Melatonin may decrease risk for and aid treatment of COVID-19 and other RNA viral infections.

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.

Azithromycin and glucosamine may amplify the type 1 interferon response to RNA viruses in a complementary fashion.

Previous research demonstrates that, in clinically relevant concentrations, azithromycin can boost the ability of RNA viruses to induce type 1 interferon by amplifying the expression and virally-mediated activation of MDA5. O-GlcNAcylation of MAVS, a down-stream target of MDA5, renders it more effective for type 1 interferon induction. High-dose glucosamine administration up-regulates O-GlcNAcylation by increasing the cellular pool of UDP-N-acetylglucosamine. Hence, it is proposed that joint administration of azithromycin and high-dose glucosamine, early in the course of RNA virus infections, may interact in a complementary fashion to aid their control by enhancing type 1 interferon induction.

Harnessing adenosine A2A receptors as a strategy for suppressing the lung inflammation and thrombotic complications of COVID-19: Potential of pentoxifylline and dipyridamole.

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.

Oxidative stress therapy for solid tumors - a proposal.

Many cancers are deficient in catalase activity, and maintain a moderate level of oxidative stress to aid their proliferation and survival. It may prove feasible to achieve substantial selective tumor kill with a three-pronged strategy for acutely exacerbating oxidative stress in cancer cells: inducing increased production of oxidants in tumors with sustained high-dose infusions of sodium ascorbate and menadione, while concurrently undercutting the antioxidant defenses of cancer cells by imposing glucose deprivation - as with 2-deoxyglucose administration or a hypoglycemic insulin clamp - and by suppressing hypoxia-inducible factor-1 activity with available agents such as salicylate, rapamycin, and irinotecan. Inhibition of pyruvate dehydrogenase-1 with dichloroacetate may also promote oxidative stress in hypoxic cancer cells. Cell culture studies could be employed to devise effective protocols that could be tested in xenografted rodents and, ultimately, in exploratory clinical trials.

Practical strategies for suppressing hypoxia-inducible factor activity in cancer therapy.

The utility of anti-angiogenic strategies for cancer control is strongly compromised by hypoxia-driven phenotypic changes in cancer cells, which make cancer cells more invasive and more prone to give rise to metastases. A key mediator of this phenotypic shift is the transcription factor hypoxia-inducible factor-1 (HIF-1), which acts directly and indirectly to promote the epidermal-mesenchymal transition, boost cancer invasiveness, increase production of angiogenic factors, and induce chemoresistance. In some cancers, HIF-1 activity is constitutively elevated even in aerobic environments, making the cancer harder to treat and control. Practical strategies for suppressing HIF-1 activation may include the following: inhibiting NF-kappaB activation with salicylic acid and/or silibinin, which should decrease transcription of the HIF-1alpha gene; suppressing translation of HIF-1alpha mRNA with drugs that inhibit mTOR or topoisomerase I; supporting the effective activity of prolyl hydroxylases - which promote proteasomal degradation of HIF-1alpha under aerobic conditions - with antioxidant measures, alpha-ketoglutarate, and possibly dichloroacetate; promoting the O(2)-independent proteasomal degradation of HIF-1alpha with agents that inhibit the chaperone protein Hsp90; and blocking HIF-1 binding to its DNA response elements with anthracyclines. The utility of various combinations of these strategies should be tested in cancer cell cultures and rodent xenograft models; initial efforts in this regard have yielded encouraging results. Comprehensive strategies for suppressing HIF-1 activity can be expected to complement the efficacy of cancer chemotherapy and of effective anti-angiogenic regimens.

Potential complementarity of high-flavanol cocoa powder and spirulina for health protection.

