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Background: Non-alcoholic steatohepatitis (NASH) has become one of the most common liver diseases and is still without approved pharmacotherapy. Lifestyle interventions using exercise and diet change remain the current treatment of choice and even a small weight loss (5-7%) can already have a beneficial effect on NASH. However, the underlying molecular mechanisms of exercise and diet interventions remain largely elusive, and it is unclear whether they exert their health effects via similar or different pathways., Methods: Ldlr-/-.Leiden mice received a high fat diet (HFD) for 30 weeks to establish a severe state of NASH/fibrosis with simultaneous atherosclerosis development. Groups of mice were then either left untreated (control group) or were treated for 20 weeks with exercise (running wheel), diet change (switch to a low fat chow diet) or the combination thereof. The liver and distant organs including heart, white adipose tissue (WAT) and muscle were histologically examined. Comprehensive transcriptome analysis of liver, WAT and muscle revealed the organ-specific effects of exercise and diet and defined the underlying pathways., Results: Exercise and dietary change significantly reduced body weight, fat mass, adipocyte size and improved myosteatosis and muscle function with additive effects of combination treatment. WAT inflammation was significantly improved by diet change, tended to be reduced with exercise, and combination therapy had no additive effect. Hepatic steatosis and inflammation were almost fully reversed by exercise and diet change, while hepatic fibrosis tended to be improved with exercise and was significantly improved with diet change. Additive effects for the combination therapy were shown for liver steatosis and associated liver lipids, and atherosclerosis, but not for hepatic inflammation and fibrosis. Pathway analysis revealed complementary effects on metabolic pathways and lipid handling processes, thereby substantiating the added value of combined lifestyle treatment., Conclusions: Exercise, diet change and the combination thereof can reverse established NASH/fibrosis in obese Ldlr-/-.Leiden mice. In addition, the lifestyle interventions had beneficial effects on atherosclerosis, WAT inflammation and muscle function. For steatosis and other parameters related to adiposity or lipid metabolism, exercise and dietary change affected more distinct pathways that acted complementary when the interventions were combined resulting in an additive effect for the combination therapy on important endpoints including NASH and atherosclerosis. For inflammation, exercise and diet change shared several underlying pathways resulting in a net similar effect when the interventions were combined., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Ursolic acid (UA) is a natural pentacyclic triterpenoid found in a number of plants such as apples, thyme, oregano, hawthorn and others. Several in vitro and in vivo studies have presented its anti-inflammatory and anti-apoptotic properties. The inhibition of NF-κB-mediated inflammatory pathways and the increased scavenging of reactive oxygen species (ROS) in numerous ways seem to be the most beneficial effects of UA. In mice and rats, administration of UA appears to slow down the development of cardiovascular diseases (CVDs), especially atherosclerosis and cardiac fibrosis. Upregulation of endothelial-type nitric oxide synthase (eNOS) and cystathionine-λ-lyase (CSE) by UA may suggest its vasorelaxant property. Inhibition of metalloproteinases activity by UA may contribute to better outcomes in aneurysms management. UA influence on lipid and glucose metabolism remains inconsistent, and additional studies are essential to verify its efficacy. Furthermore, UA derivatives appear to have a beneficial impact on the cardiovascular system. This review aims to summarize recent findings on beneficial effects of UA that may make it a promising candidate for clinical trials for the management of CVDs.

Endothelial dysfunction is a key player in both the onset and development of atherosclerosis. No study has examined whether healthy dietary patterns can improve microvascular endothelial function in patients with coronary heart disease (CHD) in the long-term and whether this relationship can affect patient's risk of CHD recurrence. In the CORDIOPREV study, a randomized, double-blind, controlled trial, dietary intervention with either the Mediterranean diet or a low-fat diet was implemented in 1,002 CHD patients. A laser-doppler flowmetry was performed at baseline and after 6 years of follow up in 664 patients, evaluating the effects of this dietary intervention on microvascular basal flow and reactive hyperaemia area, as well as on the risk of CHD recurrence, based on the TRS2P risk score. Basal flow (97.78 ± 2.79 vs. 179.31 ± 5.06 arbitrary perfusion units, 83.38% increase, p < 0.001) and reactive hyperaemia area (4233.3 ± 127.73 vs. 9695.9 ± 205.23 arbitrary perfusion units per time, 129.04% increase, p < 0.001) improved after the dietary intervention in the cohort, without finding differences due to the diet (p > 0.05 for the diet-effect). When patients were stratified to low, moderate or high-risk of recurrence, basal flow was similarly increased in all three groups. However, reactive hyperaemia area was improved to a greater extent in patients at the low-risk group compared with those at moderate or high-risk. No differences were observed between diets. Healthy dietary patterns can improve microvascular endothelial function and this improvement persists in the long-term. Patients with a low-risk of CHD recurrence show a greater improvement in reactive vasodilation to ischemia than patients in the moderate or high-risk groups., (© 2021. The Author(s).)

Sesamol, a major ingredient in sesame seeds ( Sesamum indicum L.) and its oil, is considered a powerful functional food ingredient. However, few studies have investigated its effects on high-fat, high carbohydrate and high-cholesterol (HF-HCC) diet-induced nonalcoholic steatohepatitis (NASH) complicated with atherosclerosis. The present study elucidates the protective effects of sesamol against NASH and atherosclerosis in HF-HCC diet-fed rats. Sprague-Dawley rats were supplemented with or without sesamol in drinking water (0.05 mg mL -1 , 0.1 mg mL -1 and 0.2 mg mL -1 ) from the beginning to end. At the end of the experiment, sesamol supplementation suppressed HF-HCC diet-induced body weight gain and increased absolute liver and adipose tissue weights in rats. Serum biochemical analyses showed that sesamol supplementation improved HF-HCC diet-induced metabolism disorders and damaged vascular endothelial function. Histological examinations displayed that dietary sesamol not only alleviated hepatic balloon degeneration, steatosis, inflammation and fibrosis, but also mitigated lipid accumulation and fibrous elements in the aorta arch in HF-HCC diet-fed rats. In addition, sesamol supplementation inhibited hepatic NOD-like receptor protein 3 (NLRP3) expression and ERS-IRE1 signaling pathway activation. Moreover, sesamol treatment decreased uric acid levels both in serum and the liver by its effect on the inhibition of xanthine oxidase (XO) activity and/or its expression, which might be closely associated with the inhibitions of NLRP3 expression and ERS-IRE1 signaling pathway activation in HF-HCC diet-fed rats. These findings demonstrated that sesamol alleviated NASH and atherosclerosis in HF-HCC diet-fed rats, and may be a potent dietary supplement for protection against these diseases.

The atherosclerosis "iron hypothesis" generates a fair amount of debate since it has been proposed. Here, we revisited the "iron hypothesis" by examining whether dietary iron overload would intensify iron deposition in plaques and thus lead to further exacerbation of atherosclerosis in apolipoprotein E knockout (ApoE KO) mice. ApoE KO mice were fed either a normal chow diet (ND) or a high fat diet (HFD) supplemented with or without 2% carbonyl iron (Fe) for 16 weeks. However, contrary to our assumption, dietary iron overloading did not intensify, but rather diminished the atherosclerotic lesion area by 65.3%, which was accompanied by significantly decreased serum total cholesterol, triglyceride and low-density lipoprotein cholesterol contents, together with hepatic lipid accumulation decline, despite the evident existence of aortic iron accumulation and the typical signs of iron overload in ApoE KO mice. Using isobaric tag for absolute quantification (iTRAQ) proteomics approach, hepatic CD36 and fatty acid binding proteins-mediated fatty acid (FA) uptake and trafficking impairment were identified as the key potential pathomechanisms by which iron overload diminishes atherosclerotic lesions. Furthermore, downstream hepatic FA de novo biosynthesis was enhanced and FA oxidation was inhibited to compensate for the FA deficiency triggered by iron overload-impaired fatty acid uptake and trafficking. Our findings suggested that dietary iron overload is not atherogenic in ApoE KO mice, and more research efforts are warranted to revisit the "iron hypothesis" of atherosclerosis., (Copyright © 2021. Published by Elsevier B.V.)

