Nutraceutical Prevention of Diabetic Complications-Focus on Dicarbonyl and Oxidative Stress.

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.

Monounsaturated Fat vs Saturated Fat: Effects on Cardio-Metabolic Health and Obesity.

For over 40 years saturated fat, the fat found primarily in animal foods, was thought to be the main culprit for increasing cholesterol levels and causing heart disease. During this same time vegetable oils were promoted as being heart healthy because they could lower cholesterol. However, recently the evidence implicating saturated fat as being harmful to heart health has been challenged and more studies are beginning to show the harms from consuming industrially produced vegetable oils. Furthermore, monounsaturated fats, found in olives, olive oil, certain nuts and avocadoes have been promoted as being part of a healthy Mediterranean diet. This paper will provide a brief review comparing the effects of saturated fat to monounsaturated fat.

A Fundamental Role for Oxidants and Intracellular Calcium Signals in Alzheimer's Pathogenesis-And How a Comprehensive Antioxidant Strategy May Aid Prevention of This Disorder.

Oxidative stress and increased cytoplasmic calcium are key mediators of the detrimental effects on neuronal function and survival in Alzheimer's disease (AD). Pathways whereby these perturbations arise, and then prevent dendritic spine formation, promote tau hyperphosphorylation, further amplify amyloid ß generation, and induce neuronal apoptosis, are described. A comprehensive program of nutraceutical supplementation, comprised of the NADPH oxidase inhibitor phycocyanobilin, phase two inducers, the mitochondrial antioxidant astaxanthin, and the glutathione precursor N-acetylcysteine, may have important potential for antagonizing the toxic effects of amyloid ß on neurons and thereby aiding prevention of AD. Moreover, nutraceutical antioxidant strategies may oppose the adverse impact of amyloid ß oligomers on astrocyte clearance of glutamate, and on the ability of brain capillaries to export amyloid ß monomers/oligomers from the brain. Antioxidants, docosahexaenoic acid (DHA), and vitamin D, have potential for suppressing microglial production of interleukin-1ß, which potentiates the neurotoxicity of amyloid ß. Epidemiology suggests that a health-promoting lifestyle, incorporating a prudent diet, regular vigorous exercise, and other feasible measures, can cut the high risk for AD among the elderly by up to 60%. Conceivably, complementing such lifestyle measures with long-term adherence to the sort of nutraceutical regimen outlined here may drive down risk for AD even further.

The Importance of Maintaining a Low Omega-6/Omega-3 Ratio for Reducing the Risk of Autoimmune Diseases, Asthma, and Allergies.

Up until about 100 years ago, the omega-6/3 ratio has been around 4:1 or less. However, the typical Western diet now provides an omega-6/3 ratio of approximately 20:1 in favor of omega-6. This predisposes to supraphysiologic inflammatory responses and perpetuates chronic low-grade inflammation. The overconsumption of linoleic acid, mainly from industrial omega-6 seed oils, and the lack of long-chain omega-3s in the diet creates a pro-inflammatory, pro-allergic, pro-thrombotic state. Reducing the omega-6/3 ratio, particularly through reductions in the intake of refined omega-6 seed oil, and increasing the intake of marine omega-3s, either through dietary means or supplementation, may be an effective strategy for reducing inflammation, allergies, and autoimmune reactions.

Magnesium and Vitamin D Deficiency as a Potential Cause of Immune Dysfunction, Cytokine Storm and Disseminated Intravascular Coagulation in covid-19 patients.

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.

The Importance of Maintaining a Low Omega-6/Omega-3 Ratio for Reducing the Risk of Inflammatory Cytokine Storms.

Inflammatory cytokine storms in the lungs are a potential consequence of RNA viruses. One issue that may increase the risk of developing inflammatory cytokine storms in the lungs during viral infections is an imbalance in the dietary omega-6/3 ratio. Indeed, over the past 100 years the omega-6/3 ratio in the Western world has increased from approximately 4:1 to 20:1. This has increased the production of pro-inflammatory metabolites from omega-6 and reduced the anti-inflammatory metabolites from omega-3s. A high dietary omega-6/3 ratio may promote excessive inflammation, which may be contributing to inflammatory cytokine storms in the lungs during viral infections.

The Benefits of Omega-3 Fats for Stabilizing and Remodeling Atherosclerosis.

The majority of acute coronary syndromes are caused by the rupture of plaques rendered vulnerable by oxidized lipids, inflammation, and a thin fibrous cap with reduced collagen and smooth muscle cell content.2 Thus, stabilizing and reversing vulnerable atherosclerotic plaques can help to prevent cardiovascular events. In this regard, long-chain omega-3 fatty acids have a plethora of data for stabilizing vulnerable atherosclerotic plaques as well as reversing atherosclerosis. This review paper will summarize the observational data as well as animal and human studies supporting such a role and further discuss the current controversies around omega-3 supplementation.

