Potential benefits and risks of omega-3 fatty acids supplementation to patients with COVID-19.

Studies have shown that infection, excessive coagulation, cytokine storm, leukopenia, lymphopenia, hypoxemia and oxidative stress have also been observed in critically ill Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) patients in addition to the onset symptoms. There are still no approved drugs or vaccines. Dietary supplements could possibly improve the patient's recovery. Omega-3 fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), present an anti-inflammatory effect that could ameliorate some patients need for intensive care unit (ICU) admission. EPA and DHA replace arachidonic acid (ARA) in the phospholipid membranes. When oxidized by enzymes, EPA and DHA contribute to the synthesis of less inflammatory eicosanoids and specialized pro-resolving lipid mediators (SPMs), such as resolvins, maresins and protectins. This reduces inflammation. In contrast, some studies have reported that EPA and DHA can make cell membranes more susceptible to non-enzymatic oxidation mediated by reactive oxygen species, leading to the formation of potentially toxic oxidation products and increasing the oxidative stress. Although the inflammatory resolution improved by EPA and DHA could contribute to the recovery of patients infected with SARS-CoV-2, Omega-3 fatty acids supplementation cannot be recommended before randomized and controlled trials are carried out.

Burdock (Arctium lappa L.) root attenuates preneoplastic lesion development in a diet and thioacetamide-induced model of steatohepatitis-associated hepatocarcinogenesis.

Nonalcoholic steatohepatitis (NASH) is considered growing risk factor for hepatocellular carcinoma development in high-income countries. Diet- and chemically induced rodent models have been applied for the translational study of NASH-associated hepatocarcinogenesis due to their morphological and molecular similarities to the corresponding human disease. Arctium lappa L. (burdock) root tea has been extensively consumed in Traditional Chinese Medicine due to its potential therapeutic properties. Indeed, the bioactive compounds of A. lappa root, as the polyphenols, have already showed antioxidant and anti-inflammatory properties in different in vivo and in vitro bioassays. In this study, we investigated whether burdock root ethanolic extract (BRE) administration attenuates NASH-associated hepatocarcinogenesis. Eight-week-old male Wistar rats received choline-deficient high-fat diet for 8 weeks and multiple thioacetamide doses for 4 weeks in order to induce NASH and preneoplastic glutathione-S-transferase pi (GST-P)+ preneoplastic foci. Subsequently, rats were treated with BRE (100 or 200 mg/kg body weight) or vehicle by oral gavage for 2 weeks. BRE displayed high levels of chlorogenic and caffeic acids and BRE administration reduced total fatty acid and lipid hydroperoxide levels, while increasing the activities of antioxidant superoxide dismutase and catalase enzymes in the liver. Furthermore, burdock intervention diminished the size of GST-P+ remodeling preneoplastic lesions (PNLs) and displayed a trend on reducing hepatocyte proliferation (Ki-67) inside them. These findings suggest that short-term exposure to BRE alleviated remodeling PNL development in NASH-associated hepatocarcinogenesis.

Cardiovascular Disease Prevention: The Earlier the Better? A Review of Plant Sterol Metabolism and Implications of Childhood Supplementation.

Atherosclerosis is the underlying cause of major cardiovascular events. The development of atherosclerotic plaques begins early in life, indicating that dietary interventions in childhood might be more effective at preventing cardiovascular disease (CVD) than treating established CVD in adulthood. Although plant sterols are considered safe and consistently effective in lowering plasma cholesterol, the health effects of early-life supplementation are unclear. Studies suggest there is an age-dependent effect on plant sterol metabolism: at a younger age, plant sterol absorption might be increased, while esterification and elimination might be decreased. Worryingly, the introduction of low-cholesterol diets in childhood may unintentionally favor a higher intake of plant sterols. Although CVD prevention should start as early as possible, more studies are needed to better elucidate the long-term effects of plant sterol accumulation and its implication on child development.

Comparison between red wine and isolated trans-resveratrol on the prevention and regression of atherosclerosis in LDLr (-/-) mice.

