Dietary patterns, caloric restrictions for management of cardiovascular disease and cancer; a brief review.

Cardiovascular disease (CVD) and cancers are overall still identified as the two most prevalent non-communicable diseases globally. Their prevention and potential reversal (in particular CVD risk) was seen effective with the modification of dietary intake that was applied in several different populations. Although the findings from epidemiological studies provide support that adhering to dietary patterns such as the Mediterranean diet can reduce incidence and prevalence of CVD and some forms of cancer, the mechanistic aspects of disease modulation associated with both diseases can be seen in dietary management. Several studies have already explored the potential modes of action of certain nutrients in well controlled large clinical trials. However, the clinical trials designed to determine the effects of adhering to a particular diet are relatively hard to conduct and these studies are faced with several obstacles particularly in the populations that are identified with a high risk of CVD or different cancers. Therefore, it is important to understand potential underlying and shared mechanisms of action and to explore how healthy dietary patterns may modulate the occurrence, initiation, and progression of such diseases. The aim of this review is to summarise and conceptualize the current understanding relating to healthy dietary patterns, and briefly discuss the opportunities that epigenetic research may bring and how it may assist to further interpret epidemiological and clinical evidence.

Consumption of walnuts suppresses the conversion of palmitic to palmitoleic acid and enhances omega-3 fatty acid metabolism in the heart of fructose-fed rats.

Walnut consumption mostly has a positive implication for cardiovascular health. Walnut diet effects on the cardiac fatty acid (FA) metabolism of healthy rats and those with fructose diet-induced metabolic burden were analysed. Both walnuts and fructose increased CD36 transporter level and the nuclear content of some/all of Lipin 1/PPARα/PGC-1 complex partners, as well as cytosolic and nuclear FOXO1. However, fructose, independently of walnuts, increased the content of palmitic (PA), oleic, and vaccenic acid (VA), while in walnut-fed rats failed to increase palmitoleic acid (POA) level and the POA/PA ratio, as well as total MUFA content. In opposite, walnuts reduced the level of PA and VA and increased alpha-linolenic, eicosapentaenoic and docosapentaenoic acid level, regardless of fructose. In conclusion, both fructose and walnuts stimulated the uptake and oxidation of FA in the heart, but the walnuts, opposite to fructose, favourably altered cardiac FA profile in healthy and metabolically compromised rats.

Beneficial effect of walnuts on vascular tone is associated with Akt signalling, voltage-dependent calcium channel LTCC and ATP-sensitive potassium channel Kv1.2.

Consumption of walnuts is beneficial for cardiovascular health. To study walnut effects on proteins involved in vascular tone regulation, control and fructose-fed rats were subjected to walnut diet for 6 weeks. In contrast with increased energy intake and body mass gain, aortic protein level of L-type calcium channel alpha subunit was decreased and the level of SUR2B subunit of ATP-sensitive K + channel was increased in healthy rats subjected to walnuts, together with improved Akt phosphorylation. Upon the walnut diet in rats subjected to fructose overload, the rise in energy intake and body mass gain, was followed by an increase in blood insulin. Although SUR2B level was elevated, the level of sodium-calcium exchanger NCX1 and inducible nitric oxide synthase were reduced and increased, respectively. In summary, walnut consumption was accompanied with moderate beneficial vascular effect in healthy rats, while an effect of walnut in rats with metabolic disturbances was rather controversial.

Fructose-rich diet and walnut supplementation differently regulate rat hypothalamic and hippocampal glucose transporters expression.

BACKGROUND: Nutritional modulations may be considered a strategy to protect mental health. Neuronal homeostasis is highly dependent on the availability of glucose, which represents the primary energy source for the brain. In this study, we evaluated the effects of walnut intake and fructose-rich diet on the expression of glucose transporters (GLUTs) in two rat brain regions: hypothalamus and hippocampus. RESULTS: Our results show that walnut supplementation of fructose-fed animals restored the hypothalamic content of GLUT1 and GLUT3 protein. Furthermore, walnut intake did not affect increased hypothalamic GLUT2 content upon fructose consumption. These effects were accompanied by distinctive alterations of hippocampal GLUTs levels. Specifically, walnut intake increased GLUT1 content, whereas GLUT2 protein was decreased within the rat hippocampus after both individual and combined treatments. CONCLUSION: Overall, our study suggests that walnut supplementation exerted modulatory effects on the glucose transporters within specific brain regions in the presence of developed metabolic disorder. © 2021 Society of Chemical Industry.

