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1.
Targeting beta-catenin signaling for prevention of colorectal cancer - Nutraceutical, drug, and dietary options.
Iloki Assanga, SB, Lewis Luján, LM, McCarty, MF
European journal of pharmacology. 2023;:175898
Abstract
Progressive up-regulation of β-catenin signaling is very common in the transformation of colorectal epithelium to colorectal cancer (CRC). Practical measures for opposing such signaling hence have potential for preventing or slowing such transformation. cAMP/PKA activity in colon epithelium, as stimulated by COX-2-generated prostaglandins and β2-adrenergic signaling, boosts β-catenin activity, whereas cGMP/PKG signaling has the opposite effect. Bacterial generation of short-chain fatty acids (as supported by unrefined high-carbohydrate diets, berberine, and probiotics), dietary calcium, daily aspirin, antioxidants opposing cox-2 induction, and nicotine avoidance, can suppress cAMP production in colonic epithelium, whereas cGMP can be boosted via linaclotides, PDE5 inhibitors such as sildenafil or icariin, and likely high-dose biotin. Selective activation of estrogen receptor-β by soy isoflavones, support of adequate vitamin D receptor activity with UV exposure or supplemental vitamin D, and inhibition of CK2 activity with flavanols such as quercetin, can also oppose β-catenin signaling in colorectal epithelium. Secondary bile acids, the colonic production of which can be diminished by low-fat diets and berberine, can up-regulate β-catenin activity by down-regulating farnesoid X receptor expression. Stimulation of PI3K/Akt via insulin, IGF-I, TLR4, and EGFR receptors boosts β-catenin levels via inhibition of glycogen synthase-3β; plant-based diets can down-regulate insulin and IGF-I levels, exercise training and leanness can keep insulin low, anthocyanins and their key metabolite ferulic acid have potential for opposing TLR4 signaling, and silibinin is a direct antagonist for EGFR. Partially hydrolyzed phytate can oppose growth factor-mediated down-regulation of β-catenin by inhibiting Akt activation. Multifactorial strategies for safely opposing β-catenin signaling can be complemented with measures that diminish colonic mutagenesis and DNA hypomethylation - such as avoidance of heme-rich meat and charred or processed meats, consumption of phase II-inductive foods and nutraceuticals (e.g., Crucifera), and assurance of adequate folate status.
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2.
Nutraceuticals/Drugs Promoting Mitophagy and Mitochondrial Biogenesis May Combat the Mitochondrial Dysfunction Driving Progression of Dry Age-Related Macular Degeneration.
Lewis Luján, LM, McCarty, MF, Di Nicolantonio, JJ, Gálvez Ruiz, JC, Rosas-Burgos, EC, Plascencia-Jatomea, M, Iloki Assanga, SB
Nutrients. 2022;(9)
Abstract
In patients with age-related macular degeneration (AMD), the crucial retinal pigment epithelial (RPE) cells are characterized by mitochondria that are structurally and functionally defective. Moreover, deficient expression of the mRNA-editing enzyme Dicer is noted specifically in these cells. This Dicer deficit up-regulates expression of Alu RNA, which in turn damages mitochondria-inducing the loss of membrane potential, boosting oxidant generation, and causing mitochondrial DNA to translocate to the cytoplasmic region. The cytoplasmic mtDNA, in conjunction with induced oxidative stress, triggers a non-canonical pathway of NLRP3 inflammasome activation, leading to the production of interleukin-18 that acts in an autocrine manner to induce apoptotic death of RPE cells, thereby driving progression of dry AMD. It is proposed that measures which jointly up-regulate mitophagy and mitochondrial biogenesis (MB), by replacing damaged mitochondria with "healthy" new ones, may lessen the adverse impact of Alu RNA on RPE cells, enabling the prevention or control of dry AMD. An analysis of the molecular biology underlying mitophagy/MB and inflammasome activation suggests that nutraceuticals or drugs that can activate Sirt1, AMPK, Nrf2, and PPARα may be useful in this regard. These include ferulic acid, melatonin urolithin A and glucosamine (Sirt1), metformin and berberine (AMPK), lipoic acid and broccoli sprout extract (Nrf2), and fibrate drugs and astaxanthin (PPARα). Hence, nutraceutical regimens providing physiologically meaningful doses of several or all of the: ferulic acid, melatonin, glucosamine, berberine, lipoic acid, and astaxanthin, may have potential for control of dry AMD.
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3.
Nutraceutical Prevention of Diabetic Complications-Focus on Dicarbonyl and Oxidative Stress.