The Benefits of Marine Omega-3s for the Prevention and Treatment of Cardiovascular Disease.

There has been a raging debate whether marine omega-3s are effective for the prevention of cardiovascular disease. Our review paper discusses the landmark clinical studies testing the benefits of marine omega-3s. Moreover, for the first time, the REDUCE-IT study tested a high dose of marine omega-3s (4 grams of icosapent ethyl per day) on top of statin therapy in patients with established cardiovascular disease or with diabetes and additional risk factors with concomitant high triglyceride levels and noted a highly significant 25% reduction in the primary endpoint. Thus, in patients who are not in the early post myocardial infarction setting, high dose marine omega-3s (4 grams per day) may be required to provide cardiovascular benefit when given on top of optimized medical therapy.

Salt and hypertension: what do we know?

PURPOSE OF REVIEW: To evaluate the evidence for population-wide sodium restriction. RECENT FINDINGS: The recommendations for population-wide sodium restriction largely rely on one surrogate marker (blood pressure). However, recent evidence suggests that when looking beyond blood pressure (e.g. heart rate, aldosterone, renin, cholesterol, triglycerides, noradrenaline and adrenaline), the net effect of sodium restriction is likely harmful. Prospective studies support the notion that those consuming the lowest amounts of salt are at the highest risk of cardiovascular events and premature death. SUMMARY: There is no definitive proof that sodium restriction reduces cardiovascular events or death. It is time for the dietary guidelines to look at the totality of the evidence and reconsider the advice around population-wide sodium restriction.

Minimizing Membrane Arachidonic Acid Content as a Strategy for Controlling Cancer: A Review.

Many cancers and pre-cancerous lesions convert membrane-bound arachidonic acid (AA) to eicosanoids that promote the survival, growth, and spread of cancer. In contrast, the long-chain omega-3s eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can competitively inhibit AA's interaction with the enzymes that give rise to eicosanoids, while acting as precursors for alternative eicosanoids which oppose cancer development and growth. Hence, minimizing the AA content of cancer membranes, while boosting that of EPA and DHA, is a rational strategy for cancer prevention and control. The former goal can be achieved by eating a plant-based diet (inherently free of AA); by avoiding foods high in linoleic acid; by down-regulating the expression of delta-6-desaturase (D6D), rate-limiting for the conversion of linoleic acid to AA; and by competitively decreasing flux of linoleic acid through D6D with a high intake of alpha-linolenic acid (ALA) from flaxseed. ALA and DHA, potent agonists for the farnesoid X receptor, can be expected to suppress D6D transcription, and AMP-activated kinase (AMPK) activators and a cholesterol-free diet also have potential in this regard. Hence, a plant-based diet low in linoleic acid, complemented by an ample intake of flaxseed and supplemental fish oil, with or without metformin and other D6D-antagonist agents, may aid prevention and control of some cancers.

Sugar addiction: is it real? A narrative review.

In animal studies, sugar has been found to produce more symptoms than is required to be considered an addictive substance. Animal data has shown significant overlap between the consumption of added sugars and drug-like effects, including bingeing, craving, tolerance, withdrawal, cross-sensitisation, cross-tolerance, cross-dependence, reward and opioid effects. Sugar addiction seems to be dependence to the natural endogenous opioids that get released upon sugar intake. In both animals and humans, the evidence in the literature shows substantial parallels and overlap between drugs of abuse and sugar, from the standpoint of brain neurochemistry as well as behaviour.

Not Salt But Sugar As Aetiological In Osteoporosis: A Review.

Salt has notoriously been blamed for causing an increase in the urinary excretion of calcium, and thus is a considered a risk factor for osteoporosis. However, the increase in the urinary excretion of calcium with higher sodium intakes can be offset by the increased intestinal absorption of dietary calcium. Thus, the overall calcium balance does not appear to be reduced with a higher sodium intake. However, the other ubiquitous white crystal, sugar, may lead to osteoporosis by increasing inflammation, hyperinsulinemia, increased renal acid load, reduced calcium intake, and increased urinary calcium excretion. Sugar, not salt, is the more likely white crystal to be a risk factor for osteoporosis when overconsumed.

Comparative safety and efficacy of statins for primary prevention in human immunodeficiency virus-positive patients: a systematic review and meta-analysis.

