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1.
Open Heart ; 9(1)2022 03.
Article in English | MEDLINE | ID: covidwho-1752901

ABSTRACT

Ferulic acid, a bacterial metabolite of anthocyanins, seems likely to be a primary mediator of the health benefits associated with anthocyanin-rich diets, and has long been employed in Chinese cardiovascular medicine. In rodent studies, it has exerted wide-ranging antioxidant and anti-inflammatory effects, the molecular basis of which remains rather obscure. However, recent studies indicate that physiologically relevant concentrations of ferulic acid can boost expression of Sirt1 at mRNA and protein levels in a range of tissues. Sirt1, a class III deacetylase, functions to detect a paucity of oxidisable substrate, and in response works in various ways to promote cellular survival and healthful longevity. Sirt1 promotes 'cell cleansing' and cell survival by boosting autophagy, mitophagy, mitochondrial biogenesis, phase 2 induction of antioxidant enzymes via Nrf2, and DNA repair-while inhibiting NF-kB-driven inflammation, apoptosis, and cellular senescence, and boosting endothelial expression of the protective transcription factor kruppel-like factor 2. A deficit of the latter appears to mediate the endothelial toxicity of the SARS-CoV-2 spike protein. Ferulic acid also enhances the activation of AMP-activated kinase (AMPK) by increasing expression and activity of its activating kinase LKB1-whereas AMPK in turn amplifies Sirt1 activity by promoting induction of nicotinamide phosphoribosyltranferase, rate-limiting for generation of Sirt1's obligate substrate NAD+. Curiously, AMPK acts by independent mechanisms to potentiate many of the effects mediated by Sirt1. Hence, it is proposed that ferulic acid may exert complementary or synergistic health-promoting effects when used in conjunction with clinically useful AMPK activators, such as the nutraceutical berberine. Additional nutraceuticals which might have potential for amplifying certain protective effects of ferulic acid/berberine are also discussed.


Subject(s)
Berberine , COVID-19 , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Anthocyanins , Berberine/pharmacology , Coumaric Acids , Humans , Longevity , SARS-CoV-2 , Sirtuin 1/genetics , Sirtuin 1/metabolism , Spike Glycoprotein, Coronavirus
4.
Open Heart ; 8(1)2021 03.
Article in English | MEDLINE | ID: covidwho-1143081

ABSTRACT

A recent retrospective study has provided evidence that COVID-19 infection may be notably less common in those using supplemental melatonin. It is suggested that this phenomenon may reflect the fact that, via induction of silent information regulator 1 (Sirt1), melatonin can upregulate K63 polyubiquitination of the mitochondrial antiviral-signalling protein, thereby boosting virally mediated induction of type 1 interferons. Moreover, Sirt1 may enhance the antiviral efficacy of type 1 interferons by preventing hyperacetylation of high mobility group box 1 (HMGB1), enabling its retention in the nucleus, where it promotes transcription of interferon-inducible genes. This nuclear retention of HMGB1 may also be a mediator of the anti-inflammatory effect of melatonin therapy in COVID-19-complementing melatonin's suppression of nuclear factor kappa B activity and upregulation of nuclear factor erythroid 2-related factor 2. If these speculations are correct, a nutraceutical regimen including vitamin D, zinc and melatonin supplementation may have general utility for the prevention and treatment of RNA virus infections, such as COVID-19 and influenza.


Subject(s)
COVID-19/drug therapy , Melatonin/adverse effects , RNA Virus Infections/drug therapy , Antioxidants/adverse effects , COVID-19/epidemiology , Humans , RNA Virus Infections/epidemiology , Risk Factors , SARS-CoV-2
5.
Mo Med ; 118(1): 68-73, 2021.
Article in English | MEDLINE | ID: covidwho-1068428

ABSTRACT

Magnesium and vitamin D each have the possibility of affecting the immune system and consequently the cytokine storm and coagulation cascade in COVID-19 infections. Vitamin D is important for reducing the risk of upper respiratory tract infections and plays a role in pulmonary epithelial health. While the importance of vitamin D for a healthy immune system has been known for decades, the benefits of magnesium has only recently been elucidated. Indeed, magnesium is important for activating vitamin D and has a protective role against oxidative stress. Magnesium deficiency increases endothelial cell susceptibility to oxidative stress, promotes endothelial dysfunction, reduces fibrinolysis and increases coagulation. Furthermore, magnesium deficient animals and humans have depressed immune responses, which, when supplemented with magnesium, a partial or near full reversal of the immunodeficiency occurs. Moreover, intracellular free magnesium levels in natural killer cells and CD8 killer T cells regulates their cytotoxicity. Considering that magnesium and vitamin D are important for immune function and cellular resilience, a deficiency in either may contribute to cytokine storm in the novel coronavirus 2019 (COVID-19) infection.