McCarty, MF, DiNicolantonio, JJ, O'Keefe, JH
Current issues in molecular biology. 2022;(9):4314-4338
Abstract
Oxidative and dicarbonyl stress, driven by excess accumulation of glycolytic intermediates in cells that are highly permeable to glucose in the absence of effective insulin activity, appear to be the chief mediators of the complications of diabetes. The most pathogenically significant dicarbonyl stress reflects spontaneous dephosphorylation of glycolytic triose phosphates, giving rise to highly reactive methylglyoxal. This compound can be converted to harmless lactate by the sequential activity of glyoxalase I and II, employing glutathione as a catalyst. The transcription of glyoxalase I, rate-limiting for this process, is promoted by Nrf2, which can be activated by nutraceutical phase 2 inducers such as lipoic acid and sulforaphane. In cells exposed to hyperglycemia, glycine somehow up-regulates Nrf2 activity. Zinc can likewise promote glyoxalase I transcription, via activation of the metal-responsive transcription factor (MTF) that binds to the glyoxalase promoter. Induction of glyoxalase I and metallothionein may explain the protective impact of zinc in rodent models of diabetic complications. With respect to the contribution of oxidative stress to diabetic complications, promoters of mitophagy and mitochondrial biogenesis, UCP2 inducers, inhibitors of NAPDH oxidase, recouplers of eNOS, glutathione precursors, membrane oxidant scavengers, Nrf2 activators, and correction of diabetic thiamine deficiency should help to quell this.
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4.
Ferulic acid and berberine, via Sirt1 and AMPK, may act as cell cleansing promoters of healthy longevity.
DiNicolantonio, JJ, McCarty, MF, Assanga, SI, Lujan, LL, O'Keefe, JH
Open heart. 2022;(1)
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.
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5.
Nutraceutical activation of Sirt1: a review.
DiNicolantonio, JJ, McCarty, MF, O'Keefe, JH
Open heart. 2022;(2)
Abstract
The deacetylase sirtuin 1 (Sirt1), activated by calorie restriction and fasting, exerts several complementary effects on cellular function that are favourable to healthspan; it is often thought of as an 'anti-aging' enzyme. Practical measures which might boost Sirt1 activity are therefore of considerable interest. A number of nutraceuticals have potential in this regard. Nutraceuticals reported to enhance Sirt1 synthesis or protein expression include ferulic acid, tetrahydrocurcumin, urolithin A, melatonin, astaxanthin, carnosic acid and neochlorogenic acid. The half-life of Sirt1 protein can be enhanced with the natural nicotinamide catabolite N1-methylnicotinamide. The availability of Sirt1's obligate substrate NAD+ can be increased in several ways: nicotinamide riboside and nicotinamide mononucleotide can function as substrates for NAD+ synthesis; activators of AMP-activated kinase-such as berberine-can increase expression of nicotinamide phosphoribosyltransferase, which is rate limiting for NAD+ synthesis; and nutraceutical quinones such as thymoquinone and pyrroloquinoline quinone can boost NAD+ by promoting oxidation of NADH. Induced ketosis-as via ingestion of medium-chain triglycerides-can increase NAD+ in the brain by lessening the reduction of NAD+ mediated by glycolysis. Post-translational modifications of Sirt1 by O-GlcNAcylation or sulfonation can increase its activity, suggesting that administration of glucosamine or of agents promoting hydrogen sulfide synthesis may aid Sirt1 activity. Although resveratrol has poor pharmacokinetics, it can bind to Sirt1 and activate it allosterically-as can so-called sirtuin-activating compound drugs. Since oxidative stress can reduce Sirt1 activity in multiple ways, effective antioxidant supplementation that blunts such stress may also help preserve Sirt1 activity in some circumstances. Combination nutraceutical regimens providing physiologically meaningful doses of several of these agents, capable of activating Sirt1 in complementary ways, may have considerable potential for health promotion. Such measures may also amplify the benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors in non-diabetic disorders, as these benefits appear to reflect upregulation of Sirt1 and AMP-activated protein kinase activities.
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6.
Coenzyme Q10 deficiency can be expected to compromise Sirt1 activity.
