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1.
An update on lipid oxidation and inflammation in cardiovascular diseases.
Zhong, S, Li, L, Shen, X, Li, Q, Xu, W, Wang, X, Tao, Y, Yin, H
Free radical biology & medicine. 2019;:266-278
Abstract
Cardiovascular diseases (CVD), including ischemic heart diseases and cerebrovascular diseases, are the leading causes of morbidity and mortality worldwide. Atherosclerosis is the major underlying factor for most CVD. It is well-established that oxidative stress and inflammation are two major mechanisms leading to atherosclerosis. Under oxidative stress, polyunsaturated fatty acids (PUFA)-containing phospholipids and cholesterol esters in cellular membrane and lipoproteins can be readily oxidized through a free radical-induced lipid peroxidation (LPO) process to form a complex mixture of oxidation products. Overwhelming evidence demonstrates that these oxidized lipids are actively involved in the inflammatory responses in atherosclerosis by interacting with immune cells (such as macrophages) and endothelial cells. In addition to lipid lowering in the prevention and treatment of atherosclerotic CVD, targeting chronic inflammation has been entering the medical realm. Clinical trials are under way to lower the lipoprotein (a) (Lp(a)) and its associated oxidized phospholipids, which will provide clinical evidence that targeting inflammation caused by oxidized lipids is a viable approach for CVD. In this review, we aim to give an update on our understanding of the free radical oxidation of LPO, analytical technique to analyze the oxidation products, especially the oxidized phospholipids and cholesterol esters in low density lipoproteins (LDL), and focusing on the experimental and clinical evidence on the role of lipid oxidation in the inflammatory responses associated with CVD, including myocardial infarction and calcific aortic valve stenosis. The challenges and future directions in understanding the role of LPO in CVD will also be discussed.
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2.
A systematic review of the effects of increasing arachidonic acid intake on PUFA status, metabolism and health-related outcomes in humans.
Calder, PC, Campoy, C, Eilander, A, Fleith, M, Forsyth, S, Larsson, PO, Schelkle, B, Lohner, S, Szommer, A, van de Heijning, BJM, et al
The British journal of nutrition. 2019;(11):1201-1214
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Abstract
We conducted a systematic review of randomised controlled trials (RCT) of increased intake of arachidonic acid (ARA) on fatty acid status and health outcomes in humans. We identified twenty-two articles from fourteen RCT. Most studies were conducted in adults. These used between 80 and 2000 mg ARA per d and were of 1-12 weeks duration. Supplementation with ARA doses as low as 80 mg/d increased the content of ARA in different blood fractions. Overall there seem to be few marked benefits for adults of increasing ARA intake from the typical usual intake of 100-200 mg/d to as much as 1000 mg/d; the few studies using higher doses (1500 or 2000 mg/d) also report little benefit. However, there may be an impact of ARA on cognitive and muscle function which could be particularly relevant in the ageing population. The studies reviewed here suggest no adverse effects in adults of increased ARA intake up to at least 1000-1500 mg/d on blood lipids, platelet aggregation and blood clotting, immune function, inflammation or urinary excretion of ARA metabolites. However, in many areas there are insufficient studies to make firm conclusions, and higher intakes of ARA are deserving of further study. Based on the RCT reviewed, there are not enough data to make any recommendations for specific health effects of ARA intake.
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Leukocyte telomere length and serum polyunsaturated fatty acids, dietary habits, cardiovascular risk factors and features of myocardial infarction in elderly patients.
Kalstad, AA, Tveit, S, Myhre, PL, Laake, K, Opstad, TB, Tveit, A, Schmidt, EB, Solheim, S, Arnesen, H, Seljeflot, I
BMC geriatrics. 2019;(1):376
Abstract
BACKGROUND Telomeres are non-coding sequences at the end of eukaryote chromosomes, which in complex with associated proteins serve to protect subtelomeric DNA. Telomeres shorten with each cell division, are regarded as a biomarker for aging and have also been suggested to play a role in atherosclerosis and cardiovascular disease (CVD). The aim of the present study was to explore the associations between leukocyte telomere length and serum polyunsaturated fatty acids, diet, cardiovascular risk factors and features of myocardial infarction (MI) in elderly patients. METHODS The material is based upon the first 299 included patients in the OMEMI trial, where patients aged 70-82 years of age are randomized to receive omega-3 supplements or corn oil (placebo) after MI. Patients were included 2-8 weeks after the index MI. DNA was extracted from whole blood, and leukocyte telomere length (LTL) was analyzed by qPCR and reported as a number relative to a reference gene. Serum long chain polyunsaturated fatty acid (LCPUFA) content was analyzed by gas chromatography. Diet was evaluated with the validated SmartDiet food frequency questionnaire. Medical records, patient interviews and clinical examination provided previous medical history and anthropometric data. Non-parametric statistical tests were used. RESULTS Median (25, 75 percentile) LTL was 0.55 (0.42, 0.72). Patients had a median age of 75 years, 70.2% were male and 45.2% used omega-3 supplements. There was a weak, but significant correlation between LTL and linoleic acid (r = 0.139, p = 0.017), but not with other LCPUFAs. There was a trend towards longer telomeres with a healthier diet, but this did not reach statistical significance (p = 0.073). No associations were found between LTL and CVD risk factors or features of MI. CONCLUSIONS In our population of elderly with a recent myocardial infarction LTL was associated with linoleic acid concentrations, but not with other LCPUFAs. Patients with a healthy diet tended to have longer telomeres. The limited associations may be due to age and the narrow age-span in our population. Further studies, designed to detect longitudinal changes should be performed to explore the role of telomeres in cardiovascular aging. TRIAL REGISTRATION Clinical trials no. NCT01841944, registration date April 29, 2013.