Subject(s)
COVID-19/complications , Cytokine Release Syndrome/etiology , Disseminated Intravascular Coagulation/etiology , Immune System Diseases/etiology , Magnesium Deficiency/complications , Vitamin D Deficiency/complications , Animals , CD8-Positive T-Lymphocytes/drug effects , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/virology , Humans , Killer Cells, Natural/drug effects , Magnesium/administration & dosage , Magnesium/pharmacology , Magnesium/therapeutic use , Oxidative Stress/drug effects , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Vitamin D/administration & dosage , Vitamin D/pharmacology , Vitamin D/therapeutic use , Vitamins/administration & dosage , Vitamins/pharmacology , Vitamins/therapeutic use
6.
Nutrients ; 13(1)2020 Dec 25.
Article in English | MEDLINE | ID: covidwho-1016213

ABSTRACT

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-1ß and pro-interleukin-18 to active interleukin-1ß 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.


Subject(s)
Antioxidants/therapeutic use , COVID-19 , Dietary Supplements , Inflammasomes/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , SARS-CoV-2/metabolism , Animals , COVID-19/diet therapy , COVID-19/metabolism , COVID-19/pathology , Humans
7.
Nutrients ; 13(1):47, 2021.
Article in English | ScienceDirect | ID: covidwho-984579

ABSTRACT

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-1βand pro-interleukin-18 to active interleukin-1βand 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.

8.
Open Heart ; 7(2)2020 09.
Article in English | MEDLINE | ID: covidwho-772161

ABSTRACT

Risk factors for COVID-19 patients with poorer outcomes include pre-existing conditions: obesity, type 2 diabetes mellitus, cardiovascular disease (CVD), heart failure, hypertension, low oxygen saturation capacity, cancer, elevated: ferritin, C reactive protein (CRP) and D-dimer. A common denominator, hyperinsulinaemia, provides a plausible mechanism of action, underlying CVD, hypertension and strokes, all conditions typified with thrombi. The underlying science provides a theoretical management algorithm for the frontline practitioners.Vitamin D activation requires magnesium. Hyperinsulinaemia promotes: magnesium depletion via increased renal excretion, reduced intracellular levels, lowers vitamin D status via sequestration into adipocytes and hydroxylation activation inhibition. Hyperinsulinaemia mediates thrombi development via: fibrinolysis inhibition, anticoagulation production dysregulation, increasing reactive oxygen species, decreased antioxidant capacity via nicotinamide adenine dinucleotide depletion, haem oxidation and catabolism, producing carbon monoxide, increasing deep vein thrombosis risk and pulmonary emboli. Increased haem-synthesis demand upregulates carbon dioxide production, decreasing oxygen saturation capacity. Hyperinsulinaemia decreases cholesterol sulfurylation to cholesterol sulfate, as low vitamin D regulation due to magnesium depletion and/or vitamin D sequestration and/or diminished activation capacity decreases sulfotransferase enzyme SULT2B1b activity, consequently decreasing plasma membrane negative charge between red blood cells, platelets and endothelial cells, thus increasing agglutination and thrombosis.Patients with COVID-19 admitted with hyperglycaemia and/or hyperinsulinaemia should be placed on a restricted refined carbohydrate diet, with limited use of intravenous dextrose solutions. Degree/level of restriction is determined by serial testing of blood glucose, insulin and ketones. Supplemental magnesium, vitamin D and zinc should be administered. By implementing refined carbohydrate restriction, three primary risk factors, hyperinsulinaemia, hyperglycaemia and hypertension, that increase inflammation, coagulation and thrombosis risk are rapidly managed.


Subject(s)
Coronavirus Infections/therapy , Diet, Carbohydrate-Restricted , Dietary Supplements , Hyperinsulinism/therapy , Insulin/blood , Magnesium/therapeutic use , Pneumonia, Viral/therapy , Thrombosis/therapy , Vitamin D/therapeutic use , Betacoronavirus/pathogenicity , Biomarkers/blood , Blood Glucose/metabolism , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Dietary Supplements/adverse effects , Host-Pathogen Interactions , Humans , Hyperinsulinism/blood , Hyperinsulinism/epidemiology , Ketones/blood , Magnesium/blood , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , Prognosis , Risk Factors , SARS-CoV-2 , Thrombosis/blood , Thrombosis/epidemiology , Thrombosis/virology , Vitamin D/blood , Zinc/therapeutic use
10.
Med Hypotheses ; 143: 110051, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-624899