Background and Aims: High-quality of the carbohydrates consumed, apart from their total amount, appear to protect from cardiovascular disease (CVD). However, the relationship between the quality of carbohydrates and the early appearance of atherosclerosis has not yet been described. Our objective was to estimate the association between the quality of dietary carbohydrates and subclinical atherosclerosis in femoral and carotid arteries., Methods: Cross-sectional study of femoral and carotid atherosclerosis assessed using ultrasounds of 2074 middle-aged males, 50.9 (SD 3.9) years old, with no previous CVD, and pertaining to the Aragon Workers' Health Study (AWHS) cohort. Food frequency questionnaires were used to calculate a carbohydrate quality index (CQI) defined as: consumption of dietary fiber, a lower glycemic index, the ratio of whole grains/total grains, and the ratio of solid carbohydrates/total carbohydrates. The presence of plaques across four CQI intervals was studied using adjusted logistic regression models., Results: The CQI showed a direct inverse association with subclinical atherosclerosis in femoral territories. Participants with a higher consumption of high-quality carbohydrates (13-15 points) were less likely to have femoral plaques when compared with participants in the lowest index interval (4-6 points) (OR = 0.59; 95% CI = 0.39, 0.89; p = 0.005). No association was found between the CQI and the presence of subclinical atherosclerosis in carotid territories. A lower consumption of high-quality carbohydrates tended to be associated with a greater atherosclerosis extension, considered as the odds for having more affected territories (p = 0.011)., Conclusions: Among middle-aged males, a high-quality intake of carbohydrates is associated with a lower prevalence of femoral artery subclinical atherosclerosis when compared with a lower consumption. Thus, indicating an early relationship between the quality of carbohydrates and the development of CVD., Competing Interests: Conflicts of interest None., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We examined whether peripheral leukocytes of mice derived from in vitro αMEM-cultured embryos and exhibiting type 2 diabetes had higher expression of inflammatory-related genes associated with the development of atherosclerosis. Also, we examined the impact of a barley diet on inflammatory gene expression. Adult mice were produced by embryo transfer, after culturing two-cell embryos for 48 h in either α minimal essential media (α-MEM) or potassium simplex optimized medium control media. Mice were fed either a barley or rice diet for 10 weeks. Postprandial blood glucose and mRNA levels of several inflammatory genes, including Tnfa and Nox2, in blood leukocytes were significantly higher in MEM mice fed a rice diet compared with control mice. Barley intake reduced expression of S100a8 and Nox2. In summary, MEM mice exhibited postprandial hyperglycemia and peripheral leukocytes with higher expression of genes related to the development of atherosclerosis, and barley intake reduced some gene expression., (© The Author(s) 2021. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Background: Epidemiologic studies suggest that fruit and vegetable (F&V) consumption is inversely associated with incidence of cardiovascular disease (CVD). However, evidence for causality is lacking, and the underlying mechanisms are not well understood., Objectives: We aimed to determine whether there is a causal relation between consuming high levels of F&V and prevention of atherosclerosis, the hallmark of CVD pathogenesis. Furthermore, the underlying mechanisms were determined., Methods: Six-week-old male LDL receptor-knockout mice were randomly assigned to 3 diet groups (12 mice/group) for 20 wk: control (CON, 10% kcal fat, 0.20 g/kg cholesterol), atherogenic (Ath, 27% kcal fat, 0.55 g/kg cholesterol), and Ath supplemented with 15% F&V (Ath + FV) (equivalent to 8-9 servings/d in humans). F&V was added as a freeze-dried powder that was prepared from the 24 most commonly consumed F&Vs in the United States. Body weight, aortic atherosclerotic lesion area, hepatic steatosis area, serum lipid profile and proinflammatory cytokine TNF-α concentrations, gut microbiota, and liver TNF-α and fatty acid synthase (Fasn) mRNA concentrations were assessed., Results: F&V supplementation did not affect weight gain. Mice fed the Ath + FV diet had a smaller aortic atherosclerotic lesion area (71.7% less) and hepatic steatosis area (80.7% less) than those fed the Ath diet (both P < 0.001) independent of impact on weight, whereas no difference was found between Ath + FV and CON groups in these 2 pathologic markers. Furthermore, F&V supplementation prevented Ath diet-induced dyslipidemia (high concentrations of serum TG and VLDL cholesterol and lower concentrations of HDL cholesterol), reduced serum TNF-α concentration (by 21.5%), suppressed mRNA expression of liver TNF-α and Fasn, and ameliorated Ath-induced gut microbiota dysbiosis., Conclusions: Our results indicate that consuming a large quantity and variety of F&Vs causally attenuates diet-induced atherosclerosis and hepatic steatosis in mice. These effects of F&Vs are associated with, and may be mediated through, improved atherogenic dyslipidemia, alleviated gut dysbiosis, and suppressed inflammation., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background and Objective: Malondialdehyde (MDA) may increase influenced by free radicals due to lipid oxidation. Tomato induction considers able to prevent free radical damage and atherosclerosis. Therefore, this study aims to understand the effect of steamed-tomato extracts on MDA and its potential as an early diagnosis of atherosclerosis., Materials and Methods: A total of 24 healthy 12 weeks-old male-rats were divided into four treatment groups, equally. A normal control group (K 1 ) was rats with placebo treatment. A negative control group (K 2 ) was the rats supplemented with 2 mL kg -1 b.wt. per day of cholesterol until cholesterol. A K 3 group was atherosclerosis rats given with 20 mg kg -1 b.wt. per day of atorvastatin and a K 4 was atherosclerotic rats supplemented with 16 mg kg -1 b.wt. per day of tomato extract. All treatments were carried out for 60 consecutive days., Results: Tomato extract in the K 4 group was succeeded in lowering MDA production. Carotenoid compounds in tomato extract are well known to be prevention agents against lipid oxidation and inhibit free radicals. MDA levels have increased significantly in atherosclerosis conditions, making it potentially noticeable during early atherosclerotic, therefore, potentially developed as biomarkers., Conclusion: MDA levels increase significantly and simultaneously after high cholesterol diets and in line with lipid parameters and damaged blood vessels. The steamed-tomato extract can reduce MDA, lipids levels and protect endothelial from lipid oxidation. More research should be conducted to breakdown the MDA function in the molecular pathway, including MDA correlation to microRNA expression and cell signaling.

It is known that cardiovascular disease can result in cognitive impairment. However, whether oat fiber improves cognitive behavior through a cardiovascular-related mechanism remains unclear. The present work was aimed to elucidate the potential of oat fiber on cognitive behavior by targeting the neuroinflammation signal and microbiome-gut-brain axis in a mouse model of atherosclerosis. Male low-density lipoprotein receptor knock-out (LDLR -/- ) mice were treated with a high fat/cholesterol diet without or with 0.8% oat fiber for 14 weeks. Behavioral tests indicated that LDLR -/- mice exhibited a significant cognitive impairment; however, oat fiber can improve cognitive behavior by reducing latency to the platform and increasing the number of crossing and swimming distance in the target quadrant. Oat fiber can inhibit A β plaque processing in both the cortex and hippocampus via decreasing the relative protein expression of GFAP and IBα1. Notably, oat fiber inhibited the nod-like receptor family pyrin domain-containing 3 inflammasome activation and blocked the toll-like receptor 4 signal pathway in both the cortex and hippocampus, accompanied by a reduction of circulating serum lipopolysaccharide. In addition, oat fiber raised the expressions of short-chain fatty acid (SCFA) receptors and tight junction proteins (zonula occludens-1 and occludin) and improved intestinal microbiota diversity via increasing the contents of gut metabolites SCFAs. In summary, the present study provided experimental evidence that dietary oat fiber retarded the progression of cognitive impairment in a mouse model of atherosclerosis. Mechanistically, the neuroprotective potential was related to oat fiber and its metabolites SCFAs on the diversity and abundance of gut microbiota that produced anti-inflammatory metabolites, leading to repressed neuroinflammation and reduced gut permeability through the microbiome-gut-brain axis.

The consumption of phosphorus in Western populations largely exceeds the recommended intake, while vitamin D supply is often insufficient. Both situations are linked to an increased cardiovascular risk. A 17-week two-factorial study with Ldl receptor -/- mice was conducted to investigate the cardiovascular impact of dietary phosphorus [adequate (0.3%; P 0.3 ) vs. high (1.5%; P 1.5 )] in combination with a low (50 IU/kg; D 50 ) or adequate vitamin D diet (1000 IU/kg; D 1000 ). The data demonstrate that mice fed the P 1.5 vs. P 0.3 diets developed smaller vascular lesions (p = 0.013) and cardiac hypotrophy (p = 0.011), which were accompanied by diminished IGF1 and insulin signalling activity in their hearts. Vitamin D showed no independent effect on atherogenesis and heart morphology. Feeding P 1.5 vs. P 0.3 diets resulted in markedly reduced serum triacylglycerols (p < 0.0001) and cholesterol (p < 0.0001), higher faecal lipid excretion (p < 0.0001) and a reduced mRNA abundance of hepatic sterol exporters and lipoprotein receptors. Minor hypocholesterolaemic and hypotriglyceridaemic effects were also found in mice fed the D 1000 vs. D 50 diets (p = 0.048, p = 0.026). To conclude, a high phosphorus intake strongly affected the formation of vascular lesions, cardiac morphology, and lipid metabolism, although these changes are not indicative of an increased cardiovascular risk.

