Omega-3 (n-3) Fatty Acid-Statin Interaction: Evidence for a Novel Therapeutic Strategy for Atherosclerotic Cardiovascular Disease.

Managing atherosclerotic cardiovascular disease (ASCVD) often involves a combination of lifestyle modifications and medications aiming to decrease the risk of cardiovascular outcomes, such as myocardial infarction and stroke. The aim of this article is to discuss possible omega-3 (n-3) fatty acid-statin interactions in the prevention and treatment of ASCVD and to provide evidence to consider for clinical practice, highlighting novel insights in this field. Statins and n-3 fatty acids (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) are commonly used to control cardiovascular risk factors in order to treat ASCVD. Statins are an important lipid-lowering therapy, primarily targeting low-density lipoprotein cholesterol (LDL-C) levels, while n-3 fatty acids address triglyceride (TG) concentrations. Both statins and n-3 fatty acids have pleiotropic actions which overlap, including improving endothelial function, modulation of inflammation, and stabilizing atherosclerotic plaques. Thus, both statins and n-3 fatty acids potentially mitigate the residual cardiovascular risk that remains beyond lipid lowering, such as persistent inflammation. EPA and DHA are both substrates for the synthesis of so-called specialized pro-resolving mediators (SPMs), a relatively recently recognized feature of their ability to combat inflammation. Interestingly, statins seem to have the ability to promote the production of some SPMs, suggesting a largely unrecognized interaction between statins and n-3 fatty acids with relevance to the control of inflammation. Although n-3 fatty acids are the major substrates for the production of SPMs, these signaling molecules may have additional therapeutic benefits beyond those provided by the precursor n-3 fatty acids themselves. In this article, we discuss the accumulating evidence that supports SPMs as a novel therapeutic tool and the possible statin-n-3 fatty acid interactions relevant to the prevention and treatment of ASCVD.

Pros and Cons of Long-Chain Omega-3 Polyunsaturated Fatty Acids in Cardiovascular Health.

The long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are found in seafood, supplements, and concentrated pharmaceutical preparations. Prospective cohort studies demonstrate an association between higher intakes of EPA+DHA or higher levels of EPA and DHA in the body and lower risk of developing cardiovascular disease (CVD), especially coronary heart disease and myocardial infarction, and of cardiovascular mortality in the general population. The cardioprotective effect of EPA and DHA is due to the beneficial modulation of a number of risk factors for CVD. Some large trials support the use of EPA+DHA (or EPA alone) in high-risk patients, although the evidence is inconsistent. This review presents key studies of EPA and DHA in the primary and secondary prevention of CVD, briefly describes potential mechanisms of action, and discusses recently published RCTs and meta-analyses. Potential adverse aspects of long-chain omega-3 fatty acids in relation to CVD are discussed.

The supplementation of a high dose of fish oil during pregnancy and lactation led to an elevation in Mfsd2a expression without any changes in docosahexaenoic acid levels in the retina of healthy 2-month-old mouse offspring.

Introduction: During fetal development, the proper development of neural and visual systems relies on the maternal supplementation of omega-3 fatty acids through placental transfer. Pregnant women are strongly advised to augment their diet with additional sources of omega-3, such as fish oil (FO). This supplementation has been linked to a reduced risk of preterm birth, pre-eclampsia, and perinatal depression. Recently, higher doses of omega-3 supplementation have been recommended for pregnant women. Considering that omega-3 fatty acids, particularly docosahexaenoic acid (DHA), play a crucial role in maintaining the delicate homeostasis required for the proper functioning of the retina and photoreceptors the effects of high-dose fish oil (FO) supplementation during pregnancy and lactation on the retina and retinal pigmented epithelium (RPE) in healthy offspring warrant better understanding. Methods: The fatty acid content and the changes in the expression of the genes regulating cholesterol homeostasis and DHA transport in the retina and RPE were evaluated following the high-dose FO supplementation. Results: Our study demonstrated that despite the high-dose FO treatment during pregnancy and lactation, the rigorous DHA homeostasis in the retina and RPE of the two-month-old offspring remained balanced. Another significant finding of this study is the increase in the expression levels of major facilitator superfamily domain-containing protein (Mfsd2a), a primary DHA transporter. Mfsd2a also serves as a major regulator of transcytosis during development, and a reduction in Mfsd2a levels poses a major risk for the development of leaky blood vessels. Conclusion: Impairment of the blood-retinal barrier (BRB) is associated with the development of numerous ocular diseases, and a better understanding of how to manipulate transcytosis in the BRB during development can enhance drug delivery through the BRB or contribute to the repair of central nervous system (CNS) barriers.