Vitamin D Is Inversely Related to Obesity: Cross-Sectional Study in a Small Cohort of Serbian Adults.

Objective: Vitamin D (vitD) mediates numerous health conditions other than bone health and mineralization. Its role in cardiometabolic condition is still inconclusive. Methods: We conducted a cross-sectional study in 87 apparently healthy Serbian adults. We assessed their dietary intake, anthropometric and biochemical parameters, blood pressure, and vitD status (as serum 25-hydroxyvitamin D, 25(OH)D). Unexpectedly, the status was significantly higher in January than in July. Therefore, we pooled the data from two time points, to enhance the statistical power for carrying out association analyses. We employed linear regression models to evaluate the associations between vitD status and the obesity biomarkers of serum lipids and blood pressure. Results: Mean vitD intake of 3.85 ± 4.71 µg in the cohort was below recommended. Of the subjects in the pooled cohort, 60.58% were vitD deficient (with serum 25(OH)D below 50 nmol/L), with the majority of them being women who were overweight. VitD status tended to be inversely related to percent body fat and waist/height ratio in the crude regression model. After age and gender adjustment, the status was significantly related to waist circumference, waist/height ratio, and waist/hip ratio (ß = -0.116, 95% confidence interval [CI]: -0.206, -0.025, ß = -0.001, 95% CI: -0.001, 0.000, and ß = -0.001, 95% CI: -0.001, 0.000, respectively). These associations remained only within women. Fully adjusted models supported the notion of vitD being independently associated with central adiposity, regardless of age, gender, and total obesity. Conclusions: In apparently healthy adults with low vitD intake, vitD status was inversely associated with obesity parameters, pronouncedly in women. Our data support the need for development and implementation of public health policies on increasing vitD intake also as part of obesity management strategies.

Type of dietary fat intakes in relation to all-cause and cause-specific mortality in US adults: an iso-energetic substitution analysis from the American National Health and Nutrition Examination Survey linked to the US mortality registry.

Accumulating evidence indicates that saturated fat intake is related to mortality risk increase, whereas unsaturated fat intake is associated with reduced mortality risk. The aim of the present study was to estimate the mortality risk reduction related to a dietary change from saturated fat to mono- or polyunsaturated fat intake. The American National Health and Nutrition Examination Surveys conducted between 1999 and 2010 were linked to the 2011 national US death registry resulting in an observational prospective mortality study. Proportional hazards Cox models were used to evaluate the association between saturated, monounsaturated and polyunsaturated fat with all-cause and cause-specific mortality. Substitution analysis was conducted to estimate an iso-energetic substitution of 10 % of the energy from dietary fat intake applied to the substitution of saturated fat with an equal amount of energy from monounsaturated or polyunsaturated fat. The highest tertile intakes of saturated fat resulted in an increased risk (12 %) of all-cause and specific-cause mortality, whereas the highest tertile intakes of polyunsaturated fat resulted in a reduced risk (7 %) of all-cause and specific-cause mortality when compared with the corresponding lowest tertile. Iso-energetic substitution revealed that a substitution of 10 % of energy (from total fat) from saturated fat to an equal amount of energy from monounsaturated or polyunsaturated fat resulted in a significant reduction of the mortality risk ranging from 4 to 8 %. Iso-energetic substitution of saturated fat with monounsaturated and polyunsaturated fat reduced all-cause and specific-cause mortality in US adults.

Design, formulation and sensory evaluation of a polyphenol-rich food placebo: an example of aronia juice for food intervention studies.