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Lipid Metabolism and Signaling in Platelet Function.
Paes, AMA, Gaspar, RS, Fuentes, E, Wehinger, S, Palomo, I, Trostchansky, A
Advances in experimental medicine and biology. 2019;:97-115
Abstract
Modern society has changed its diet composition, transitioning to a higher intake of saturated fat with a 50% increase of cardiovascular risk (CVD). Within the context of increased CVD, there is an induction of a prothrombotic phenotype mainly due to increased platelet reactivity as well as decreased platelet response to inhibitors. Platelets maintain haemostasis through both blood components and endothelial cells that secrete inhibitory or stimulatory molecules to regulate thrombus formation. There exist a correlation between platelets' polyunsaturated fatty acid (PUFA) and the increase in platelet reactivity. The aim of this chapter is to review the metabolism of the main PUFAs involved in platelet function associated with the role that their enzyme-derived oxidized metabolites exert in platelet function and fate. Finally, how lipid metabolism in the organism affect platelet aggregation and activation and the pharmacological modulation of these processes will also be discussed.
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5.
Redox lipidomics to better understand brain aging and function.
Pamplona, R, Borras, C, Jové, M, Pradas, I, Ferrer, I, Viña, J
Free radical biology & medicine. 2019;:310-321
Abstract
Human prefrontal cortex (PFC) is a recently evolutionary emerged brain region involved in cognitive functions. Human cognitive abilities decline during aging. Yet the molecular mechanisms that sustain the preservation or deterioration of neurons and PFC functions are unknown. In this review, we focus on the role of lipids in human PFC aging. As the evolution of brain lipid concentrations is particularly accelerated in the human PFC, conferring a specific lipid profile, a brief approach to the lipidome of PFC was consider along with the relationship between lipids and lipoxidative damage, and the role of lipids in human PFC aging. In addition, the specific targets of lipoxidative damage in human PFC, the affected biological processes, and their potential role in the cognitive decline associated with aging are discussed. Finally, interventions designed to modify this process are considered. We propose that the dysfunction of key biological processes due to selective protein lipoxidation damage may have a role the cognitive decline of PFC during aging.
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Increased plasma levels of the lipoperoxyl radical-derived vitamin E metabolite α-tocopheryl quinone are an early indicator of lipotoxicity in fatty liver subjects.
Torquato, P, Bartolini, D, Giusepponi, D, Piroddi, M, Sebastiani, B, Saluti, G, Galarini, R, Galli, F
Free radical biology & medicine. 2019;:115-125
Abstract
Lipid peroxidation is one of the earliest pathogenic events of non-alcoholic fatty liver disease (NAFLD). In this context, an increased oxidation of the lipoperoxyl radical scavenger α-tocopherol (α-TOH) should occur already in the subclinical phases of the disease to compensate for the increase oxidation of the lipid excess of liver and possibly of other tissues. However, this assumption remains unsupported by direct analytical evidence. In this study, GC-MS/MS and LC-MS/MS procedures have been developed and applied for the first time to measure the vitamin E oxidation metabolite α-tocopheryl quinone (α-TQ) in plasma of fatty liver (FL) subjects that were compared in a pilot cross-sectional study with healthy controls. The protein adducts of 4-hydroxynonenal (4-HNE) and the free form of polyunsaturated free fatty acids (PUFA) were measured as surrogate indicators of lipid peroxidation. α-TQ formation was also investigated in human liver cells after supplementation with α-TOH and/or fatty acids (to induce steatosis). Compared with controls, FL subjects showed increased (absolute and α-TOH-corrected) levels of plasma α-TQ and 4-HNE, and decreased concentrations of PUFA. α-TQ levels positively correlated with indices of liver damage and metabolic dysfunction, such as alanine aminotransferase, bilirubin and triglycerides, and negatively correlated with HDL cholesterol. Fatty acid supplementation in human hepatocytes stimulated the generation of cellular oxidants and α-TOH uptake leading to increased α-TQ formation and secretion in the extracellular medium - both were markedly stimulated by α-TOH supplementation. In conclusion, plasma α-TQ represents an early biomarker of the lipoperoxyl radical-induced oxidation of vitamin E and lipotoxicity of the fatty liver.