Background & Aims: Circulating microvesicles (cMV) are small phospholipid-rich vesicles that contribute to the atherothrombotic process, and are biomarkers of cardiovascular disease (CVD) burden and progression. Diet is a cornerstone for CVD prevention, but dietary effects on cMV shedding are poorly characterized. We aimed at assessing the long term effects of a Mediterranean diet compared to a low-fat diet (LFD) on MV shedding by cells of the blood and vascular compartments in patients at high cardiovascular risk treated as per guidelines., Methods: A total of 155 participants from the PREDIMED trial free of cardiovascular events after a mean follow-up of 5 years (n = 53 from the Mediterranean diet supplemented with extra-virgin olive oil -EVOO-; n = 49 from the Mediterranean diet supplemented with mixed nuts -Nuts-; and n = 53 from the LFD) were included in the study. At baseline and after one-year intervention, cMV were quantified and characterized by flow cytometry to identify their activated parental cell origin and prothrombotic potential by Annexin V (AV) binding., Results: After one year of dietary intervention, platelet-derived PAC-1 + /AV + and CD62P + /AV + cMV concentrations were lower in the Nuts group compared with the LFD and EVOO interventions (P = 0.036 and 0.003, respectively). In addition, prothrombotic cMV carrying tissue factor (CD142 + /AV + ) and CD11a + /AV + cMV derived from activated cells, were significantly lower in both Mediterranean diet (EVOO and Nuts) interventions compared to one year of LFD (P < 0.0001 and 0.028, respectively). SMAα + /AV - cMV were lower in the LFD compared to the Nuts group after one year of intervention (P = 0.038)., Conclusions: cMV are markers of cell activation and vascular injury that appear to be sensitive to dietary changes. Following a Mediterranean diet rich in EVOO or nuts is associated with lower cell activation towards a pro-atherothrombotic phenotype, suggesting a delay in the development of CV complications., Competing Interests: Conflict of interest ER has received research funding through his institution from the California Walnut Commission, has received personal money from this company for the preparation of lectures, and is a nonpaid member of its Scientific Advisory Committee. All other authors declare no competing interests., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Purpose of Review: There is an extensive literature on the efficacy of the low carbohydrate diet (LCD) for weight loss, and in the improvement of markers of the insulin-resistant phenotype, including a reduction in inflammation, atherogenic dyslipidemia, hypertension, and hyperglycemia. However, critics have expressed concerns that the LCD promotes unrestricted consumption of saturated fat, which may increase low-density lipoprotein (LDL-C) levels. In theory, the diet-induced increase in LDL-C increases the risk of cardiovascular disease (CVD). The present review provides an assessment of concerns with the LCD, which have focused almost entirely on LDL-C, a poor marker of CVD risk. We discuss how critics of the LCD have ignored the literature demonstrating that the LCD improves the most reliable CVD risk factors., Recent Findings: Multiple longitudinal clinical trials in recent years have extended the duration of observations on the safety and effectiveness of the LCD to 2-3 years, and in one study on epileptics, for 10 years., Summary: The present review integrates a historical perspective on the LCD with a critical assessment of the persistent concerns that consumption of saturated fat, in the context of an LCD, will increase risk for CVD.

Scope: To assess whether following a Mediterranean diet (MedDiet) improves atherothrombosis biomarkers in high cardiovascular risk individuals., Methods and Results: In 358 random volunteers from the PREvención con DIeta MEDiterránea trial, the 1-year effects on atherothrombosis markers of an intervention with MedDiet, enriched with virgin olive oil (MedDiet-VOO; n = 120) or nuts (MedDiet-Nuts; n = 119) versus a low-fat control diet (n = 119), and whether large increments in MedDiet adherence (≥3 score points, versus compliance decreases) and intake changes in key food items are associated with 1-year differences in biomarkers. Differences are observed between 1-year changes in the MedDiet-VOO intervention and control diet on the activity of platelet activating factor acetylhydrolase in high-density lipoproteins (HDLs) (+7.5% [95% confidence interval: 0.17; 14.8]) and HDL-bound α 1 -antitrypsin levels (-6.1% [-11.8; -0.29]), and between the MedDiet-Nuts intervention and the control arm on non-esterified fatty acid concentrations (-9.3% [-18.1; -0.53]). Large MedDiet adherence increments are associated with less fibrinogen (-9.5% [-18.3; -0.60]) and non-esterified fatty acid concentrations (-16.7% [-31.7; -1.74]). Increases in nut, fruit, vegetable, and fatty fish consumption, and decreases in processed meat intake are linked to enhancements in biomarkers., Conclusion: MedDiet improves atherothrombosis biomarkers in high cardiovascular risk individuals., (© 2020 Wiley-VCH GmbH.)

Accumulating evidence has suggested that medium-, long-, and medium-chain (MLM) structured lipids have anti-obesity effects, but whether they can alleviate the development of atherosclerosis (AS) and affect the composition of the gut microbiota in high-fat diet-fed ApoE-/- mice has not been elucidated. The present study found that MLM structured lipid supplementation could significantly decrease obesity-related parameters compared with high-fat diet alone in ApoE-/- mice. Additionally, MLM structured lipids could significantly decrease the blood glucose and increase the serum total antioxidant capacity (T-AOC) and superoxide dismutase (SOD) levels. Additionally, high-dose MLM structured lipids supplementation could reduce the area of atherosclerotic lesions and decrease the expression of VCAM-1, MCP-1 and CD68, which are related to inflammation in aortic tissue. Further analysis showed that MLM structured lipids could significantly reduce lipid accumulation in the adipose tissue of high-fat diet-fed ApoE-/- mice. The relative protein expression of SREBP-1, ACC, FAS, C/EBPα and PPARγ was decreased and the ratio of p-AMPK/AMPK was increased in epididymis white adipose tissue (eWAT) after MLM structured lipids treatment. Additionally, MLM structured lipids supplementation regulated the bacterial composition, including reducing the Firmicutes/Bacteroidetes ratio, increasing the relative abundance of short-chain fatty acid-producing bacteria (Blautia and Anaerotruncus), decreasing the relative abundance of [Ruminococcus] torques group, Ruminiclostridium 9, Catenibacterium and [Eubacterium] fissicatena group. Spearman's correlation analysis revealed significant correlations between changes in the gut microbiota and atherosclerosis-related indices. The results demonstrated that the alleviating effects of MLM structured lipids supplementation on AS in high-fat diet-fed ApoE-/- mice were closely related to reshaping the composition of the gut microbiota.

Calorie restriction (CR) ameliorates various diseases including cardiovascular disease. However, its protection and underlying mechanisms against atherosclerosis remain un-fully elucidated. In this study, we fed apoE deficient (apoE -/- ) mice in Control group a high-fat diet (HFD, 21% fat plus 0.5% cholesterol) or in CR group a CR diet (CRD, 2% fat plus 0.5% cholesterol, ∼40% calorie restriction and same levels of cholesterol, vitamins, minerals and amino acids as in HFD). After 16 weeks feeding, compared with HFD, CRD substantially reduced atherosclerosis in mice. CRD increased SMC and collagen content but reduced macrophage content, necrotic core and vascular calcification in lesion areas. Mechanistically, CRD attenuated bodyweight gain, improved lipid profiles but had little effect on macrophage lipid metabolism. CRD also inhibited expression of inflammatory molecules in lesions. Taken together, our study demonstrates CRD effectively reduces atherosclerosis in apoE -/- mice, suggesting it as a potent and reproducible therapy for atherosclerosis management., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Postmenopausal status is associated with an increase in total and abdominal body fat as well as increased incidence of insulin resistance and cardiovascular disease. The purpose of this study was to determine if watermelon supplementation affects select systemic markers of atherosclerosis and measures of insulin resistance in overweight and obese postmenopausal women. We hypothesized that overweight and obese postmenopausal women consuming 100% watermelon puree daily for 6 weeks would have improved levels of select systemic markers connected with cardiovascular disease without changing markers of insulin resistance. To test this hypothesis, overweight and obese postmenopausal women were recruited to participate in this study. Participants were randomly assigned to either the control group (no intervention) or the watermelon puree group (WM) for 6 weeks. Plasma concentration of markers connected with atherosclerosis and glycemic control were measured pre- and poststudy. A significant 6% decrease in soluble vascular cell adhesion molecule-1 occurred pre- to poststudy in WM, P = .003. The pattern of change in fasting blood glucose (P = .633), insulin (P = .158), and homeostatic model assessment-estimated insulin resistance (P = .174) did not differ between groups. Pre- to poststudy increases were measured in the fasting plasma concentration of l-arginine (8%, P = .005), cis-lycopene (32%, P = .003), and trans-lycopene (42%, P = .003) in WM. We conclude that 6 weeks of watermelon supplementation improved soluble vascular cell adhesion molecule-1 levels, a marker connected to atherogenesis, independent of changes in body composition or glycemic control., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The P2Y 12 receptor is a key player in platelet activation and a major target for antithrombotic drugs. The beneficial effects of P2Y 12 receptor antagonists might, however, not be restricted to the primary and secondary prevention of arterial thrombosis. Indeed, it has been established that platelet activation also has an essential role in inflammation. Additionally, nonplatelet P2Y 12 receptors present in immune cells and vascular smooth muscle cells might be effective players in the inflammatory response. This review will investigate the biological and clinical impact of P2Y 12 receptor inhibition beyond its platelet-driven antithrombotic effects, focusing on its anti-inflammatory role. We will discuss the potential molecular and cellular mechanisms of P2Y 12 -mediated inflammation, including cytokine release, platelet-leukocyte interactions and neutrophil extracellular trap formation. Then we will summarize the current evidence on the beneficial effects of P2Y 12 antagonists during various clinical inflammatory diseases, especially during sepsis, acute lung injury, asthma, atherosclerosis, and cancer.