Products suitable for use as controls in food interventions designed to demonstrate the role of minor components are largely lacking. In the present study, we aimed to develop a formulation to be used as a placebo in a clinical trial designed to assess the effects of aronia juice polyphenols on platelet function. Three formulations with the same nutrient composition as aronia juice were prepared by mixing various nutrients, artificial colours and flavours with water. The similarity of formulations to aronia juice in terms of taste, colour, smell and texture was assessed by six food panellists. The final placebo was tested for its impact on platelet function, biochemical and anthropometric parameters in a 4-week long study. No significant changes in platelet function, or in several cardiovascular and safety markers were recorded. Formulation suitable for use as a placebo for dietary intervention studies using aronia juice has been developed and demonstrated to be well tolerated in humans.

Pharmacogenetics in cancer therapy - 8 years of experience at the Institute for Oncology and Radiology of Serbia.

PURPOSE: Pharmacogenetics is a study of possible mechanism by which an individual's response to drugs is genetically determined by variations in their DNA sequence. The aim of pharmacogenetics is to identify the optimal drug and dose for each individual based on their genetic constitution, i.e. to individualize drug treatment. This leads to achieving the maximal therapeutic response for each patient, while reducing adverse side effects of therapy and the cost of treatment. A centralized pharmacogenetics service was formed at the Institute for Oncology and Radiology of Serbia (IORS) with the aim to provide a personalized approach to cancer treatment of Serbian patients. METHODS: Analyses of KRAS mutations in metastatic colorectal cancer, EGFR mutations in advanced non-small cell lung cancer, CYP2D6 polymorphism in breast cancer, DPD polymorphism in colorectal cancer and MTHFR polymorphism in osteosarcoma have been performed by real time polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Mutation testing analyses were successful for 1694 KRAS samples and 1821 EGFR samples, while polymorphism testing was successful for 9 CYP2D6 samples, 65 DPD samples and 35 MTHFR samples. CONCLUSIONS: Pharmacogenetic methods presented in this paper provide cancer patients in Serbia the best possible choice of treatment at the moment.

Effects of glucomannan-enriched, aronia juice-based supplement on cellular antioxidant enzymes and membrane lipid status in subjects with abdominal obesity.

The aim of this study was to analyze the effects of a 4-week-long consumption of glucomannan-enriched, aronia juice-based supplement on anthropometric parameters, membrane fatty acid profile, and status of antioxidant enzymes in erythrocytes obtained from postmenopausal women with abdominal obesity. Twenty women aged 45-65 with a mean body mass index (BMI) of 36.1 ± 4.4 kg/m(2) and waist circumference of 104.8 ± 10.1 cm were enrolled. Participants were instructed to consume 100 mL of supplement per day as part of their regular diet. A significant increase in the content of n-3 (P < 0.05) polyunsaturated fatty acids in membrane phospholipids was observed, with a marked increase in the level of docosahexaenoic fatty acid (P < 0.05). Accordingly, a decrease in the n-6 and n-3 fatty acids ratio was observed (P < 0.05). The observed effects were accompanied with an increase in glutathione peroxidase activity (P < 0.05). Values for BMI (P < 0.001), waist circumference (P < 0.001), and systolic blood pressure (P < 0.05) were significantly lower after the intervention. The obtained results indicate a positive impact of tested supplement on cellular oxidative damage, blood pressure, and anthropometric indices of obesity.

Lifestyle management of hypertension: International Society of Hypertension position paper endorsed by the World Hypertension League and European Society of Hypertension.

Hypertension, defined as persistently elevated systolic blood pressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) at least 90 mmHg (International Society of Hypertension guidelines), affects over 1.5 billion people worldwide. Hypertension is associated with increased risk of cardiovascular disease (CVD) events (e.g. coronary heart disease, heart failure and stroke) and death. An international panel of experts convened by the International Society of Hypertension College of Experts compiled lifestyle management recommendations as first-line strategy to prevent and control hypertension in adulthood. We also recommend that lifestyle changes be continued even when blood pressure-lowering medications are prescribed. Specific recommendations based on literature evidence are summarized with advice to start these measures early in life, including maintaining a healthy body weight, increased levels of different types of physical activity, healthy eating and drinking, avoidance and cessation of smoking and alcohol use, management of stress and sleep levels. We also discuss the relevance of specific approaches including consumption of sodium, potassium, sugar, fibre, coffee, tea, intermittent fasting as well as integrated strategies to implement these recommendations using, for example, behaviour change-related technologies and digital tools.

