Ferulic acid and berberine, via Sirt1 and AMPK, may act as cell cleansing promoters of healthy longevity.

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.

C-Phycocyanin-derived Phycocyanobilin as a Potential Nutraceutical Approach for Major Neurodegenerative Disorders and COVID-19- induced Damage to the Nervous System.

The edible cyanobacterium Spirulina platensis and its chief biliprotein C-Phycocyanin have shown protective activity in animal models of diverse human health diseases, often reflecting antioxidant and anti-inflammatory effects. The beneficial effects of C-Phycocyanin seem likely to be primarily attributable to its covalently attached chromophore Phycocyanobilin (PCB). Within cells, biliverdin is generated from free heme and it is subsequently reduced to bilirubin. Although bilirubin can function as an oxidant scavenger, its potent antioxidant activity reflects its ability to inactivate some isoforms of NADPH oxidase. Free bilirubin can also function as an agonist for the aryl hydrocarbon receptor (AhR); this may explain its ability to promote protective Treg activity in cellular and rodent models of inflammatory disease. AhR agonists also promote transcription of the gene coding for Nrf-2, and hence can up-regulate phase 2 induction of antioxidant enzymes, such as HO-1. Hence, it is proposed that C-Phycocyanin/PCB chiefly exert their protective effects via inhibition of NADPH oxidase activity, as well as by AhR agonism that both induces Treg activity and up-regulates phase 2 induction. This simple model may explain their potent antioxidant/antiinflammatory effects. Additionally, PCB might mimic biliverdin in activating anti-inflammatory signaling mediated by biliverdin reductase. This essay reviews recent research in which CPhycocyanin and/or PCB, administered orally, parenterally, or intranasally, have achieved marked protective effects in rodent and cell culture models of Ischemic Stroke and Multiple Sclerosis, and suggests that these agents may likewise be protective for Alzheimer's disease, Parkinson's disease, and in COVID-19 and its neurological complications.

The Aging Bowel Dysfunction and Elderly Vulnerability towards COVID-19 Infection.

Severe acute respiratory syndrome coronavirus 2, primarily a respiratory tract virus, also affects the enteric organs. The most affected sector of the community are the retirement and nursing home elderly residents. Along their life the senescent gastrointestinal functions are deteriorating and failing to fully execute their digestive, absorptive, mucosal barriers, and immune protective duties. Adding the decreased motility, increased intestinal permeability, dysbiosis, morbid chronic disease background, the consumed polypharmacy enteric adverse effects to the presence of the SARS-CoV-2 host receptor along the intestinal tracts put the basis for the current hypothesis. It is hypothesized that the disadvantages and failures of the aging enteric tract contribute to the elderly morbidity and mortality during the current new coronavirus pandemic. In a more optimistic look, several nutraceuticals can prevent or restore the dysfunctional intestinal barrier functions, mainly in the elderly and potentially in those who are SARS-CoV-2 infected.

Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond.

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.

Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond

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.