Atherosclerosis, the underlying cause of cardiovascular diseases such as myocardial infarction, cerebrovascular accident, and peripheral vascular disease, is the leading cause of global mortality. Current therapies against atherosclerosis, which mostly target the dyslipidemia associated with the disease, have considerable residual risk for cardiovascular disease together with various side effects. In addition, the outcomes from clinical trials on many promising pharmaceutical agents against atherosclerosis (e.g., low-dose methotrexate, inhibitors against cholesteryl ester transfer protein) have been disappointing. Nutraceuticals such as probiotic bacteria have, therefore, generated substantial recent interest for the prevention of atherosclerosis and potentially as add-ons with current pharmaceutical drugs. This review will discuss the current understanding of the anti-atherogenic actions of probiotics from preclinical and clinical studies together with their potential underlying mechanisms of action., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Low molecular weight metabolites produced by the intestinal microbiome that have been associated with health and disease as metabolites need to be constantly absorbed from the intestinal lumen and transported to intestinal epithelial cells and blood. Polyamines, especially spermidine and spermine, are bioactive chemicals which promote autophagy and suppress inflammation. The main source of exogenous polyamines is the intestinal lumen, where they are produced by intestinal microbiome. Considering the intestinal microbiome as a manufacturing plant for bioactive substances, we developed a novel hybrid putrescine biosynthesis system strategy, in which the simultaneous intake of Bifidobacterium animalis ssp. lactis LKM512 (Bifal) and arginine (Arg) upregulates the production of the putrescine, a precursor of spermidine and spermine, in the gut by controlling the bacterial metabolism beyond its vast diversity and inter-individual differences. In a clinical trial, healthy individuals with a body mass index near the maximum "healthy" range (25 kg/m 3 ; n = 44) were randomized to consume either normal yogurt containing Bifal and Arg (Bifal + Arg YG) or placebo (normal yogurt) for 12 weeks. The change in reactive hyperemia index determined by EndoPAT from week 0 to 12 in the Bifal + Arg YG group was significantly higher than that in the placebo group, indicating that Bifal + Arg YG intake improved vascular endothelial function. In addition, the concentrations of fecal putrescine and serum spermidine in the Bifal+ Arg YG group were significantly higher than those in the placebo group. These findings suggest that consuming Bifal + Arg YG prevents or reduces atherosclerosis risk by upregulating blood spermidine levels, which subsequently induces autophagy.

Objective: Oxidized phospholipids (OxPL), such as the oxidized derivatives of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine, 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine, and 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine, have been shown to be the principal biologically active components of minimally oxidized LDL (low-density lipoprotein). The role of OxPL in cardiovascular diseases is well recognized, including activation of inflammation within vascular cells. Atherosclerotic Apoe -/- mice fed a high-fat diet develop antibodies to OxPL, and hybridoma B-cell lines producing natural anti-OxPL autoantibodies have been successfully generated and characterized. However, as yet, no studies have been reported demonstrating that treatment with OxPL neutralizing antibodies can be used to prevent or reverse advanced atherosclerosis. Approach and Results: Here, using a screening against 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine/1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphorylcholine, we generated a novel IgM autoantibody, 10C12, from the spleens of Apoe -/- mice fed a long-term Western diet, that demonstrated potent OxPL neutralizing activity in vitro and the ability to inhibit macrophage accumulation within arteries of Apoe -/- mice fed a Western diet for 4 weeks. Of interest, 10C12 failed to inhibit atherosclerosis progression in Apoe -/- mice treated between 18 and 26 weeks of Western diet feeding likely due at least in part to high levels of endogenous anti-OxPL antibodies. However, 10C12 treatment caused a 40% decrease in lipid accumulation within aortas of secreted IgM deficient, sIgM -/- Apoe -/- , mice fed a low-fat diet, when the antibody was administrated between 32-40 weeks of age., Conclusions: Taken together, these results provide direct evidence showing that treatment with a single autoimmune anti-OxPL IgM antibody during advanced disease stages can have an atheroprotective outcome.

Objective: A Mediterranean diet supplemented with olive oil and nuts prevents cardiovascular disease in clinical studies, but the underlying mechanisms are incompletely understood. We investigated whether the preventive effect of the diet could be due to inhibition of atherosclerosis and foamy monocyte formation in Ldlr -/- mice fed with a diet in which milkfat in a Western diet (WD) was replaced with extra-virgin olive oil and nuts (EVOND). Approach and Results: Ldlr -/- mice were fed EVOND or a Western diet for 3 (or 6) months. Compared with the Western diet, EVOND decreased triglyceride and cholesterol levels but increased unsaturated fatty acid concentrations in plasma. EVOND also lowered intracellular lipid accumulation in circulating monocytes, indicating less formation of foamy monocytes, compared with the Western diet. In addition, compared with the Western diet, EVOND reduced monocyte expression of inflammatory cytokines, CD36, and CD11c, with decreased monocyte uptake of oxLDL (oxidized LDL [low-density lipoprotein]) ex vivo and reduced CD11c + foamy monocyte firm arrest on vascular cell adhesion molecule-1 and E-selectin-coated slides in an ex vivo shear flow assay. Along with these changes, EVOND compared with the Western diet reduced the number of CD11c + macrophages in atherosclerotic lesions and lowered atherosclerotic lesion area of the whole aorta and aortic sinus., Conclusions: A diet enriched in extra-virgin olive oil and nuts, compared with a Western diet high in saturated fat, lowered plasma cholesterol and triglyceride levels, inhibited foamy monocyte formation, inflammation, and adhesion, and reduced atherosclerosis in Ldlr -/- mice.

Trimethylamine- N -oxide (TMAO) is a risk factor for atherosclerosis. We compared the potency of fish oil with flaxseed oil in reducing TMAO-exacerbated atherogenesis. Five groups of ApoE -/- mice were given one of five diets, namely, a low-fat diet, a Western high fat diet (WD), a WD plus 0.2% TMAO, and two WDs containing 0.2% TMAO with 50% lard being replaced by flaxseed oil or fish oil. TMAO accelerated atherosclerosis and disturbed cholesterol homeostasis. Compared with flaxseed oil, fish oil was more effective in inhibiting TMAO-induced atherogenesis by lowering plasma cholesterol and inflammatory cytokines. Both oils could reverse TMAO-induced decrease in fecal acidic sterols. Fish oil promoted fecal output of neutral sterols and downregulated hepatic cholesterol biosynthesis. Fish oil was more effective than flaxseed oil in promoting the growth of short-chain fatty acid-producing bacteria and lowering microbial generation of lipopolysaccharide. In conclusion, fish oil is more potent than flaxseed oil to ameliorate TMAO-exacerbated atherogenesis.

The research literature on atherosclerosis includes findings investigating the atherosclerotic effect of oxysterols, which are the oxidation products of cholesterol; and the literature on oxysterols refers to mechanisms by which oxysterols cause phospholipid packing defects in cell membranes. This review synthesizes these two bodies of research findings to describe how oxysterols cause phospholipid packing defects within the membranes of vascular endothelial cells, potentially increasing cell permeability of low-density lipoprotein cholesterol which may lead to atheroma formation. Exogenous sources of oxysterols are provided by dietary intake of animal-based foods that contain cholesterol oxidation products. This review proposes an explanation for the anti-atherosclerotic effect of plant-based dietary patterns, which is attributed to restriction or avoidance of dietary oxysterol intake from animal-based foods. Furthermore, raw-milk cheeses play an important role in the traditional French diet-low oxysterol content in these unheated foods may contribute to the French paradox, in which reduced coronary heart disease is associated with a diet high in saturated fat and cholesterol., (Copyright © 2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Purpose of Review: This review presents the current available evidence of the effects of several dietary patterns on atherosclerotic cardiovascular disease (ASCVD) risk in patients with type 2 diabetes (T2D)., Recent Findings: Evidence demonstrates improvements in cardiovascular risk factors with some dietary patterns in the general population. However, evidence is limited for glycemic control and cardiovascular benefit in patients with T2D for Dietary Approaches to Stop Hypertension and plant-based dietary patterns. Evidence suggests that carbohydrate-restricted dietary patterns improve glycemic control and decrease the use of anti-hyperglycemic medications. The Mediterranean dietary pattern has the most evidence for glycemic control and decreased ASCVD risk in patients with T2D. There is no evidence on ASCVD outcomes in patients with T2D for any other dietary pattern. The Mediterranean dietary pattern has the most evidence for cardiovascular benefit in patients with T2D. Future research should examine the effect of dietary patterns on ASCVD outcomes.