Metabolically Healthy Overweight and Obesity, Transition to Metabolically Unhealthy Status and Cognitive Function: Results from the Framingham Offspring Study.

AIMS: To evaluate the association between metabolically healthy overweight/obesity (MHO) status and longitudinal cognitive function while also considering the stability of the condition. METHODS: In total, 2892 participants (mean age 60.7 (9.4) years) from Framingham Offspring Study completed health assessments every four years since 1971. Neuropsychological testing was repeated every four years starting from 1999 (Exam 7) to 2014 (Exam 9) (mean follow-up: 12.9 (3.5) years). Standardized neuropsychological tests were constructed into three factor scores (general cognitive performance, memory, processing speed/executive function). Healthy metabolic status was defined as the absence of all NCEP ATP III (2005) criteria (excluding waist circumference). MHO participants who scored positively for one or more of NCEP ATPIII parameters in the follow-up period were defined as unresilient MHO. RESULTS: No significant difference on the change in cognitive function over time was observed between MHO and metabolically healthy normal weight (MHN) individuals (all p > 0.05). However, a lower processing speed/executive functioning scale score was observed in unresilient MHO participants compared to resilient MHO participants (ß = -0.76; 95% CI = -1.44, -0.08; p = 0.030). CONCLUSIONS: Retaining a healthy metabolic status over time represents a more important discriminant in shaping cognitive function compared to body weight alone.

Effects of Walnut-Rich Diet on Cation-Handling Proteins in the Heart of Healthy and Metabolically Compromised Male Rats.

The transport of cations in the cardiomyocytes, crucial for the functioning of the heart, can be affected by walnut diet due to the high content of polyunsaturated fatty acids. Healthy and metabolically compromised rats (drinking 10% fructose solution) were subjected to a diet supplemented with 2.4 g of walnuts for 6 weeks to investigate the effect on proteins involved in cation transport in the heart cells. Fructose increased the level of the α1 subunit of Na+/K+-ATPase and the phosphorylation of extracellular signal-regulated kinase 1/2 in the heart of control and walnut-eating rats, while elevated L-type calcium channel α (LTCCα), sodium-calcium exchanger 1 (NCX1), and Maxi Kα level were observed only in rats that did not consume walnuts. However, walnuts significantly increased the cardiac content of LTCC, NCX1, and Maxi Kα, as well as Kir6.1 and SUR2B subunits of KATP channel, but only in fructose-naive rats. In animals that drank fructose, a significant increasing effect of walnuts was observed only in Akt kinase phosphorylation, which may be a part of the antiarrhythmic mechanism of decreasing cation currents in cardiomyocytes. The walnut diet-induced increase in LTCC and NCX1 expression in healthy rats may indicate intense cardiac calcium turnover, whereas the effect on Kir6.1 and SUR2B subunits suggests stimulation of KATP channel transport in the cardiac vasculature. The effects of walnuts on the cation-handling proteins in the heart, mostly limited to healthy animals, suggest the possible use of a walnut-supplemented diet in the prevention rather than the treatment of cardiological channelopathies.

Metabolic Syndrome, Cognitive Impairment and the Role of Diet: A Narrative Review.

BACKGROUND: This narrative review presents the association between metabolic syndrome (MetS), along with its components, and cognition-related disorders, as well as the potential reversal role of diet against cognitive impairment by modulating MetS. METHODS: An electronic research in Medline (Pubmed) and Scopus was conducted. RESULTS: MetS and cognitive decline share common cardiometabolic pathways as MetS components can trigger cognitive impairment. On the other side, the risk factors for both MetS and cognitive impairment can be reduced by optimizing the nutritional intake. Clinical manifestations such as dyslipidemia, hypertension, diabetes and increased central body adiposity are nutrition-related risk factors present during the prodromal period before cognitive impairment. The Mediterranean dietary pattern stands among the most discussed predominantly plant-based diets in relation to cardiometabolic disorders that may prevent dementia, Alzheimer's disease and other cognition-related disorders. In addition, accumulating evidence suggests that the consumption of specific dietary food groups as a part of the overall diet can improve cognitive outcomes, maybe due to their involvement in cardiometabolic paths. CONCLUSIONS: Early MetS detection may be helpful to prevent or delay cognitive decline. Moreover, this review highlights the importance of healthy nutritional habits to reverse such conditions and the urgency of early lifestyle interventions.