Recent studies show that ingestion of flavanol-rich cocoa powder provokes increased endothelial production of nitric oxide - an effect likely mediated by epicatchin - and thus may have considerable potential for promoting vascular health. The Kuna Indians of Panama, who regularly consume large amounts of flavanol-rich cocoa, are virtually free of hypertension and stroke, even though they salt their food. Of potentially complementary merit is the cyanobacterium spirulina, which has been used as a food in certain cultures. Spirulina is exceptionally rich in phycocyanobilin (PCB), which recently has been shown to act as a potent inhibitor of NADPH oxidase; this effect likely rationalizes the broad range of anti-inflammatory, cytoprotective, and anti-atherosclerotic effects which orally administered spirulina has achieved in rodent studies. In light of the central pathogenic role which NADPH oxidase-derived oxidant stress plays in a vast range of disorders, spirulina or PCB-enriched spirulina extracts may have remarkable potential for preserving and restoring health. Joint administration of flavanol-rich cocoa powder and spirulina may have particular merit, inasmuch as cocoa can mask the somewhat disagreeable flavor and odor of spirulina, whereas the antioxidant impact of spirulina could be expected to amplify the bioactivity of the nitric oxide evoked by cocoa flavanols in inflamed endothelium. Moreover, there is reason to suspect that, by optimizing cerebrovascular perfusion while quelling cerebral oxidant stress, cocoa powder and spirulina could collaborate in prevention of senile dementia. Thus, food products featuring ample amounts of both high-flavanol cocoa powder and spirulina may have considerable potential for health promotion, and merit evaluation in rodent studies and clinical trials.

High-dose folate and dietary purines promote scavenging of peroxynitrite-derived radicals--clinical potential in inflammatory disorders.

Reduced folates have been shown to reconstitute the proper activity of "uncoupled" endothelial nitric oxide synthase in inflamed endothlelium. There is recent evidence that this phenomenon may reflect an ability of reduced folates to scavenge peroxynitrite - or, more likely, nitrogen dioxide and carbonate radicals derived from carbonate-induced decomposition of peroxynitrite. This suggests that, at least in those tissues capable of achieving high intracellular levels of reduced folates following high-dose folate administration, high-dose folate may have important anti-inflammatory potential. It would be of interest to examine the impact of high-dose folate in rodent models of disorders in which peroxynitrite plays a key pathogenic role - including diabetes, septic or hemorrhagic shock, ischemia-reperfusion, congestive heart failure, and inflammatory mutagenesis. In particular, this strategy may be useful in many pathologies in which oxidant-mediated PARP activation leads to cell death or dysfunction. Recent evidence that high-dose folate administration preserves myocyte viability following cardiac ischemia-reperfusion likely reflects folate's impact on the cytotoxicity of peroxynitrite. For use in medical emergencies, parenteral leucovorin (racemic 5-formyltetrahydrofolate) is already clinically available. Since uric acid can also function physiologically as a scavenger of peroxynitrite-derived radicals, supplemental inosine or dietary nucleic acids - which raise tissue levels of urate more effectively than does oral uric acid - may usefully complement the protective impact of high-dose folate on nitroxidative stress. Epidemiological associations of high urate levels with low risk for Parkinson's disease may reflect urate's radical scavenging activity, and suggest the possible utility of dietary purines in prevention or treatment of CNS inflammatory disorders.

The hyperpolarizing impact of glycine on endothelial cells may be anti-atherogenic.

Studies to date indicate that endothelial cells express glycine-activated chloride channels, which promote hyperpolarization of the endothelial plasma membrane. If such channels are expressed by endothelial cells lining conduit arteries, glycine is likely to have anti-atherogenic activity. This reflects the fact that endothelial hyperpolarization promotes calcium influx, activating the endothelial isoform of nitric oxide synthase, while also down-regulating the activity of the membrane-bound NADPH oxidase, chief endothelial source of superoxide. Since macrophages express glycine-activated chloride channels that suppress production of oxidants and cytokines, glycine may also oppose atherogenesis by influencing intimal macrophage function. In rats, supplemental glycine exerts anti-inflammatory and anti-angiogenic effects attributed to chloride channel activation. Administration of large daily doses of glycine would appear to be practical and safe, and has already been shown to inhibit protein glycation in human diabetics.

Regular thermal therapy may promote insulin sensitivity while boosting expression of endothelial nitric oxide synthase--effects comparable to those of exercise training.