DiNicolantonio, JJ, McCarty, MF, O'Keefe, JH
Open heart. 2022;(1)
Abstract
For reasons that remain unclear, endogenous synthesis and tissue levels of coenzyme Q10 (CoQ10) tend to decline with increasing age in at least some tissues. When CoQ10 levels are sufficiently low, this compromises the efficiency of the mitochondrial electron transport chain, such that production of superoxide by site 2 increases and the rate of adenosine triphosphate production declines. Moreover, CoQ10 deficiency can be expected to decrease activities of Sirt1 and Sirt3 deacetylases, believed to be key determinants of health span. Reduction of the cytoplasmic and mitochondrial NAD+/NADH ratio consequent to CoQ10 deficit can be expected to decrease the activity of these deacetylases by lessening availability of their obligate substrate NAD+ The increased oxidant production induced by CoQ10 deficiency can decrease the stability of Sirt1 protein by complementary mechanisms. And CoQ10 deficiency has also been found to lower mRNA expression of Sirt1. An analysis of the roles of Sirt1/Sirt3 in modulation of cellular function helps to rationalise clinical benefits of CoQ10 supplementation reported in heart failure, hypertension, non-alcoholic fatty liver disease, metabolic syndrome and periodontal disease. Hence, correction of CoQ10 deficiency joins a growing list of measures that have potential for amplifying health protective Sirt1/Sirt3 activities.
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7.
The second phase of brain trauma can be controlled by nutraceuticals that suppress DAMP-mediated microglial activation.
McCarty, MF, Lerner, A
Expert review of neurotherapeutics. 2021;(5):559-570
Abstract
INTRODUCTION A delayed second wave of brain trauma is mediated in large part by microglia that are activated to a pro-inflammatory M1 phenotype by DAMP proteins released by dying neurons. These microglia can promote apoptosis or necrosis in neighboring neurons by producing a range of pro-inflammatory cytokines and the deadly oxidant peroxynitrite. This second wave could therefore be mitigated with agents that blunt the post-traumatic M1 activation of microglia and that preferentially promote a pro-healing M2 phenotype. AREAS COVERED The literature on nutraceuticals that might have clinical potential in this regard. EXPERT OPINION The chief signaling pathway whereby DAMPs promote M1 microglial activation involves activation of toll-like receptor 4 (TLR4), NADPH oxidase, NF-kappaB, and the stress activated kinases JNK and p38. The green tea catechin EGCG can suppress TLR4 expression. Phycocyanobilin can inhibit NOX2-dependent NADPH oxidase, ferulate and melatonin can oppose pro-inflammatory signal modulation by NADPH oxidase-derived oxidants. Long-chain omega-3 fatty acids, the soy isoflavone genistein, the AMPK activator berberine, glucosamine, and ketone bodies can down-regulate NF-kappaB activation. Vitamin D activity can oppose JNK/p38 activation. A sophisticated program of nutraceutical supplementation may have important potential for mitigating the second phase of neuronal death and aiding subsequent healing.
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8.
Maintaining Effective Beta Cell Function in the Face of Metabolic Syndrome-Associated Glucolipotoxicity-Nutraceutical Options.
McCarty, MF, DiNicolantonio, JJ
Healthcare (Basel, Switzerland). 2021;(1)
Abstract
In people with metabolic syndrome, episodic exposure of pancreatic beta cells to elevated levels of both glucose and free fatty acids (FFAs)-or glucolipotoxicity-can induce a loss of glucose-stimulated insulin secretion (GSIS). This in turn can lead to a chronic state of glucolipotoxicity and a sustained loss of GSIS, ushering in type 2 diabetes. Loss of GSIS reflects a decline in beta cell glucokinase (GK) expression associated with decreased nuclear levels of the pancreatic and duodenal homeobox 1 (PDX1) factor that drives its transcription, along with that of Glut2 and insulin. Glucolipotoxicity-induced production of reactive oxygen species (ROS), stemming from both mitochondria and the NOX2 isoform of NADPH oxidase, drives an increase in c-Jun N-terminal kinase (JNK) activity that promotes nuclear export of PDX1, and impairs autocrine insulin signaling; the latter effect decreases PDX1 expression at the transcriptional level and up-regulates beta cell apoptosis. Conversely, the incretin hormone glucagon-like peptide-1 (GLP-1) promotes nuclear import of PDX1 via cAMP signaling. Nutraceuticals that quell an increase in beta cell ROS production, that amplify or mimic autocrine insulin signaling, or that boost GLP-1 production, should help to maintain GSIS and suppress beta cell apoptosis in the face of glucolipotoxicity, postponing or preventing onset of type 2 diabetes. Nutraceuticals with potential in this regard include the following: phycocyanobilin-an inhibitor of NOX2; agents promoting mitophagy and mitochondrial biogenesis, such as ferulic acid, lipoic acid, melatonin, berberine, and astaxanthin; myo-inositol and high-dose biotin, which promote phosphatidylinositol 3-kinase (PI3K)/Akt activation; and prebiotics/probiotics capable of boosting GLP-1 secretion. Complex supplements or functional foods providing a selection of these agents might be useful for diabetes prevention.