Walnut supplementation after fructose-rich diet is associated with a beneficial fatty acid ratio and increased ACE2 expression in the rat heart.

Increased fructose consumption has been linked with chronic inflammation and metabolic syndrome (MetS). Activation of the renin-angiotensin system (RAS) and NF-κB have been detected in MetS. Walnuts are a rich source of polyunsaturated omega-3 fatty acids (n-3 PUFA) that were suggested to exert anti-inflammatory effects related to cardio-metabolic health. We hypothesized that walnut supplementation has the capacity to revert unfavorable fructose-rich diet (FRD)-induced activation of cardiac RAS and NF-κB in male rats. Due to the lack of similar studies, we investigated the effects of walnut supplementation (6 weeks) on the expression of four RAS molecules (ACE, ACE2, AT1R, and AT2R) and NF-κB in rat heart after FRD (10% w/v, 9 weeks). In addition, we followed the changes in the n-6/n-3 PUFA ratio in the total pool of heart lipids after both treatments to elucidate the walnut effects on fatty acids in the heart. 36 animals (9 per group) participated in the experiment. FRD significantly increased the ACE protein level in the heart (p < 0.001). Walnut supplementation significantly increased the ACE2 protein level in the heart of FRD (p < 0.001). In addition, walnut supplementation showed a significant main effect on the arachidonic acid/eicosapentaenoic acid ratio (p = 0.004). Walnut supplementation significantly reduced this ratio, in comparison with both, the control group (C vs. FW, p < 0.05) and the FRD group (F vs. FW, p < 0.05). However, walnut treatment failed to revert the significant effect of fructose (p < 0.001) on the elevation of NF-κB protein level. Our results suggest a beneficial effect of walnut supplementation on ACE2 protein level and n-6/n-3 PUFA level in the heart of the animal model of MetS. Such results highlight the approach of omega-3-rich walnut supplementation in the stimulation of endogenous production of favorable molecules in the heart which could be an affordable nutritional treatment formaintenance of cardio-metabolic health.

Is There a FADS2-Modulated Link between Long-Chain Polyunsaturated Fatty Acids in Plasma Phospholipids and Polyphenol Intake in Adult Subjects Who Are Overweight?

Dietary polyphenols promote cardiometabolic health and are linked with long-chain polyunsaturated fatty acids in plasma phospholipids (LC-PUFA). The FADS2 polymorphisms are associated with LC-PUFA metabolism and overweight/obesity. This 4-week study examined the link between polyphenol intake, FADS2 variants (rs174593, rs174616, rs174576) and obesity in 62 overweight adults (BMI ≥ 25), allocated to consume 100 mL daily of either: Aronia juice, a rich source of polyphenols, with 1177.11 mg polyphenols (expressed as gallic acid equivalents)/100 mL (AJ, n = 22), Aronia juice with 294.28 mg polyphenols/100 mL (MJ, n = 20), or nutritionally matched polyphenol-lacking placebo as a control (PLB, n = 20). We analyzed LC-PUFA (% of total pool) by gas chromatography and FADS2 variants by real-time PCR. Four-week changes in LC-PUFA, BMI, and body weight were included in statistical models, controlling for gender and PUFA intake. Only upon AJ and MJ, the presence of FADS2 variant alleles affected changes in linoleic, arachidonic, and eicosapentaenoic acid (EPA). Upon MJ treatment, changes in EPA were inversely linked with changes in BMI (ß= -0.73, p = 0.029) and weight gain (ß= -2.17, p = 0.024). Only in subjects drinking AJ, the link between changes in EPA and anthropometric indices was modified by the rs174576 variant allele. Our results indicate the interaction between FADS2, fatty acid metabolism, and polyphenol intake in overweight subjects.