To ascertain the effect of calcium rich diet and/ or vitamin D supplementation on atherogenic parameters in high salt loaded rats. Thirty male rats were randomly assigned into five groups of six rats each, namely; control; salt only; salt + Calcium; salt + Vit. D and salt + Vit. D + Calcium. High salt diet constituted 8% NaCl diet + 1% NaCl drinking water, while calcium diet was made from 2.5% CaCl2 diet. Serum lipids and atherogenic indices were estimated using standard laboratory procedures. The control rats took normal rodent chow, the feeding lasted 6 weeks. Rats fed high salt diet only had significantly (p<0.05) reduced high density lipoprotein cholesterol levels, however this was significantly (p<0.05) increased upon treatment with calcium rich diet and vitamin D supplementation. The high salt groups placed on Vit. D and/or calcium diet supplementation had a significant (p<0.05) decrease in low density lipoproteins, total cholesterol and atherogenic indices (cardiac risk ratio, atherogenic coefficient and atherogenic index of plasma) compared to the group fed on high salt only. These results suggest the ameliorative potentials of calcium rich diets and vitamin D supplementation against atherogenic tendencies and possibly cardiovascular diseases.

Objective: To investigate the effect of Lactobacillus rhamnosus GR-1 on atherosclerotic progression in apolipoprotein-E knockout (ApoE-/-) mice fed with a high-fat diet and the underlying mechanisms of its action., Materials and Methods: Eight-week-old ApoE-/- mice were treated with Lactobacillus rhamnosus GR-1 daily for 12 weeks. ApoE-/- mice in the vehicle group and wild type (WT) mice were treated with normal saline. Serum lipid levels, histopathological analysis of the aorta, oxidative and inflammatory indexes and activation of the nuclear factor-kappa B (NF-κB) signaling pathway were examined., Results: Compared to ApoE-/- mice in the vehicle group, no changes in body weight or serum lipid levels were found in ApoE-/- mice treated with Lactobacillus rhamnosus GR-1. However, the administration of GR-1 slowed down the development of atherosclerosis and reduced plaque formation. Additionally, GR-1 attenuated the development of oxidative stress and chronic inflammation in a dose-dependent manner in ApoE-/- mice fed a high-fat diet. Furthermore, in ApoE-/- mice treated with GR-1, GR-1 was demonstrated to have a role in inhibiting the translocation of NF-κB p65 from the cytoplasm to the nucleus and suppressing the degradation of IκB-α., Conclusions: We showed that the administration of GR-1 decreased atherosclerotic lesion size in ApoE-/- mice by reducing oxidative stress and inflammation. Additionally, the NF-κB signaling pathway might mediate these effects.

Objective: Atherosclerosis is a major contributor to cardiovascular disease, with a higher burden on men than women during the occupational age. Intake of individual dietary antioxidants is inversely associated with risk of atherosclerosis development. We aimed to understand the relationship between dietary composite antioxidant intake and the carotid intima media thickness (cIMT), which is a proxy of atherosclerosis progression., Approach and Results: We performed a cross-sectional analysis that included 894 members of the Kardiovize cohort, a random urban sample population. Nutrient intakes were derived by 24-h recall. We constructed a composite dietary antioxidant index (CDAI), based on zinc, selenium, vitamin A, vitamin C, vitamin E and carotenoids. We considered the CDAI as the exposure variable and primary outcomes were the following cardio-metabolic parameters: body mass index (BMI), waist-to-hip ratio (WHR), body fat mass (BFM), systolic and diastolic blood pressure, triglycerides, HDL and LDL cholesterol, and cIMT. Associations and interactions between variables were evaluated using linear regression analyses. In women, a 1 mg increase in dietary intake of zinc or vitamin E decreased the cIMT by 3.36 and 1.48 µm, respectively, after adjusting for covariates. Similarly, the cIMT decreased by 4.72 µm for each one-unit increase in CDAI (p = 0.018). Beyond CDAI, age (β = 3.61; SE=0.89; p = 0.001), systolic blood pressure (β = 1.30; SE=0.59; p = 0.029) and triglycerides (β = 22.94; SE=10.09; p = 0.024) were significant predictors of cIMT in women. By contrast, we found no association between CDAI and cIMT in men., Conclusions: CDAI negatively associates with cIMT in women. These findings indicate that combined intake of nutrients with anti-oxidant properties might prevent the initiation and progression of arterial lesions in a sex-specific manner., (Copyright © 2018 Elsevier Inc. All rights reserved.)

It has been demonstrated that regular fish consumption is associated with a reduced mortality from atherosclerotic cardiovascular disease (ASCVD). However, data are scarce regarding the correlation between the changes in the serum eicosapentaenoic acid/arachidonic acid (EPA/AA) ratio associated with regular fish consumption and the changes in the serum lipid profile variables. This study was designed as a hospital-based longitudinal study to investigate the relationship between the changes in the serum EPA/AA ratio and changes of the serum lipid levels in patients with one or more risk factors for ASCVD. In 475 patients followed-up for at least 1 year, univariable and multivariable regression analyses conducted after adjustments for the risk factors of ASCVD revealed that the absolute change of the EPA/AA ratio (∆EPA/AA ratio) was independently and significantly associated with the changes of the serum levels of low-density lipoprotein cholesterol (LDL-C) (β = - 0.129, p = 0.005), triglyceride (TG) (β = - 0.108, p = 0.019), non-high-density lipoprotein cholesterol (non-HDL-C) (β = - 0.149, p = 0.001), and TG/HDL-C ratio, a marker of the LDL particle size (β = - 0.104, p = 0.02), while not being correlated with any other lipid parameters. On the other hand, while the ∆ docosahexaenoic acid (DHA)/AA ratio was inversely correlated with the changes of the serum HDL-C level and positively correlated with the changes of the TG/HDL-C ratio, possibly serving to promote development of atherosclerosis. The results suggest that an increase of the EPA/AA ratio might be associated with decrease of the serum levels of LDL-C, TG and non-HDL-C levels, as well as with an increase of the TG/HDL-C ratio, which represents increased LDL particle size, all of which play a role in the development of ASCVD. A high EPA/AA ratio, but not DHA/AA ratio, derived from fish consumption might reduce the risk of ASCVD through reducing the risk of development of atherosclerosis.Clinical Trial Registration Information: UMIN ( http://www.umin.ac.jp/ ), Study ID: UMIN000010603.

Atherosclerosis is one of the most prevalent reasons for premature death in adults. Despite the several conventional drugs in the market; many patients are not completely treated. Here we comprehensively review current clinical evidence regarding the efficacy of dietary polyphenols in atherosclerosis and related complications. PubMed, Cochrane library and Scopus were searched from inception until August 2016 to obtain clinical trials in which polyphenols were evaluated in cardiovascular parameters related to atherosclerosis. From total of 13031 results, 49 clinical trials were finally included. Tyrosol derivatives from virgin olive oil, catechins and theaflavins from green and black tea, cocoa polyphenols, and red grape resveratrol, as well as anthocyanins were the most studied polyphenolic compounds which could regulate lipid profile, inflammation and oxidative stress, blood pressure, endothelial function, and cell adhesion molecules. The most important limitations of the included trials were small sample size, short follow up, and unqualified methodology. Future well-designed clinical trials are necessary to provide better level of evidence for clinical decision making.

Context: Polyphenols and flavonoids in artichoke leaf tincture (ALT) protect cells against oxidative damage., Objectives: We examined ALT effects on deoxyribonucleic acid (DNA) damage and lipid profiles in rat plasma and gene expression in rat aorta [haemeoxygenase-1 (HO1), haemeoxygenase-2 (HO2), NADPH oxidase 4 (NOX-4), monocyte chemoattractant protein-1 (MCP-1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)]., Materials and Methods: Eighteen male Wistar albino rats were divided into three groups (n = 6/group): The control group (CG) was fed with standard pellet chow for 11 weeks; the AD group was fed for a similar period of time with pellet chow supplemented with 2% cholesterol, 3% sunflower oil and 1% sodium cholate. The ADA group was fed with pellet chow (for 1 week), the atherogenic diet (see above) for the following 4 weeks and then with ALT (0.1 mL/kg body weight) and atherogenic diet for 6 weeks. According to HPLC analysis, the isolated main compounds in ALT were chlorogenic acid, caffeic acid, isoquercitrin and rutin., Results: Normalized HO-1 [0.11 (0.04-0.24)] and MCP-1 [0.29 (0.21-0.47)] mRNA levels and DNA scores [12.50 (4.50-36.50)] were significantly lower in the ADA group than in the AD group [0.84 (0.35-2.51)], p = 0.021 for HO-1 [0.85 (0.61-3.45)], p = 0.047 for MCP-1 and [176.5 (66.50-221.25)], p = 0.020 for DNA scores. HO-1 mRNA was lower in the ADA group than in the CG group [0.30 (0.21-0.71), p = 0.049]., Conclusions: Supplementation with ALT limited the effects of the atherogenic diet through reduced MCP-1 expression, thereby preventing oxidative damage.