The efficacy and safety of different statins for human immunodeficiency virus (HIV)-positive patients in the primary prevention setting remain to be established. In the present meta-analysis, 18 studies with 736 HIV-positive patients receiving combination antiretroviral therapy (cART) and treated with statins in the primary prevention setting were included (21.0% women, median age 44.1 years old). The primary endpoint was the effect of statin therapy on total cholesterol (TC) levels. Rosuvastatin 10 mg and atorvastatin 10 mg provided the largest reduction in TC levels [mean -1.67, 95% confidence interval (CI) (-1.99, -1.35) mmol/L; and mean -1.44, 95% CI (-1.85, -1.02) mmol/L, respectively]. Atorvastatin 80 mg and simvastatin 20 mg provided the largest reduction in low-density lipoprotein (LDL) [mean -2.10, 95% CI (-3.39, -0.81) mmol/L; and mean -1.57, 95% CI (-2.67, -0.47) mmol/L, respectively]. Pravastatin 10-20 mg [mean 0.24, 95% CI (0.10, 0.38) mmol/L] and atorvastatin 10 mg [mean 0.15, 95% CI (0.007, 0.23) mmol/L] had the largest increase in high-density lipoprotein, whereas atorvastatin 80 mg [mean -0.60, 95% CI (-1.09, -0.11) mmol/L] and simvastatin 20 mg [mean -0.61, 95% CI (-1.14, -0.08) mmol/L] had the largest reduction in triglycerides. The mean discontinuation rate was 0.12 per 100 person-years [95% CI (0.05, 0.20)], and was higher with atorvastatin 10 mg [26.5 per 100 person-years, 95% CI (-13.4, 64.7)]. Meta-regression revealed that nucleoside reverse transcriptase inhibitors-sparing regimens were associated with reduced efficacy for statin's ability to lower TC. Statin therapy significantly lowers plasma TC and LDL levels in HIV-positive patients and is associated with low rates of adverse events. Statins are effective and safe when dose-adjusted for drug-drug interactions with cART.

Good Fats versus Bad Fats: A Comparison of Fatty Acids in the Promotion of Insulin Resistance, Inflammation, and Obesity.

Recently, debate has erupted in both the scientific community and throughout the lay public around whether a low-fat or low-carbohydrate diet is better for weight loss. In other words, is it better to cut fat or cut carbohydrate for weight loss. However, going beyond this debate (fat versus carbohydrate), are questions around whether certain fatty acids are worse for promoting insulin resistance, inflammation, and obesity. The overall evidence in the literature suggests that medium-chain saturated fats (such as lauric acid, found in coconut oil) and monounsaturated fat (oleic acid, found in olive oil) are less likely to promote insulin resistance, inflammation, and fat storage compared to long-chain saturated fatty acids (such as stearic acid found in large quantities in butter, but particularly palmitic acid found in palm oil) especially when consumed on top of a diet moderate in refined carbohydrates. Compared to long-chain saturated fats, lauric acid and oleic acid have an increased fatty acid oxidation rate, are more likely to be burned for energy and less likely to be stored in adipose tissue, and thus promote increased energy expenditure. Omega-6 polyunsaturated fatty acids (PUFAs), such as linoleic acid, as found in vegetable oils may contribute to obesity, whereas omega-3 PUFA may be protective. Importantly, both olive oil as part of a Mediterranean diet, and omega-3 from fish and fish oil have been proven to reduce risk of cardiovascular (CV) events.

The Microvascular and Macrovascular Benefits of Fibrates in Diabetes and the Metabolic Syndrome: A review.

BACKGROUND: The purpose of this article is to discuss the evidence regarding potential macrovascular and microvascular benefits of fibrate therapy in general and fenofibrate specifically. METHODS: We performed a literature review summarizing the results of studies testing fibrates on relevant. RESULTS: Although statins are the first line therapy with an unparalleled amount of evidence for reducing the risk of cardiovascular disease (CVD) in patients with dyslipidemia and the metabolic syndrome (MetS), there are several landmark studies that have focused on the potential benefits of fibrate therapy for reducing CVD risk. Fibrates confer benefits mostly for patients with diabetes mellitus (DM), MetS, and atherogenic dyslipidemia. Recently, many studies have shown that fibrates confer benefits on the vascular system as well as the liver and kidneys. Fibrates also have demonstrable benefits in cohorts of patients with DM and renal disease. CONCLUSIONS: Fibrates appear to provide significant microvascular and macrovascular benefits particularly in patients with DM, MetS, or renal disease.

Problems with the 2015 Dietary Guidelines for Americans: An Alternative.