Polyunsaturated fatty acids and metabolic health: novel insights.

PURPOSE OF REVIEW: This review aims to discuss the potential roles of omega-3 (ω-3) and omega-6 (ω-6) polyunsaturated fatty acids (PUFAs) in the prevention and treatment of metabolic diseases, to provide the latest evidence from epidemiological and clinical studies, and to highlight novel insights into this field. RECENT FINDINGS: Higher dietary or circulating ω-3 PUFA levels are related to a lower risk of metabolic syndrome. Novel findings in obesity indicate higher proportions of ω-6 and ω-3 PUFAs, a modulated oxylipin profile and an altered transcriptome in subcutaneous white adipose tissue, that seem resistant to the effects of ω-3 PUFAs compared with what occurs in normal weight individuals. ω-3 PUFAs may improve the blood lipid profile and glycemic outcomes in patients with type 2 diabetes mellitus and reduce liver fat in nonalcoholic fatty liver disease (NAFLD); the findings of several recent meta-analyses support these effects. Genetic background affects inter-individual variability in the insulin sensitivity response to ω-3 PUFA supplementation. ω-3 PUFAs have prebiotic effects, altering the gut microbiota. SUMMARY: Although evidence for health benefits of ω-3 PUFAs is strong, recent findings suggest a more personalized approach to ω-3 PUFA intake for individuals at high risk for metabolic diseases.

Beneficial Outcomes of Omega-6 and Omega-3 Polyunsaturated Fatty Acids on Human Health: An Update for 2021.

Oxidative stress and inflammation have been recognized as important contributors to the risk of chronic non-communicable diseases. Polyunsaturated fatty acids (PUFAs) may regulate the antioxidant signaling pathway and modulate inflammatory processes. They also influence hepatic lipid metabolism and physiological responses of other organs, including the heart. Longitudinal prospective cohort studies demonstrate that there is an association between moderate intake of the omega-6 PUFA linoleic acid and lower risk of cardiovascular diseases (CVDs), most likely as a result of lower blood cholesterol concentration. Current evidence suggests that increasing intake of arachidonic acid (up to 1500 mg/day) has no adverse effect on platelet aggregation and blood clotting, immune function and markers of inflammation, but may benefit muscle and cognitive performance. Many studies show that higher intakes of omega-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are associated with a lower incidence of chronic diseases characterized by elevated inflammation, including CVDs. This is because of the multiple molecular and cellular actions of EPA and DHA. Intervention trials using EPA + DHA indicate benefit on CVD mortality and a significant inverse linear dose-response relationship has been found between EPA + DHA intake and CVD outcomes. In addition to their antioxidant and anti-inflammatory roles, omega-3 fatty acids are considered to regulate platelet homeostasis and lower risk of thrombosis, which together indicate their potential use in COVID-19 therapy.

Fucus spiralis extract and fractions: anticancer and pharmacological potentials.

PURPOSE: Sea macroalgae are an important source of biologically highly valuable compounds. The main aim of this study was to investigate the in vitro anticancer properties and chemical composition of the dichloromethane-methanol extract and three fractions of the Fucus spiralis from coastline of Morocco. METHODS: Fractions were made from dichloromethane:methanol (1:1) extract of Fucus spiralis: petroleum-ether, ethyl-acetate and n-butanol. Extract and fractions were screened for in vitro cytotoxicity by MTT assay against human cervical adenocarcinoma (HeLa), colorectal adenocarcinoma (LS-174T), lung carcinoma (A549), and normal human lung fibroblasts (MRC-5). Cell cycle distribution of the HeLa cells was evaluated using flow cytometry. Acridine orange (AO)-ethidium bromide (EB) staining was used to assess morphological changes of HeLa cells under fluorescence microscope. Anti-migration and anti-angiogenic properties were investigated using scratch and tube formation assays against human endothelium-derived permanent EA.hy926 cell line. Antidiabetic activity was tested using anti-α-glucosidase assay. Antimicrobial effect was tested using micro- dilution method. RESULTS: Petroleum-ether fraction оf Fucus spiralis rich in fatty acids exerted the highest cytotoxicity against HeLa cells. Ethyl-acetate and petroleum-ether fractions induced the highest accumulation of the HeLa cells in sub-G1 and G2/M phases. Extract and fractions showed proapoptotic effect on HeLa cells under fluorescent microscope. They exhibited antimigratory and antiangiogenic effects in vitro. IC50 value for α-glucosidase inhibitory activity was much stronger than standard acarbose. n-Butanol fraction exerted the highest antibacterial and antifungal activity. CONCLUSIONS: The investigation of various biological activities of the extract and fractions obtained from Fucus spiralis may suggest a promising anticancer and pharmacological potential of this edible macroalga.