The protective effects of a dietary intervention as a useful tool in the prevention of atherosclerosis disease has gained greater attention in recent years. Several epidemiological studies have demonstrated the importance of diet in reducing expensive treatments or possible undesirable side effects. The main aim of this review is to examine the effects of specific nutrients on the development and progression of atherosclerosis in patients with cardiovascular disease. Various mechanisms have been proposed to explain the cardioprotective effect of different nutrients. In this sense, results have shown stabilization of vulnerable atherosclerotic plaques or downregulation of biomarkers related to inflammation through nutrients such as Omega-3 polyunsaturated fatty acids, hydroxytyrosol of extra virgin olive oil, lycopen, phytosterols of plants, or flavonols of fruits and vegetables, among others. The accumulated evidence on the anti-inflammatory effects related to these nutrients is summarized in the present review.

Sleep duration and sleep quality are important predictors of risk for cardiovascular disease (CVD). One potential link between sleep health and CVD is through lifestyle factors such as diet. To clarify the association between diet and sleep, we assessed the associations of sleep duration and insomnia symptoms with current Mediterranean-style diet (aMed) and with historical changes in aMed score. Actigraphy-measured sleep duration and self-reported insomnia symptoms categorized as insomnia with short sleep (<6 hr/night), insomnia without short sleep, no insomnia with short sleep, and no insomnia or short sleep were obtained from 2068 individuals who also had dietary intake data. A 10-point aMed score, derived from a self-report food frequency questionnaire, was collected concurrently with the sleep assessment and 10 years before. Compared with individuals who currently reported a low aMed score, those with a moderate-high aMed score were more likely to sleep 6-7 vs. <6 hr/night (p < 0.01) and less likely to report insomnia symptoms occurring with short sleep (vs. no insomnia or short sleep alone; p < 0.05). An increase in aMed score over the preceding 10 years was not associated with sleep duration or insomnia symptoms. However, compared with those with decreasing aMed score, individuals with an unchanging score reported fewer insomnia symptoms (p ≤ 0.01). These results suggest that a Mediterranean-style diet is associated with adequate sleep duration, less insomnia symptoms, and less likely to have insomnia accompanied by short sleep. Further research should identify possible mediators through which diet may promote adequate sleep duration and reduce the risk of insomnia.

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Atherosclerosis is a chronic disease associated with oxidative stress and inflammatory activation and is the main underlying trigger for cardiovascular disease. There are many cardiovascular health products in the market; in order to evaluate the effect of these products, in this paper, a novel lipid profiling platform was established using the shot-gun mass spectrum method for the analysis of free fatty acid and phospholipids, and the high performance liquid chromatography coupled with mass spectroscopy method for the analysis of lipid mediators and triacylglycerol, respectively, in serum from male apolipoprotein E-knock out mice after different diet interventions. Changes in the four lipids above, and pathways and regulation of lipid metabolism in mice from different groups were further investigated. The result showed that all cardiovascular health products showed some certain potential to alleviate atherogenesis and ameliorate inflammation; among them, lemon apple cider vinegar drink and seal oil could significantly decrease triacylglycerol in mouse serum. The establishment of this lipidome profiling platform helps to better understand the metabolism regulation and intervention mechanism of different cardiovascular health products in chronic diseases, such as atherogenesis. This platform could be applied to other cardiovascular health products and provide reliable lipid profiling data for their potential effect.

Objective: We examined whether success in achieving the key targets of an infancy-onset 20-year dietary intervention associated with insulin sensitivity and serum lipids from early childhood to young adulthood., Research Design and Methods: The sample comprised 941 children participating in the prospective, randomized Special Turku Coronary Risk Factor Intervention Project (STRIP). Dietary counseling was given biannually based on the Nordic Nutrition Recommendations with the main aim to improve the quality of dietary fat in children's diets and the secondary aim to promote intake of vegetables, fruits, and whole-grain products. Food records and serum lipid profile were studied annually from 1 to 20 years of age, and HOMA of insulin resistance (HOMA-IR) was assessed between 7 and 20 years of age. Meeting the intervention targets for quality of dietary fat was defined as the ratio of saturated fatty acids (SAFA) to monounsaturated and polyunsaturated fatty acids (MUFA + PUFA) <1:2 and intake of SAFA <10% of total energy intake (E%). Meeting the target for intake of whole-grain products, fruits, and vegetables was indicated by a fiber intake ≥3 g/MJ., Results: Participants in the intervention group had a higher probability of meeting the targets of SAFA/(PUFA + MUFA) <1:2 (risk ratio [RR] 3.91 [95% CI 3.33-4.61]), intake of SAFA <10 E% (RR 3.33 [95% CI 2.99-3.96]), and intake of fiber >3 g/MJ (RR 1.37 [95% CI 1.04-1.80]). Participants who achieved more targets had lower HOMA-IR, lower concentrations of fasting serum glucose, insulin, LDL cholesterol, and non-HDL cholesterol, and a lower ratio of apolipoprotein (Apo) B/ApoA1 ( P values all ≤0.003)., Conclusions: Achieving the key targets of an infancy-onset 20-year dietary intervention was associated with better insulin sensitivity and serum lipid profile throughout the early life course., (© 2018 by the American Diabetes Association.)

Berry consumption has been associated with cardiovascular disease prevention in recent years. Atherosclerosis is one of the major causes of cardiovascular diseases. However, research on the prevention of atherosclerosis through consuming individual whole berries, specifically direct evidence, remains scarce. Therefore, further elucidating the role that berries play in the prevention of atherosclerosis is warranted. In this perspective, blueberries were selected to articulate research strategies for studying atheroprotective effects of berries. Studies from human subjects and various animal models are summarized. The mechanisms by which blueberries may act, through reducing oxidative stress, decreasing inflammation, improving endothelial dysfunction, regulating cholesterol accumulation and trafficking, along with potentially influencing gut microbiota, are also discussed. Blueberries contain high levels of polyphenolic compounds, which were widely indicated as major bioactive compounds. Nonetheless, the metabolites/catabolites after blueberry consumption, such as simple phenolic acids, rather than original compounds in berries, may be the actual in vivo bioactive compounds. Future research should focus on obtaining more direct evidence, preferably in humans, understanding of the mechanisms of action at the molecular level, and identifying bioactive compounds as well as which compounds act synergistically to convey health benefits. The research strategy discussed here may also be applied to the studies of other fruits and berries.

Background: Lipoprotein(a) [Lp(a)] is a highly atherogenic lipoprotein and is minimally effected by lifestyle changes. While some drugs can reduce Lp(a), diet has not consistently shown definitive reduction of this biomarker. The effect of consuming a plant-based diet on serum Lp(a) concentrations have not been previously evaluated., Hypothesis: Consumption of a defined, plant-based for 4 weeks reduces Lp(a)., Methods: Secondary analysis of a previous trial was conducted, in which overweight and obese individuals (n = 31) with low-density lipoprotein cholesterol concentrations >100 mg/dL consumed a defined, plant-based diet for 4 weeks. Baseline and 4-week labs were collected. Data were analyzed using a paired samples t-test., Results: Significant reductions were observed for serum Lp(a) (-32.0 ± 52.3 nmol/L, P = 0.003), apolipoprotein B (-13.2 ± 18.3 mg/dL, P < 0.0005), low-density lipoprotein (LDL) particles (-304.8 ± 363.0 nmol/L, P < 0.0005) and small-dense LDL cholesterol (-10.0 ± 9.2 mg/dL, P < 0.0005). Additionally, serum interleukin-6 (IL-6), total white blood cells, lipoprotein-associated phospholipase A2 (Lp-PLA2), high-sensitivity c-reactive protein (hs-CRP), and fibrinogen were significantly reduced (P ≤ 0.004)., Conclusions: A defined, plant-based diet has a favorable impact on Lp(a), inflammatory indicators, and other atherogenic lipoproteins and particles. Lp(a) concentration was previously thought to be only minimally altered by dietary interventions. In this protocol however, a defined plant-based diet was shown to substantially reduce this biomarker. Further investigation is required to elucidate the specific mechanisms that contribute to the reductions in Lp(a) concentrations, which may include alterations in gene expression., (© 2018 Wiley Periodicals, Inc.)