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Effects of Polyunsaturated Fatty Acids on Nonspecific Typical Dry Eye Disease: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
Chi, SC, Tuan, HI, Kang, YN
Nutrients. 2019;(5)
Abstract
To investigate the effects of polyunsaturated fatty acids (PUFAs) in patients with dry eye disease (DED), a multifactorial inflammatory disorder, we searched Cochrane Library, EMBASE, PubMed, and Web of Science for randomized clinical trials (RCTs) investigating the effect of PUFAs in patients with DED before March 2019. Two reviewers independently abstracted data of tear breakup time (TBUT), Schirmer's test, osmolarity, and ocular surface disease index (OSDI). We conducted pairwise meta-analysis using means and standard deviations (SDs) in a random-effects model for continuous outcomes. Thirteen eligible RCTs with 1782 patients with nonspecific typical DED were included. Patients who received PUFA treatment without other eye medications exhibited greater improvements in TBUT (MD = 1.80; p = 0.001), Schirmer test scores (MD = 0.50; p < 0.001), osmolarity (MD = -15.95; p < 0.001), and OSDI scores (MD = -10.19; p < 0.001) than those who received placebo treatment. However, the effects of PUFAs on TBUT (p < 0.001) and OSDI scores (p = 0.03) weakened with treatment duration. PUFAs are effective in treating nonspecific typical DED, particularly as a short-term treatment, with relatively few adverse events. Therefore, in real-world clinical practice, PUFA supplements are worth being suggested to patients with nonspecific typical DED who are not concurrently using other topical or systematic eye medications.
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DHA intake interacts with ELOVL2 and ELOVL5 genetic variants to influence polyunsaturated fatty acids in human milk.
Wu霞吴义, Y, Wang 烟王, Y, Tian敏田慧, H, Lu逯通, T, Yu苗于, M, Xu慧徐文, W, Liu良刘国, G, Xie林谢, L
Journal of lipid research. 2019;(5):1043-1049
Abstract
Endogenous synthesis of PUFAs is mediated by genes controlling fatty acid elongases 2 and 5 (ELOVL2 and ELOVL5) and by exogenous DHA intake. Associations between elongases and PUFA levels probably involve genetic variants of ELOVL and changes in DHA intake, but data about their combined effect on PUFA levels are sparse. We hypothesized that each factor would directly affect PUFAs and that interactions between haplotypes and DHA intake would influence PUFAs. We explored four levels of DHA intake in pregnant Chinese Han women and 10 SNPs in the ELOVL genes to determine associations with PUFAs in breast milk. The SNP rs3798713 and 3-SNP haplotype (rs2281591, rs12332786, and rs3798713) in ELOVL2 were associated with linoleic acid (LA) concentrations. However, carriers of the 3-SNP haplotype with higher DHA intake (second quartile: 14.58-43.15 mg/day) had higher concentrations of LA, arachidonic acid, EPA, and DHA compared with the interaction baseline. In ELOVL5, five SNPs (rs2294867, rs9357760, rs2397142, rs209512, and rs12207094) correlated with PUFA changes. Compared with those who had the 5-SNP haplotype C-A-C-G-A and low DHA intake (<14.58 mg/day), carriers with other haplotypes (A-A-C-A-A or C-A-C-A-A) and high DHA intake (≥118.82 mg/day) had increased EPA levels after adjustments for age and BMI. This study showed that maternal genetic variants in ELOVL2 and ELOVL5 were associated with PUFA levels in breast milk and that the combination of SNP haplotypes and higher DHA intake increased PUFA concentrations.
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Associations between long-chain PUFAs in maternal blood, cord blood, and breast milk and offspring body composition up to 5 years: follow-up from the INFAT study.