Moderate consumption of red wine has been widely associated with reduced cardiovascular risk, mainly due to its composition in phenolic compounds with antioxidant activity, such as resveratrol. The objective of this study was to compare the effect of red wine vs. trans-resveratrol consumption on the prevention and regression of atherosclerosis in LDLr (-/-) mice. This study consisted of two protocols: "Prevention" (PREV) and "Regression" (REGR). Both protocols included four groups: red wine (WINE), dealcoholized red wine (EXT), trans-resveratrol (RESV), and control (CONT). In PREV protocol, animals received a regular diet for 8 weeks and then switched to an atherogenic diet for the following 8 weeks, while the opposite was performed in REGR. Animals that received atherogenic diet after an initial period of standard diet (PREV) gained more body weight (39.25±2.30%) than the opposite (29.27±1.91%, P=.0013), suggesting an interaction between age and weight gain. Trans-resveratrol showed the highest hypocholesterolemic effect during PREV, reducing total cholesterol, LDL-C, VLDL-C and HDL-C. Supplementation with trans-resveratrol and dealcoholized red wine changed the fatty acids profile in the liver in both protocols, leading to an increase of MDA concentrations and SOD activity in the PREV protocol. In conclusion, supplementation with trans-resveratrol, red wine and the same wine without alcohol altered biomarkers of oxidative stress and lipidemia but had no effect on the prevention or regression of fatty streaks. These data suggest that cardiovascular protection associated with the "French Paradox" may be a result of synergistic effects between wine and the Mediterranean diet.

Statin dose reduction with complementary diet therapy: A pilot study of personalized medicine

OBJECTIVE: Statin intolerance, whether real or perceived, is a growing issue in clinical practice. Our aim was to evaluate the effects of reduced-dose statin therapy complemented with nutraceuticals. METHODS: First phase: Initially, 53 type 2 diabetic statin-treated patients received a supplementation with fish oil (1.7 g EPA + DHA/day), chocolate containing plant sterols (2.2 g/day), and green tea (two sachets/day) for 6 weeks. Second phase: "Good responders" to supple-mentation were identified after multivariate analysis (n»10), and recruited for a pilot protocol of statin dose reduction. "Good responders" were then provided with supplementation for 12 weeks: standard statin therapy was kept during the first 6 weeks and reduced by 50% from weeks 6e12.RESULTS: First phase: After 6 weeks of supplementation, plasma LDL-C (-13.7% 3.7,P».002) and C-reactive protein ( 35.5% 5.9,P».03) were reduced. Analysis of lathosterol and campesterol in plasma suggested that intensity of LDL-C reduction was influenced bycholesterol absorption rate rather than its synthesis. Second phase: no difference was observed for plasma lipids, inflammation, cholesterol effluxcapacity, or HDL particles after statin dose reduction when compared to standard therapy. CONCLUSIONS: Although limited by the small sample size, our study demonstrates the potential for a new therapeutic approach combining lower statin dose and specific dietary compounds. Further studies should elucidate "good responders" profile as a tool for personalized medicine. This may be particularly helpful in the many patients with or at risk for CVD who cannot tolerate high dose statin therapy. Trial registration: ClinicalTrials.gov, NCT02732223.

Statin dose reduction with complementary diet therapy: A pilot study of personalized medicine.

OBJECTIVE: Statin intolerance, whether real or perceived, is a growing issue in clinical practice. Our aim was to evaluate the effects of reduced-dose statin therapy complemented with nutraceuticals. METHODS: First phase: Initially, 53 type 2 diabetic statin-treated patients received a supplementation with fish oil (1.7 g EPA + DHA/day), chocolate containing plant sterols (2.2 g/day), and green tea (two sachets/day) for 6 weeks. Second phase: "Good responders" to supplementation were identified after multivariate analysis (n = 10), and recruited for a pilot protocol of statin dose reduction. "Good responders" were then provided with supplementation for 12 weeks: standard statin therapy was kept during the first 6 weeks and reduced by 50% from weeks 6-12. RESULTS: First phase: After 6 weeks of supplementation, plasma LDL-C (-13.7% ± 3.7, P = .002) and C-reactive protein (-35.5% ± 5.9, P = .03) were reduced. Analysis of lathosterol and campesterol in plasma suggested that intensity of LDL-C reduction was influenced by cholesterol absorption rate rather than its synthesis. Second phase: no difference was observed for plasma lipids, inflammation, cholesterol efflux capacity, or HDL particles after statin dose reduction when compared to standard therapy. CONCLUSIONS: Although limited by the small sample size, our study demonstrates the potential for a new therapeutic approach combining lower statin dose and specific dietary compounds. Further studies should elucidate "good responders" profile as a tool for personalized medicine. This may be particularly helpful in the many patients with or at risk for CVD who cannot tolerate high dose statin therapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02732223.

Influence of toll-like receptor 4 gene variants and plasma fatty acid profile on systemic inflammation: A population-based cross-sectional study.