Diet and exercise are recommended both as a prophylactic and as a therapeutic approach for patients with established coronary artery disease. We previously reported that sesame oil (SESO) and its aqueous extract (SOAE) showed antiatherosclerotic and anti-inflammatory properties. We also observed that genes involved in reverse cholesterol transport (RCT) might be activated. In this study, we tested whether post-treatment with SESO or SOAE would reduce preexisting atherosclerosis by enhancing RCT. Female low-density lipoprotein receptor knockout (LDL-R -/- ) mice were fed an atherogenic diet for 3 months, followed by post-treatment with either control or SESO or SOAE for 1 month. Plasma lipids and atherosclerotic lesions were quantified at the end of the study. RNA was extracted from the aortic tissues and used for real-time polymerase chain reaction analysis. SESO and SOAE post-treatment significantly reduced atherosclerotic lesions in LDL-R -/- mice compared to controls. No significant change in plasma cholesterol, triglyceride, or LDL cholesterol levels was observed. Aortic gene analysis showed that the SESO/SOAE post-treatment reduced inflammatory gene expression and induced genes involved in cholesterol metabolism and RCT. This is the first study that demonstrates that post-treatment with SESO and SOAE could be an effective treatment for preexisting atherosclerosis and inflammation. The study also may suggest that reducing inflammation might be conducive to an accelerated regression of lesions.

Rationale: Dietary intake is a potential risk factor for respiratory morbidity in adult populations. Few studies capture the effect of dietary patterns, representative of the combination of nutrients consumed, on self-reported respiratory morbidity in combination with objective measures of lung function., Objectives: To evaluate patterns of dietary intake in relation to respiratory morbidity and objective measures of lung function in a U.S., Methods: The ARIC (Atherosclerosis Risk in Communities) study investigators enrolled 15,792 participants from four U.S. communities between 1987 and 1989 and collected data using a validated food frequency questionnaire to assess diet. Principal component analysis was applied, and patterns representative of "Western" and "Prudent" diets emerged. We investigated cross-sectional associations between dietary patterns and pulmonary assessments that included asthma and chronic obstructive pulmonary disease (COPD) diagnosis, respiratory symptoms, and lung function. Multivariable Poisson regression models included quintiles of dietary patterns and potential confounders. Interaction of dietary patterns with obesity, sex, and smoking status was assessed in relation to all outcomes., Results: Higher scores in the "Western" dietary pattern (quintile 5 vs. quintile 1) were associated with higher prevalence of COPD (prevalence ratio [PR], 1.62; 95% confidence ratio [CI], 1.33-1.97), wheeze (PR, 1.37; 95% CI, 1.11-1.69), cough (PR, 1.32; 95% CI, 1.32-1.59), and phlegm (PR, 1.27; 95% CI, 1.05-1.54) and lower percent predicted forced expiratory volume in 1 second (FEV 1 ), percent predicted forced vital capacity (FVC), and FEV 1 /FVC ratio. Higher scores in the "Prudent" dietary pattern (quintile 5 vs. quintile 1) were associated with lower prevalence of COPD (PR, 0.82; 95% CI, 0.70-0.95) and cough (PR, 0.77; 95% CI, 0.67-0.89) and higher percent predicted FEV 1 and FEV 1 /FVC ratio. The prevalence of asthma was not related to dietary intake., Conclusions: A "Western" dietary pattern was associated with respiratory symptoms, lower lung function, and COPD in ARIC participants.

Cereal fiber is associated with decreasing the risk of cardiovascular diseases. However, whether cereal fiber modulates inflammatory response and improves atherosclerosis remains unclear. This study evaluated the anti-atherosclerotic effect of cereal fibers from oat or wheat bran and explored the potential anti-inflammatory mechanisms. Male ApoE -/- mice were given a high-fat/cholesterol (HFC) diet or a HFC diet supplemented with 0.8% oat fiber or wheat bran fiber. After 18 weeks of the feeding period, serum lipids and inflammatory cytokines were measured. The relative protein levels of the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway and nuclear factor κB (NF-κB) were determined by the western blot method in aorta tissues. Pathologically, oat fiber and wheat fiber significantly reduced atherosclerotic plaques by 43.3 and 27.1%, respectively. Biochemically, cereal fiber markedly decreased the protein levels of myeloid differentiation factor 88 (MyD88) and toll-like receptor 4 (TLR4) in aortic tissues. The expression of NF-κB was similarly inhibited by both cereal fibers. In comparison to wheat bran fiber, oat fiber had greater effects in reducing the plague size and inhibiting TLR4/MyD88/NF-κB pathways. Such differences might come from modulation of the NLRP3 inflammasome pathway because the expressions of the cleavage of caspase-1 and interleukin (IL)-1β were inhibited only by oat fiber. The present study demonstrates that cereal fibers can attenuate inflammatory response and atherosclerosis in ApoE -/- mice. Such effects are pronounced with oat fiber and likely mediated by specific inhibition of oat fiber on the NLRP3 inflammasome pathway.

The present study investigates the impact of germinated brown rice (GBR) on atherosclerosis and the underlying mechanism in low-density lipoprotein receptor-knockout (LDLr-KO) mice. The intensity of atherosclerosis in aortas of LDLr-KO mice receiving diet supplemented with 60% GBR (weight/weight) was significantly less than that in mice fed with 60% white rice (WR) or control diet ( p < 0.05); all diets contained 0.06% cholesterol. WR or GBR diet did not significantly alter plasma total or LDL-cholesterol, fecal sterols, or glucose, or the activities of antioxidant enzymes, compared to the control diet. The adhesion of monocytes to aortas from LDLr-KO mice fed with WR diet was significantly more than that from mice receiving the control diet ( p < 0.01). GBR diet decreased monocyte adhesion to aortas compared to WR diet ( p < 0.01). GBR diet also reduced the levels of plasminogen activator inhibitor-1 (PAI-1), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) in plasma, and the abundances of MCP-1, PAI-1, TNF-α, intracellular cell adhesion molecule-1, toll-like receptor-4, PAI-1, LDLr-like protein, and urokinase plasminogen activator and its receptor in aortas or hearts from LDLr-KO mice in comparison to the WR diet ( p < 0.05, 0.01, respectively). The findings suggest that GBR administration attenuated atherosclerosis and vascular inflammation in LDLr-KO mice compared to WR. The anti-atherosclerotic effect of GBR in LDLr-KO mice at least in part results from its anti-inflammatory activity.

The aim of this study was to investigate the effects of aorta and heart tissues obtained from cattle and pigs on atherosclerosis disorders. Atherosclerosis model rats were provided with the respective diets consisting of aorta and heart tissues. Administration of each tissue suppressed body weight gain as compared to that of the control. In particular, the aorta tissues of pigs and cattle demonstrated significant suppressions in body weight gain in the model rats. The aorta tissues of pigs and cattle showed a significant increase and decrease in the serum high-density lipoproteins and atherogenic index, respectively, which was correlated with the increase in apolipoprotein A1. Hematological analysis revealed that aorta tissues of pigs and cattle clearly reduced the ratio of granulocytes/lymphocytes in the atherosclerosis rats. Serum vascular cellular adhesion molecule-1 levels in the atherosclerosis rats, which were administered these aorta tissues, were also significantly reduced. Additionally, there was an increase in von Willebrand factor in the rat serum. Based on the results obtained, the aorta tissues of pigs and cattle, in particular, demonstrated positive effects in the atherosclerosis rats due to the alteration of lipid metabolism and reduction in inflammation related to atherosclerosis., (© 2018 Japanese Society of Animal Science.)

Decreased high-density lipoprotein (HDL) particle size, cholesterol poor, apolipoprotein A-I-rich HDL particles leading to smaller HDL particle size, may be associated with an anti-atherosclerotic effect. The data are sparse regarding the relationship between n-3 polyunsaturated fatty acids [n-3 PUFAs: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)] and HDL particle size. This study was designed as a hospital-based cross-sectional study to investigate the relationship between the serum levels of n-3 PUFAs and the HDL-cholesterol/apolipoprotein A-1 ratio, as estimated by the HDL particle size, in patients with the presence of one or more risk factors for atherosclerotic cardiovascular disease (ASCVD). Six hundred and forty sequential patients were enrolled in this study. The serum levels of EPA and DHA showed a strong correlation (r = 0.736, p < 0.0001). However, in a multivariate regression analysis after adjustment for ASCVD risk factors, increased serum DHA (β = - 0.745, p = 0.021), but not serum EPA (β = - 0.414, p = 0.139) or EPA + DHA (β = 0.330, p = 0.557) level, was identified as an independent indicator of decreased HDL particle size. In 476 patients followed up for at least 6 months, the absolute change (Δ) in the HDL-cholesterol/apolipoprotein A-1 ratio decreased significantly as the quartile of the Δ DHA level increased (p = 0.014), whereas no significant difference in the Δ HDL-cholesterol/apolipoprotein A-1 ratio was noted with the increase in the quartile of the Δ EPA level. Moreover, a multivariate regression analysis identified increased DHA level and decreased estimated low-density lipoprotein (LDL) particle size measured relative to the mobility value of LDL with polyacrylamide gel electrophoresis (i.e., relative LDL migration: LDL-Rm value), as independent predictors of decreased HDL-cholesterol/apolipoprotein A-1 ratio (β = - 0.171, p = 0.0003 and β = - 0.142, p = 0.002). The results suggest that increased serum DHA level, but not EPA level, might be associated with decreased HDL-cholesterol/apolipoprotein A-1 ratio, an indicator of estimated HDL particle size. Further studies are needed to investigate the useful clinical indices and outcomes of these patients. Clinical Trial Registration Information UMIN ( http://www.umin.ac.jp/ ), Study ID: UMIN000010603.