Abstract The updated 2015 Dietary Guidelines for Americans, published in January 2016, have stirred much controversy since the advisory report first appeared. Several important changes have been made, with some recommendations having greater scientific evidence for their support than others. The focus of this review is to discuss specific recommendations from the 2015 Dietary Guidelines for Americans that lack sound scientific evidence; these include: 1) Allowing approximately half of all grains to be refined; 2) The continued recommendations for fat-free or low-fat dairy and limitation of saturated fat intake to < 10% of calories; 3) Sodium intake < 2,300 mg/day; and 4) Consumption of up to 27 grams/day of "oils" (high in polyunsaturated fat or monounsaturated fat). Based on our review, the aforementioned recommendations found in the updated 2015 Dietary Guideline for Americans may increase the incidence of cardiometabolic disease, diabetes, obesity, dyslipidemia, cardiovascular disease, and possibly cancer.

Problems with the 2015 Dietary Guidelines for Americans. An Alternative.

The updated 2015 Dietary Guidelines for Americans, published in January 2016, have stirred much controversy since the advisory report first appeared. Several important changes have been made, with some recommendations having greater scientific evidence for their support than others. The focus of this review is to discuss specific recommendations from the 2015 Dietary Guidelines for Americans that lack sound scientific evidence; these include: 1) Allowing approximately half of all grains to be refined; 2) The continued recommendations for fat-free or low-fat dairy and limitation of saturated fat intake to <10% of calories; 3) Sodium intake < 2,300 mg/day; and 4) Consumption of up to 27 g/day of "oils" (high in polyunsaturated fat or monounsaturated fat). Based on our review, the aforementioned recommendations found in the updated 2015 Dietary Guidelines for Americans may increase the incidence of cardiometabolic disease, diabetes, obesity, dyslipidemia, cardiovascular disease and possibly cancer.

High dose statin loading prior to percutaneous coronary intervention decreases cardiovascular events: a meta-analysis of randomized controlled trials.

OBJECTIVE: We performed a meta-analysis of randomized controlled trials of statin loading prior to percutaneous coronary intervention (PCI). BACKGROUND: Statin loading prior to PCI has been shown to decrease peri-procedural myocardial infarction (pMI) but less is known regarding the clinical benefit of pre-procedural statin loading. METHODS: We searched for trials of statin naïve patients presenting with stable angina or NSTE-ACS and treated with statins prior to PCI. We evaluated the incidence of pMI and major cardiac events including spontaneous myocardial infarction, death, and target vessel revascularization. RESULTS: Out of 1,210 articles, 14 randomized controlled trials were included in this meta-analysis. Among 3,146 patients, 1,591 patients were randomized to a loading dose of statin before PCI and 1,555 patients were given statin therapy initiated only after the PCI. Statin loading prior to PCI was associated with a 56% relative reduction in pMI (OR: 0.44, 95% CI: 0.35-0.56; P < 0.00001). There was a 41% reduction in clinical events in follow-up in the group of patients treated with statin loading prior to PCI (OR: 0.59, 95% CI: 0.38-0.92, P = 0.02). When stratified according to the clinical presentation, the results were only significant for those patients with NSTE-ACS (OR: 0.18, 95% CI: 0.07-0.47; P = 0.0005) and was not noted in the group of patients who underwent PCI for stable angina (OR: 0.92, 95% CI: 0.53-1.61; P = 0.78). CONCLUSIONS: High dose statin therapy given prior to PCI in patients with NSTE-ACS is associated with a reduction in pMI and short-term clinical events. © 2013 Wiley Periodicals, Inc.

How calorie-focused thinking about obesity and related diseases may mislead and harm public health. An alternative.

Prevailing thinking about obesity and related diseases holds that quantifying calories should be a principal concern and target for intervention. Part of this thinking is that consumed calories - regardless of their sources - are equivalent; i.e. 'a calorie is a calorie'. The present commentary discusses various problems with the idea that 'a calorie is a calorie' and with a primarily quantitative focus on food calories. Instead, the authors argue for a greater qualitative focus on the sources of calories consumed (i.e. a greater focus on types of foods) and on the metabolic changes that result from consuming foods of different types. In particular, the authors consider how calorie-focused thinking is inherently biased against high-fat foods, many of which may be protective against obesity and related diseases, and supportive of starchy and sugary replacements, which are likely detrimental. Shifting the focus to qualitative food distinctions, a central argument of the paper is that obesity and related diseases are problems due largely to food-induced physiology (e.g. neurohormonal pathways) not addressable through arithmetic dieting (i.e. calorie counting). The paper considers potential harms of public health initiatives framed around calorie balance sheets - targeting 'calories in' and/or 'calories out' - that reinforce messages of overeating and inactivity as underlying causes, rather than intermediate effects, of obesity. Finally, the paper concludes that public health should work primarily to support the consumption of whole foods that help protect against obesity-promoting energy imbalance and metabolic dysfunction and not continue to promote calorie-directed messages that may create and blame victims and possibly exacerbate epidemics of obesity and related diseases.