Regular thermal therapy, using saunas or hot baths, has the potential to improve impaired insulin sensitivity and boost endothelial expression of the "constitutive" isoform of nitric oxide synthase--effects, analogous to those of aerobic training that should promote vascular health. Previous clinical reports suggest that hot tubs may be beneficial for diabetic control, and that sauna therapy can decrease blood pressure in essential hypertension and provide symptomatic benefit in congestive heart failure. For those who lack ready access to a sauna or communal hot tub, regular hot baths at home may suffice as practical thermal therapy. Thermal therapy might be viewed as an alternative to exercise training in patients too physically impaired for significant aerobic activity.

A two-phase strategy for treatment of oxidant-dependent cancers.

In many cancers, a chronic increase in oxidant stress - associated with elevated levels of hydrogen peroxide - contributes to the increased proliferative rate, diminished apoptosis, increased angiogenic and metastatic capacity, and chemoresistance that often characterize advanced malignancies. This oxidant stress often reflects up-regulation of expression and activity of NADPH oxidase, and/or decreased activity of catalase, which functions as suppressor gene in oxidant-dependent cancers. These characteristics of oxidant-dependent cancers suggest a dual strategy for treatment of these cancers. Since ascorbate can react spontaneously with molecular oxygen to generate hydrogen peroxide, high-dose intravenous ascorbate should be selectively toxic to tumors that are low in catalase activity - as suggested by numerous cell culture studies. Measures which concurrently improve the oxygenation of hypoxic tumor regions would be expected to boost the efficacy of such therapy; calcitriol and high-dose selenium might also be useful in this regard. Secondly, during the intervals between sessions of ascorbate therapy, administration of agents which can safely inhibit NADPH oxidase would be expected to slow the proliferation and spread of surviving tumor cells - while providing selection pressure for a further decline in catalase activity. In effect, cancers treated in this way would be whipsawed between lethally excessive and inadequately low oxidant stress. An additional possibility is that ascorbate-induced oxidant stress in tumors might potentiate the cell kill achieved with concurrently administered cytotoxic drugs, inasmuch as oxidant mechanisms appear to play a mediating role in the apoptosis induced by many such drugs, largely via activation of c-Jun NH(2)-terminal kinase; cell culture studies would be useful for evaluating this possibility.

Efficacy of a novel chitosan formulation on fecal fat excretion: a double-blind, crossover, placebo-controlled study.

The ability of a novel chitosan formulation to influence gastrointestinal fat absorption in vivo was examined in a double-blind, placebo-controlled, crossover study by determining the content of total fat in feces in two groups of subjects. Twenty-nine normal healthy subjects were recruited for the study. Twenty-four participants completed the test period with the chitosan formulation, and 21 completed the placebo phase of study. During the placebo and the test periods, the subjects were administered six capsules three times daily 10 minutes before meals for three days and for the two days of the stool collection. A daily serving of six tablets of the test compound contained 2100 mg chitosan and 300 mg psyllium husk seeds. In respect to the baseline period, the test compound increased fat excretion significantly whether the test period preceded or proceeded the placebo period (p<0.02 and p<0.05 respectively). In contrast, essentially no changes were seen during the placebo loading periods. Compared to the difference between placebo period and its baseline period, a statistically significant increase in fecal fat excretion was observed over baseline following oral supplementation of a novel formulation of chitosan and psyllium husk seeds [+3.63 gm/day +/- 0.83 (SEM) vs. -0.15 gm/day +/- 0.94 (SEM) (p=0.004)]. The average daily increase in fecal fat of 3-4 grams over control could account for a decrease in calorie consumption of 30-40 kcal per day. A total of 19 subjects completed both parts of the study. Examining the data from these 19 subjects by ANOVA, it was found that the period when the test compounds were given was statistically significantly different from the placebo baseline, placebo experimental, and test baseline periods. Using multiple comparisons, it was ascertained that the novel formulation containing chitosan plus psyllium husk seeds increases fecal fat excretion.