Scope: Mannan oligosaccharides (MOS) have proven effective at improving growth performance, while also reducing hyperlipidemia and inflammation. As atherosclerosis is accelerated both by hyperlipidemia and inflammation, we aim to determine the effect of dietary MOS on atherosclerosis development in hyperlipidemic ApoE*3-Leiden.CETP (E3L.CETP) mice, a well-established model for human-like lipoprotein metabolism., Methods and Results: Female E3L.CETP mice were fed a high-cholesterol diet, with or without 1% MOS for 14 weeks. MOS substantially decreased atherosclerotic lesions up to 54%, as assessed in the valve area of the aortic root. In blood, IL-1RA, monocyte subtypes, lipids, and bile acids (BAs) were not affected by MOS. Gut microbiota composition was determined using 16S rRNA gene sequencing and MOS increased the abundance of cecal Bacteroides ovatus. MOS did not affect fecal excretion of cholesterol, but increased fecal BAs as well as butyrate in cecum as determined by gas chromatography mass spectrometry., Conclusion: MOS decreased the onset of atherosclerosis development via lowering of plasma cholesterol levels. These effects were accompanied by increased cecal butyrate and fecal excretion of BAs, presumably mediated via interactions of MOS with the gut microbiota., (© 2018 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aims: Fish by-products valorization on account of their richness in bioactive compounds may represent a better alternative to marine products with a view to economic profitability and sustainable development. In this study, we compared the effect of sardine by-product proteins (SBy-P), with those of the fillets (SF-P) or casein (Cas), on growth parameters, serum leptin level, lipids disorders, lipid peroxidation and reverse cholesterol transport, in diet-induced obese rats., Main Methods: Obesity was induced by feeding rats a high-fat diet (20% sheep fat), during 12 weeks. At body weight (BW) of 400 ± 20 g, eighteen obese rats were divided into three homogenous groups and continue to consume the high-fat diet for 4 weeks containing either, 20% SBy-P, SF-P or Cas., Key Findings: The results showed that SBy-P, compared to SF-P and Cas, efficiently reduced food intake (FI), BW gain and serum leptin level, and improved blood lipids levels and reverse cholesterol transport by reducing total cholesterol (TC), triacylglycerols (TG) and low-density lipoprotein cholesterol (LDL-HDL 1 -C) serum levels, increasing the level of high-density lipoprotein cholesterol (HDL 2 -C and HDL 3 -C), and enhancing lecithin: cholesterol acyltransferase (LCAT) activity. Furthermore, they attenuated lipid peroxidation by increasing atheroprotective activity of the paraoxonase-1 (PON-1)., Significance: Sardine by-product proteins due to their richness in certain essential amino acids, highlight weight-loss, lipid-lowering, antioxidant and anti-atherogenic potentials, contributing to the improvement of the complications associated with obesity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

High fat diet is a risk factor for the development of atherosclerosis. Hence, research studies are important to understand the cellular and molecular mechanisms of atherosclerosis pathogenesis. The current study was conducted to evaluate the role of vitamin D in modulation of aortic histopathological, immunohistochemical alterations and biochemical changes induced by high fat diet in male albino rats. Forty adult rats were divided into three major groups; group I (control), group II (High fat diet) and group III (High fat diet with vitamin D). At the end of the experiment, blood cholesterol and triglycerides were determined. Aortic arches specimens were collected for histopathological study and immunohistochemical staining. Aorta of high fat diet group showed intimal thickening with vacuolated endothelial cells. The tunica media showed areas of fibrosis and irregular vacuolated smooth muscle cells.  Many inflammatory cells were detected in the tunica adventitia. Significant reduction in area percentage of smooth muscle actin-α (SMA-α) immunoreactivity and increase in number of S100 positive dendritic cells (DCs) with significant increase in serum cholesterol and triglycerides were also detected. Concomitant vitamin D supplementation, with high fat diet, showed amelioration in histopathological aortic changes with significant increase in SMA-α immunoreactivity and decrease in S100 positive (DCs). However, serum cholesterol and triglyceride showed non-significant decrease after vitamin D supplementation. In conclusion, vitamin D administration ameliorates aortic wall histoopathological changes induced by high fat diet most probably through local modulation of S100 and SMA-α immunoreactivity. Hence, vitamin D could be suggested as a protective agent against aortic atherosclerotic changes.

Atherosclerosis is a progressive disease that is characterized by accumulation of lipids and fibrous elements in large arteries. Its etiology is involved with pathophysiological factors such as lipoprotein oxidation, inflammation, and dyslipidemia. Kimchi is a Korean fermented vegetable side dish made with vegetables and kimchi condiments. To date, numerous in vitro, in vivo, and human studies have cited the health benefits of kimchi. 3-(4'-Hydroxyl-3',5'-dimethoxyphenyl)propionic acid is one of the active compounds of kimchi, and its antioxidant and anti-atherosclerosclerotic effects have been reported. This review presents the laboratory and clinical evidence of the anti-atherosclerotic effects of kimchi based on its lipid-lowering, antioxidant, and anti-inflammatory activities.

Oats, in addition to cholesterol-lowering properties, contain unique antioxidants called avenanthramides (Avns), which inhibit both inflammatory cytokines and adhesion molecules in endothelial cells in culture. This study evaluated the effects of Avns of oats on atherosclerosis in Ldlr -/- mice, one of the most commonly used atherosclerosis mouse models with their similar cholesterol distributions to humans. The Ldlr -/- mice were fed a low fat, high fat, high fat containing regular oat brans with low levels of Avns (HFLA), or high fat containing regular oat brans with high levels of Avns (HFHA) diet. After 16 weeks of intervention, blood cholesterol and extent of aortic lesions were evaluated. We found that both oat-based diets reduced high fat diet-induced atheroma lesions in the aortic valve (p < 0.01). Furthermore, the effects of oat-based diets are more profound in HFHA mice than mice fed HFLA. Total plasma cholesterol levels were similarly reduced in both oat-supplemented mice. We concluded that oat bran diets reduce atheroma lesions and higher levels of Avns further reduce aortic lesions compared to regular oat bran. These preliminary in vivo data indicate that consumption of oats bran, with high Avns, has demonstrable beneficial effects on prevention of cardiovascular disease.

Atherosclerosis is an age-associated disease; however, diabetic atherosclerosis has higher severity beyond age range for accumulative premature senescent cells in diabetes. Recent findings suggest that rutin, a flavonoid, has potential benefits for diabetic individuals. This study was designed to evaluate the effects of rutin on premature senescence and atherosclerosis. Apolipoprotein E knockout mice exhibiting insulin resistance after 6 weeks of high-fat diet were administered with a low dose of streptozotocin (STZ) to induce diabetes. After 8 weeks of STZ administration, rutin (40 mg/kg/d) was supplemented by gavage for the last 6 weeks. We evaluated the prosperity of the plaque and diabetes using serial echocardiography, histopathologic and metabolite analysis. Premature senescence induced by hydrogen peroxide in primary vascular smooth muscle cells (VSMCs) was used to analyze the underlying mechanism. Mice with diabetes showed more severe plaque burden on aortic arteries and less smooth muscle cells but larger senescent cell ratio in plaque compared with mice with control diets. Rutin significantly improves glucose and lipid metabolic disturbance in diabetes. Moreover, rutin decreased the atherosclerotic burden and senescent cell number and increased the VSMC ratio in aortic root plaque. In vitro, we demonstrated that rutin ameliorated premature senescence induced by oxidative stress, and the protective function may be mediated by inhibiting oxidative stress and protecting telomere. Rutin administration attenuates atherosclerosis burden and stabilizes plaque by improving metabolic disturbance and alleviating premature senescence of VSMCs. Inhibition of VSMCs premature senescence with rutin may be an effective therapy for diabetic atherosclerosis., (Copyright © 2017 Elsevier Inc. All rights reserved.)