OBJECTIVE: The aim of this study was to investigate the interaction of toll-like receptor 4 (TLR4) gene single nucleotide polymorphism (SNP) and plasma fatty acid (FA) profile in modulating risk for systemic inflammation. METHODS: In all, 262 adult (19-59 y) participants of the Health Survey of São Paulo met the inclusion criteria. Anthropometric parameters, blood pressure, plasma inflammatory biomarker concentration, and fatty acid profile were measured and four SNPs of the TLR4 gene (rs4986790, rs4986791, rs11536889, and rs5030728) were genotyped. Multivariate cluster analysis was performed to stratify individuals based on levels of 11 plasma inflammatory biomarkers into two groups: inflammatory (INF) and noninflammatory (NINF). RESULTS: No association was found between any of the SNPs studied and systemic inflammation. The INF cluster had higher palmitic acid levels (P = 0.039) and estimated stearoyl coenzyme A desaturase activity (P = 0.045) and lower polyunsaturated fatty acid (P = 0.011), ω-6 fatty acid (P = 0.018), arachidonic acid (P = 0.002) levels, and estimated δ-5 desaturase activity (P = 0.025) compared with the NINF cluster. Statistically significant interaction between rs11536889 and arachidonic acid/eicosapentaenoic acid (AA/EPA) ratio (P = 0.034) was found to increase the odds of belonging to the INF cluster when individuals had the variant allele C and were at the higher percentile of AA/EPA plasma ratio. CONCLUSION: Plasma fatty acid profile modulated the odds of belonging to the INF cluster depending on genotypes of TRL4 gene polymorphisms.

Paternal selenium deficiency but not supplementation during preconception alters mammary gland development and 7,12-dimethylbenz[a]anthracene-induced mammary carcinogenesis in female rat offspring.

Breast cancer is a global public health problem and accumulating evidence indicates early-life exposures as relevant factors in the disease risk determination. Recent studies have shown that paternal nutrition can influence offspring health including breast cancer risk. Selenium is a micronutrient with essential role in central aspects of embryogenesis, male fertility and cancer and that has been extensively studied as a chemopreventive agent in several breast cancer experimental models. Thus, we designed an animal study to evaluate whether paternal selenium deficiency or supplementation during preconception could affect the female offspring mammary gland development and breast cancer susceptibility. Male Sprague-Dawley rats were fed AIN93-G diet containing 0.15 ppm (control diet), 0.05 ppm (deficient diet) or 1 ppm (supplemented diet) of selenium for 9 weeks and mated with control female rats. Mammary carcinogenesis was induced with 7,12-dimethylbenz[a]anthracene (DMBA) in their female offspring. Paternal selenium deficiency increased the number of terminal end buds, epithelial elongation and cell proliferation in the mammary gland of the female rat offspring and these effects were associated with higher susceptibility to DMBA-induced mammary tumors (increased incidence and higher grade tumors). On the other hand, paternal selenium supplementation did not influence any of these parameters. These results highlight the importance of father's nutrition including selenium status as a relevant factor affecting daughter's breast cancer risk and paternal preconception as a potential developmental stage to start disease preventive strategies.

Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons.

Studies in humans and rodents indicate that a minimum amount of stored energy is required for normal pubertal development. The adipocyte-derived hormone leptin is a key metabolic signal to the neuroendocrine reproductive axis. Humans and mice lacking leptin or the leptin receptor (LepR) (ob/ob and db/db mice, respectively) are infertile and fail to enter puberty. Leptin administration to leptin-deficient subjects and ob/ob mice induces puberty and restores fertility, but the exact site or sites of leptin action are unclear. Here, we found that genetic deletion of LepR selectively from hypothalamic Kiss1 neurons in mice had no effect on puberty or fertility, indicating that direct leptin signaling in Kiss1 neurons is not required for these processes. However, bilateral lesions of the ventral premammillary nucleus (PMV) of ob/ob mice blunted the ability of exogenous leptin to induce sexual maturation. Moreover, unilateral reexpression of endogenous LepR in PMV neurons was sufficient to induce puberty and improve fertility in female LepR-null mice. This LepR reexpression also normalized the increased hypothalamic GnRH content characteristic of leptin-signaling deficiency. These data suggest that the PMV is a key site for leptin's permissive action at the onset of puberty and support the hypothesis that the multiple actions of leptin to control metabolism and reproduction are anatomically dissociated.

Effect of eicosapentaenoic/docosahexaenoic fatty acids and soluble fibers on blood lipids of individuals classified into different levels of lipidemia.

