatment options
Early Nutritional Interventions with Zinc, Selenium and Vitamin D for Raising Anti-Viral Resistance Against Progressive COVID-19, MDPI Nutrients 2020, 12(8), 2358;
Current State of Evidence: Influence of Nutritional and Nutrigenetic Factors on Immunity in the COVID-19 Pandemic Framework, MDPI Nutrients 2020, 12(9), 2738;
A Hypothesis for the Possible Role of Zinc in the Immunological Pathways Related to COVID-19 Infection, Frontiers in Immunology 2020; 11:1736;
Statin therapy and SARS-CoV-2: an available and potential therapy?, European Heart Journal of Cardiovascular Pharmacotherapy 2020, May 7 2020;
Nutraceuticals have potential for boosting the Type I Interferon (IFN) response to RNA viruses, including influenza and coronavirus, Progress in Cardiovascular Diseases 2020 May-June; 63(3): 383-385;
Azithromycin and Glucosamine May Amplify the Type I Interferon (IFN) Response to RNA viruses in a complementary fashion, Immunology Letters 2020 Sep 28;

Sepsis and septic shock
Sepsis and septic shock: endothelial molecular pathogenesis associated with vascular microthrombotic disease, Thrombosis Journal 2019; 17: 10;