Polyphenol-Rich Aronia melanocarpa Juice Consumption Affects LINE-1 DNA Methylation in Peripheral Blood Leukocytes in Dyslipidemic Women.

Cardiovascular disease (CVD) is associated with alterations in DNA methylation and polyunsaturated fatty acid (PUFA) profile, both modulated by dietary polyphenols. The present parallel, placebo-controlled study (part of the original clinical study registered as NCT02800967 at www.clinicaltrials.gov) aimed to determine the impact of 4-week daily consumption of polyphenol-rich Aronia melanocarpa juice (AMJ) treatment on Long Interspersed Nucleotide Element-1 (LINE-1) methylation in peripheral blood leukocytes and on plasma PUFAs, in subjects (n = 54, age range of 40.2 ± 6.7 years) at moderate CVD risk, including an increased body mass index, central obesity, high normal blood pressure, and/or dyslipidemia. The goal was also to examine whether factors known to affect DNA methylation (folate intake levels, MTHFR C677T gene variant, anthropometric and metabolic parameters) modulated the LINE-1 methylation levels upon the consumption of polyphenol-rich aronia juice. Experimental analysis of LINE-1 methylation was done by MethyLight method. MTHFR C677T genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism method, and folate intake was assessed by processing the data from the food frequency questionnaire. PUFAs were measured by gas-liquid chromatography, and serum lipid profile was determined by using Roche Diagnostics kits. The statistical analyses were performed using Statistica software package. In the comparison after vs. before the treatment period, in dyslipidemic women (n = 22), we observed significant decreases in LINE-1 methylation levels (97.54 ± 1.50 vs. 98.39 ± 0.86%, respectively; P = 0.01) and arachidonic acid/eicosapentaenoic acid ratio [29.17 ± 15.21 vs. 38.42 (25.96-89.58), respectively; P = 0.02]. The change (after vs. before treatment) in LINE-1 methylation directly correlated with the presence of MTHFR 677T allele, average daily folate intake, and the change in serum low-density lipoprotein cholesterol but inversely correlated with the change in serum triacylglycerols (R = 0.72, R 2 = 0.52, adjusted R 2 = 0.36, P = 0.03). The current results imply potential cardioprotective effects of habitual polyphenol-rich aronia juice consumption achieved through the modifications of DNA methylation pattern and PUFAs in subjects at CVD risk, which should be further confirmed. Hence, the precision nutrition-driven modulations of both DNA methylation and PUFA profile may become targets for new approaches in the prevention of CVD.

Walnut Supplementation Restores the SIRT1-FoxO3a-MnSOD/Catalase Axis in the Heart, Promotes an Anti-Inflammatory Fatty Acid Profile in Plasma, and Lowers Blood Pressure on Fructose-Rich Diet.

The benefits of walnut (Juglans regia) consumption for metabolic health are known, but the molecular background underlying their putative antioxidant and anti-inflammatory/immunomodulatory effects is underexplored. We assessed that walnut supplementation (6 weeks) reverted unfavorable changes of the SIRT1/FoxO3a/MnSOD/catalase axis in the heart induced by fructose-rich diet (FRD). Intriguingly, Nox4 was increased by both FRD and walnut supplementation. FRD increased the cytosolic fraction and decreased the nuclear fraction of the uniquely elucidated ChREBP in the heart. The ChREBP nuclear fraction was decreased in control rats subjected to walnuts. In addition, walnut consumption was associated with a reduction in systolic BP in FRD and a decrease in fatty acid AA/EPA and AA/DHA ratios in plasma. In summary, the protective effect of walnut supplementation was detected in male rats following the fructose-induced decrease in antioxidative/anti-inflammatory capacity of cardiac tissue and increase in plasma predictors of low-grade inflammation. The current results provide a novel insight into the relationship between nutrients, cellular energy homeostasis, and the modulators of inflammatory/immune response in metabolic syndrome, emphasizing the heart and highlighting a track for translation into nutrition and dietary therapeutic approaches against metabolic disease.