OBJECTIVE: This study evaluated the effect of a formulation containing eicosapentaenoic acid and docosahexaenoic acid combined with soluble fibers (beta-glucan and guar gum) on fasting blood lipids used as coronary heart disease biomarkers of individuals classified into different levels of lipidemia by multivariate techniques. METHODS: Serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triacylglycerol, plasma glucose concentrations, body mass index, age, and waist circumference were determined in 99 healthy volunteers. Three clusters or subgroups were identified according to coronary heart disease risk levels. Within each cluster, individuals were randomly assigned to one of four experimental groups, with each group receiving samples of a functional formulation containing 460 mg of omega-3 polyunsaturated fatty acids and/or 580 mg of soluble fibers, and placebo to be consumed in one bottle per day (200 mL) for 6 wk. RESULTS: No significant changes were observed for triacylglycerol (P = 0.281) and total cholesterol (P = 0.082) concentrations across the three subgroups. Soluble dietary fibers improved the sensory quality of the formulation containing eicosapentaenoic acid and docosahexaenoic acid. The efficiency of cluster analysis to discriminate individuals in subgroups was confirmed by one-way analysis of variance (P < 0.003). CONCLUSION: The omega-3 polyunsaturated fatty acid supplementation equivalent to fish consumed 2.5 to 3 times per week by a functional food-containing soluble dietary fiber showed no beneficial result in terms of changes in blood lipids in individuals classified according to different levels of lipidemia. Small numbers of patients in each cluster and possibly the low dose of fish oil and soluble dietary fibers used in this study may have also contributed to the lack of these differences. Multivariate techniques proved to be a very efficient tool to solve the heterogeneity problem usually observed in human designs and to evaluate the results within subgroups categorized by n variables extracted from the same population.

Effect of chronic supplementation with branched-chain amino acids on the performance and hepatic and muscle glycogen content in trained rats.

The objective of this study was to evaluate the effects of a diet supplemented with branched-chain amino acids (BCAA; 3.57% and 4.76%) on the performance and glycogen metabolism of trained rats. Thirty-six adult male Wistar rats received the control diet (AIN-93M) (n=12) and two diets supplemented with BCAA (S1: AIN-93M+3.57% BCAA, n=12, and S2: AIN-93M+4.76% BCAA, n=12) for 6 weeks. The training protocol consisted of bouts of swimming exercise (60 min day(-1)) for 6 weeks at intensities close to the lactate threshold. On the last day of the experiment, all groups were trained for 1 h (1H) or were submitted to the exhaustion test (EX). The time to exhaustion did not differ between groups. The groups submitted to the exhaustion test presented a reduction in plasma glucose and an increase in plasma ammonia and blood lactate concentrations compared to the 1H condition. In the 1H condition, hepatic glycogen concentration was significantly higher in group S2 compared to the control diet and S1 groups (132% and 44%, respectively). Group S2 in the 1H condition presented a higher muscle glycogen concentration (45%) compared to the control diet group. In the EX condition, a significantly higher hepatic glycogen concentration was observed for group S2 compared to the control diet and S1 groups (262% and 222%, respectively). Chronic supplementation with BCAA promoted a higher hepatic and muscle glycogen concentration in trained animals, with this effect being dose dependent.

Functional foods for coronary heart disease risk reduction: a meta-analysis using a multivariate approach.

BACKGROUND: It has been difficult to identify the appropriate bioactive substance for the development of new functional foods associated with coronary heart disease, because the results of many clinical studies are contradictory. OBJECTIVE: The objective of this study was to use the multivariate statistical approach known as principal component analysis (PCA) followed by a mixed model to process data obtained from a meta-analysis aimed at evaluating simultaneously the effect of ingestion of 1 of 3 types of bioactive substances (n-3 fatty acids, soluble fibers, and phytosterols) on 1 or more of 4 biomarkers (plasma total cholesterol, triacylglycerol, LDL cholesterol, and HDL cholesterol). DESIGN: Five independent variables (number of patients per study, dose, age, body mass index, and treatment length) and 4 dependent variables (percentage change in blood total cholesterol, LDL, HDL, and triacylglycerol) from 159 studies and substudies were organized into a matrix. The original values were converted to linear correlation units, which resulted in a new matrix. RESULTS: Two principal components were enough to explain 63.73% and 84.27% of the variance in the independent and dependent variables, respectively. Phytosterols and soluble fibers had a hypocholesterolemic effect, whereas n-3 fatty acids lowered triacylglycerol and increased total, LDL, and HDL cholesterol. The PCA and mixed model showed that this behavior was independent of dose, number of patients per study, age, and body mass index but was associated with treatment length. CONCLUSIONS: PCA is useful for summarizing available scientific information in examinations of health claims for foods and supplements.