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9.
Nutraceutical Aid for Allergies - Strategies for Down-Regulating Mast Cell Degranulation.
McCarty, MF, Lerner, A, DiNicolantonio, JJ, Benzvi, C
Journal of asthma and allergy. 2021;:1257-1266
Abstract
Interactions of antigens with the mast cell FcεRI-IgE receptor complex induce degranulation and boost synthesis of pro-inflammatory lipid mediators and cytokines. Activation of spleen tyrosine kinase (Syk) functions as a central hub in this signaling. The tyrosine phosphatase SHP-1 opposes Syk activity; stimulation of NADPH oxidase by FcεRI activation results in the production of oxidants that reversibly inhibit SHP-1, up-regulating the signal from Syk. Activated AMPK can suppress Syk activation by the FcεRI receptor, possibly reflecting its ability to phosphorylate the FcεRI beta subunit. Cyclic GMP, via protein kinase G II, enhances the activity of SHP-1 by phosphorylating its C-terminal region; this may explain its inhibitory impact on mast cell activation. Hydrogen sulfide (H2S) likewise opposes mast cell activation; H2S can boost AMPK activity, up-regulate cGMP production, and trigger Nrf2-mediated induction of Phase 2 enzymes - including heme oxygenase-1, whose generation of bilirubin suppresses NADPH oxidase activity. Phycocyanobilin (PCB), a chemical relative of bilirubin, shares its inhibitory impact on NADPH oxidase, rationalizing reported anti-allergic effects of PCB-rich spirulina ingestion. Phase 2 inducer nutraceuticals can likewise oppose the up-regulatory impact of NADPH oxidase on FcεRI signaling. AMPK can be activated with the nutraceutical berberine. High-dose biotin can boost cGMP levels in mast cells via direct stimulation of soluble guanylate cyclase. Endogenous generation of H2S in mast cells can be promoted by administering N-acetylcysteine and likely by taurine, which increases the expression of H2S-producing enzymes in the vascular system. Mast cell stabilization by benifuuki green tea catechins may reflect the decreased surface expression of FcεRI.
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10.
Review - Nutraceuticals Can Target Asthmatic Bronchoconstriction: NADPH Oxidase-Dependent Oxidative Stress, RhoA and Calcium Dynamics.
McCarty, MF, DiNicolantonio, JJ, Lerner, A
Journal of asthma and allergy. 2021;:685-701
Abstract
Activation of various isoforms of NADPH oxidase contributes to the pathogenesis of asthma at multiple levels: promoting hypercontractility, hypertrophy, and proliferation of airway smooth muscle; enabling lung influx of eosinophils via VCAM-1; and mediating allergen-induced mast cell activation. Free bilirubin, which functions physiologically within cells as a feedback inhibitor of NADPH oxidase complexes, has been shown to have a favorable impact on each of these phases of asthma pathogenesis. The spirulina chromophore phycocyanobilin (PhyCB), a homolog of bilirubin's precursor biliverdin, can mimic the inhibitory impact of biliverdin/bilirubin on NADPH oxidase activity, and spirulina's versatile and profound anti-inflammatory activity in rodent studies suggests that PhyCB may have potential as a clinical inhibitor of NADPH oxidase. Hence, spirulina or PhyCB-enriched spirulina extracts merit clinical evaluation in asthma. Promoting biosynthesis of glutathione and increasing the expression and activity of various antioxidant enzymes - as by supplementing with N-acetylcysteine, Phase 2 inducers (eg, lipoic acid), selenium, and zinc - may also blunt the contribution of oxidative stress to asthma pathogenesis. Nitric oxide (NO) and hydrogen sulfide (H2S) work in various ways to oppose pathogenic mechanisms in asthma; supplemental citrulline and high-dose folate may aid NO synthesis, high-dose biotin may mimic and possibly potentiate NO's activating impact on soluble guanylate cyclase, and NAC and taurine may boost H2S synthesis. The amino acid glycine has a hyperpolarizing effect on airway smooth muscle that is bronchodilatory. Insuring optimal intracellular levels of magnesium may modestly blunt the stimulatory impact of intracellular free calcium on bronchoconstriction. Nutraceutical regimens or functional foods incorporating at least several of these agents may have utility as nutraceutical adjuvants to standard clinical management of asthma.