Vitamin D Status and Its Correlation With Anthropometric and Biochemical Indicators of Cardiometabolic Risk in Serbian Underground Coal Miners in 2016.

The status of vitamin D in underground working coal miners and its association with their cardiometabolic health is rarely studied. This study aimed to examine vitamin D (VitD) status in Serbian underground coal miners and to correlate it with anthropometric and laboratory indicators of cardiometabolic risk. Nutritional data (food frequency questionnaire, FFQ, and two times repeated 24 h recall), anthropometric data (including segmental analysis by bio-impedance analyzer TANITA BC-545N), arterial tension, and biochemical and hematological data of 103 coal miners (aged 22-63 years) were correlated with their late summer (early September) serum 25 (OH)D levels (measured by HPLC). 68.9% of the studied coal miners were overweight/obese, and 48.5% had metabolic syndrome. Their mean VitD nutritional intakes were low: 5.3 ± 3.8 µg/day (FFQ) and 4.9 ± 8 µg/day (24 h recalls), but their mean serum 25 (OH)D levels were surprisingly high (143.7 ± 41.4 nmol/L). Only 2.9% of the coal miners had 25(OH)D levels lower than 75 nmol/L (indicating an insufficient/deficient status), while 63.2% had values above 125 nmol/L (upper optimal limit), and even 10.7% had values above 200 nmol/L. There were no statistical differences in 25 (OH)D levels in the coal miners with or without metabolic syndrome (or overweight/obesity). Interestingly, 25(OH)D levels had significant positive correlations with body mass index (BMI), fat mass (FM), fat mass percentage (FM%), limbs FM%, serum triglycerides, GGT, AST, ALT, and ALT/AST ratio, and had significant negative correlations with serum HDL-cholesterol and age. All these correlations were lost after corrections for age, FM, FM%, and legs FM%. In Serbian coal miners, high levels of early September VitD levels were observed, indicating sufficient non-working-hour sun exposure during the summer period. Furthermore, the unexpected positive correlations of VitD levels with anthropometric and biochemical parameters indicative of obesity, metabolic syndrome, and fatty liver disease were found. More research is needed on the VitD status of coal miners (particularly in the winter period) and its relationship with their cardiometabolic status.

Interpreting Clinical Trials With Omega-3 Supplements in the Context of Ancestry and FADS Genetic Variation.

Human diets in developed countries such as the US have changed dramatically over the past 75 years, leading to increased obesity, inflammation, and cardiometabolic dysfunction. Evidence over the past decade indicates that the interaction of genetic variation with changes in the intake of 18-carbon essential dietary omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA), linoleic acid (LA) and α-linolenic acid (ALA), respectively, has impacted numerous molecular and clinical phenotypes. Interactions are particularly relevant with the FADS1 and FADS2 genes, which encode key fatty acid desaturases in the pathway that converts LA and ALA to their long chain (≥20 carbons), highly unsaturated fatty acid (HUFA) counterparts. These gene by nutrient interactions affect the levels and balance of n-6 and n-3 HUFA that in turn are converted to a wide array of lipids with signaling roles, including eicosanoids, docosanoids, other oxylipins and endocannabinoids. With few exceptions, n-6 HUFA are precursors of pro-inflammatory/pro-thrombotic signaling lipids, and n-3 HUFA are generally anti-inflammatory/anti-thrombotic. We and others have demonstrated that African ancestry populations have much higher frequencies (vs. European-, Asian- or indigenous Americas-ancestry populations) of a FADS "derived" haplotype that is associated with the efficient conversion of high levels of dietary n-6 PUFA to pro-inflammatory n-6 HUFA. By contrast, an "ancestral" haplotype, carrying alleles associated with a limited capacity to synthesize HUFA, which can lead to n-3 HUFA deficiency, is found at high frequency in certain Hispanic populations and is nearly fixed in several indigenous populations from the Americas. Based on these observations, a focused secondary subgroup analysis of the VITAL n-3 HUFA supplementation trial stratifying the data based on self-reported ancestry revealed that African Americans may benefit from n-3 HUFA supplementation, and both ancestry and FADS variability should be factored into future clinical trials design.

Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality.

There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.