Meyer, DM, Brei, C, Stecher, L, Much, D, Brunner, S, Hauner, H
European journal of clinical nutrition. 2019;(3):458-464
Abstract
BACKGROUND/OBJECTIVES Limited research suggests that exposure to long-chain PUFAs (LCPUFAs) during perinatal development can influence adipose tissue expansion later in life. In previous analyses, we observed that maternal LCPUFAs in late gestation promote offspring gestational growth, whereas breast milk n-3 LCPUFAS promote adipogenesis in infants up to 1 year. This follow-up analysis examines these relationships in offspring up to 5 years. SUBJECTS/METHODS In this observational study of 169 children, relationships between n-3, n-6 LCPUFAs, and the n-6/n-3 LCPUFA ratio in maternal blood at 32 weeks' gestation, cord blood, and breast milk, and anthropometry in offspring from 2 to 5 years were investigated. Body composition was assessed with indirect (i.e., body weight, BMI percentiles, sum of four skinfold thicknesses) and direct (i.e., ultrasonography, magnetic resonance imaging in a subgroup) measurement tools. RESULTS Maternal and cord blood LCPUFAs were largely not shown to be related to offspring body composition. Breast milk n-3 LCPUFAs were significantly positively related to several measurements of child anthropometry at 2 and 4 y, but only a positive relationship between n-3 LCPUFAs and lean body mass remained statistically significant at 5 y. Breast milk n-6/n-3 LCPUFA ratio was inversely related to weight and BMI percentiles at 2 y, and lean body mass at 4 and 5 y. CONCLUSIONS Results from this follow-up do not provide sufficient evidence that LCPUFAs in maternal blood, cord blood, and breast milk predict offspring adiposity in children up to 5 years.
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10.
BMI modifies the effect of dietary fat on atherogenic lipids: a randomized clinical trial.
Sundfør, TM, Svendsen, M, Heggen, E, Dushanov, S, Klemsdal, TO, Tonstad, S
The American journal of clinical nutrition. 2019;(4):832-841
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Abstract
BACKGROUND SFA intake increases LDL cholesterol whereas PUFA intake lowers it. Whether the lipid response to dietary fat differs between normal-weight and obese persons is of relevance to dietary recommendations for obese populations. OBJECTIVES We compared the effect of substituting unsaturated fat for saturated fat on LDL cholesterol and apoB concentrations in normal-weight (BMI ≤ 25 kg/m2) and obese (BMI: 30-45) subjects with elevated LDL cholesterol. METHODS We randomly assigned 83 men and women (aged 21-70 y) stratified by BMI (normal: n = 44; obese: n = 39) and elevated LDL cholesterol (mean ± SD, normal weight 4.6 ± 0.9 mmol/L; obese 4.4 ± 0.8 mmol/L) to either a PUFA diet enriched with oil-based margarine ( n = 42) or an SFA diet enriched with butter (n = 41) for 6 wk. RESULTS Seven-day dietary records showed differences of ∼9 energy percent (E%) in SFA and ∼4 E% in PUFA between the SFA and PUFA groups. In the total study population, the PUFA diet compared with the SFA diet lowered LDL cholesterol (-0.31 mmol/L; 95% CI: -0.47, -0.15 mmol/L, compared with 0.32 mmol/L; 95% CI: 0.18, 0.47 mmol/L; P < 0.001) and apoB (-0.08 g/L; 95% CI: -0.11, -0.05 g/L, compared with 0.07 g/L; 95% CI: 0.03, 0.10 g/L; P < 0.001). Tests of the BMI × diet interaction were significant for total cholesterol, LDL cholesterol, and apoB ( P values ≤ 0.009). In normal-weight compared with obese participants post-hoc comparisons found that the respective changes in LDL cholesterol were 9.7% (95% CI: 5.3%, 14.2%) compared with 5.3% (95% CI: -0.7%, 11.2%), P = 0.206, in the SFA group, and -10.4% (95% CI: -15.2%, -5.7%) compared with -2.3% (95% CI: -7.4%, 2.8%), P = 0.020, in the PUFA group. ApoB changes were 7.5% (95% CI: 3.5%, 11.4%) compared with 3.0% (95% CI: -1.7%, 7.7%), P = 0.140, in the SFA group, and -8.9% (95% CI: -12.6%, -5.2%) compared with -3.8% (95% CI: -6.3%, -1.2%), P = 0.021, in the PUFA group. Responses to dietary fat were not associated with changes in polyprotein convertase subtisilin/kexin type 9 concentrations. CONCLUSIONS BMI modifies the effect of PUFAs compared with SFAs, with smaller improvements in atherogenic lipid concentrations in obese than in normal-weight individuals, possibly supporting adjustment of dietary recommendations according to BMI. This trial was registered with www.clinicaltrials.gov as NCT02589769.