ABSTRACT

Counterproductive lung inflammation and dysregulated thrombosis contribute importantly to the lethality of advanced COVID-19. Adenosine A2A receptors (A2AR), expressed by a wide range of immune cells, as well as endothelial cells and platelets, exert cAMP-mediated anti-inflammatory and anti-thrombotic effects that potentially could be highly protective in this regard. The venerable drug pentoxifylline (PTX) exerts both anti-inflammatory and antithrombotic effects that reflect its ability to boost the responsiveness of A2AR to extracellular adenosine. The platelet-stabilizing drug dipyridamole (DIP) blocks intracellular uptake of extracellularly-generated adenosine, thereby up-regulating A2AR signaling in a way that should be functionally complementary to the impact of PTX in that regard. Moreover, DIP has recently been reported to slow the cellular replication of SARS-CoV-2 in clinically feasible concentrations. Both PTX and DIP are reasonably safe, well-tolerated, widely available, and inexpensive drugs. When COVID-19 patients can be treated within several days of symptom onset, using PTX + DIP in conjunction with hydroxychloroquine (HCQ) and an antibiotic - azithromycin (AZM) or doxycycline - might be warranted. HCQ and AZM can suppress SARS-CoV-2 proliferation in vitro and may slow the cell-to-cell spread of the virus; a large case series evaluating this combination in early-stage patients reported an impressively low mortality rate. However, whereas HCQ and AZM can promote QT interval lengthening and may be contraindicated in more advanced COVID-19 entailing cardiac damage, doxycycline has no such effect and exerts a potentially beneficial anti-inflammatory action. In contrast to HCQ, we propose that the combination of PTX + DIP can be used in both early and advanced stages of COVID-19. Concurrent use of certain nutraceuticals - yeast beta-glucan, zinc, vitamin D, spirulina, phase 2 inducers, N-acetylcysteine, glucosamine, quercetin, and magnesium - might also improve therapeutic outcomes in COVID-19.


Subject(s)
Betacoronavirus , Coronavirus Infections/drug therapy , Dipyridamole/therapeutic use , Pandemics , Pentoxifylline/therapeutic use , Pneumonia, Viral/drug therapy , Receptor, Adenosine A2A/metabolism , Adenosine A2 Receptor Agonists/therapeutic use , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/metabolism , Dietary Supplements , Fibrinolytic Agents/therapeutic use , Humans , Models, Biological , Pneumonia/etiology , Pneumonia/prevention & control , Pneumonia, Viral/complications , Pneumonia, Viral/metabolism , SARS-CoV-2 , Signal Transduction/drug effects , Thrombosis/etiology , Thrombosis/prevention & control , Virus Replication/drug effects
11.
Open Heart ; 7(1)2020 06.
Article in English | MEDLINE | ID: covidwho-595177

ABSTRACT

The high rate of thrombotic complications associated with COVID-19 seems likely to reflect viral infection of vascular endothelial cells, which express the ACE2 protein that enables SARS-CoV-2 to invade cells. Various proinflammatory stimuli can promote thrombosis by inducing luminal endothelial expression of tissue factor (TF), which interacts with circulating coagulation factor VII to trigger extrinsic coagulation. The signalling mechanism whereby these stimuli evoke TF expression entails activation of NADPH oxidase, upstream from activation of the NF-kappaB transcription factor that drives the induced transcription of the TF gene. When single-stranded RNA viruses are taken up into cellular endosomes, they stimulate endosomal formation and activation of NADPH oxidase complexes via RNA-responsive toll-like receptor 7. It is therefore proposed that SARS-CoV-2 infection of endothelial cells evokes the expression of TF which is contingent on endosomal NADPH oxidase activation. If this hypothesis is correct, hydroxychloroquine, spirulina (more specifically, its chromophore phycocyanobilin) and high-dose glycine may have practical potential for mitigating the elevated thrombotic risk associated with COVID-19.


Subject(s)
Betacoronavirus/pathogenicity , Blood Coagulation , Coronavirus Infections/virology , Endosomes/virology , Endothelial Cells/virology , NADPH Oxidases/metabolism , Pneumonia, Viral/virology , Thromboplastin/metabolism , Thrombosis/virology , Animals , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Blood Coagulation/drug effects , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/drug therapy , Coronavirus Infections/enzymology , Endosomes/drug effects , Endosomes/enzymology , Endothelial Cells/drug effects , Endothelial Cells/enzymology , Enzyme Activation , Fibrinolytic Agents/therapeutic use , Host-Pathogen Interactions , Humans , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/drug therapy , Pneumonia, Viral/enzymology , SARS-CoV-2 , Signal Transduction , Thrombosis/blood , Thrombosis/enzymology , Thrombosis/prevention & control
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