Preanalytical and analytical challenges in gas chromatographic determination of cholesterol synthesis and absorption markers.

INTRODUCTION: Cholesterol homeostasis disruption contributes to the development of different pathologies. Non-cholesterol sterols (NCSs) serve as cholesterol synthesis markers (desmosterol and lathosterol), and cholesterol absorption surrogate markers (campesterol, stigmasterol and ß-sitosterol). The study aimed to resolve certain new pre-analytical and analytical problems and ensure a reliable and validated method. MATERIALS AND METHODS: Method optimization, validation and stability studies were executed in human serum and plasma. Freeze-thaw cycles were done with and without antioxidant. Gas chromatography-mass spectrometer (GC-MS) was used for NCSs confirmation and plasticizer identification, while GC-flame ionization detector (GC-FID) was used for NCSs quantitation. RESULTS: Intra- and inter-assay variabilities for all NCSs were 2.75-9.55% and 5.80-7.75% for plasma and 3.10-5.72% and 3.05-10.92% for serum, respectively. Recovery studies showed satisfactory percentage errors for all NCSs: 93.4-105.7% in plasma and 87.5-106.9 in serum. Derivatized samples were stable up to 7days at -20°C and derivatization yield was affected by presence of plasticizers. Fatty acid amids were identified as interfering plastic leachates. Statistically different NCSs concentrations were observed after the 1st freeze-thaw cycle, in antioxidant-free samples, and after the 4th cycle in antioxidant-enriched samples. CONCLUSIONS: All of the in-house procedures proved to be useful for minimizing the preanalytical and analytical variations, as proven by the validation results.

Can non-cholesterol sterols and lipoprotein subclasses distribution predict different patterns of cholesterol metabolism and statin therapy response?

BACKGROUND: Cholesterol homeostasis disorders may cause dyslipidemia, atherosclerosis progression and coronary artery disease (CAD) development. Evaluation of non-cholesterol sterols (NCSs) as synthesis and absorption markers, and lipoprotein particles quality may indicate the dyslipidemia early development. This study investigates associations of different cholesterol homeostasis patterns with low-density (LDL) and high-density lipoproteins (HDL) subclasses distribution in statin-treated and statin-untreated CAD patients, and potential use of aforementioned markers for CAD treatment optimization. METHODS: The study included 78 CAD patients (47 statin-untreated and 31 statin-treated) and 31 controls (CG). NCSs concentrations were quantified using gas chromatography- flame ionization detection (GC-FID). Lipoprotein subclasses were separated by gradient gel electrophoresis. RESULTS: In patients, cholesterol-synthesis markers were significantly higher comparing to CG. Cholesterol-synthesis markers were inversely associated with LDL size in all groups. For cholesterol homeostasis estimation, each group was divided to good and/or poor synthetizers and/or absorbers according to desmosterol and ß-sitosterol median values. In CG, participants with reduced cholesterol absorption, the relative proportion of small, dense LDL was higher in those with increased cholesterol synthesis compared to those with reduced synthesis (p<0.01). LDL I fraction was significantly higher in poor synthetizers/poor absorbers subgroup compared to poor synthetizers/good absorbers (p<0.01), and good synthetizers/poor absorbers (p<0.01). Statin-treated patients with increased cholesterol absorption had increased proportion of LDL IVB (p<0.05). CONCLUSIONS: The results suggest the existence of different lipoprotein abnormalities according to various patterns of cholesterol homeostasis. Desmosterol/ß-sitosterol ratio could be used for estimating individual propensity toward dyslipidemia development and direct the future treatment.

Active Lactobacillus rhamnosus LA68 or Lactobacillus plantarum WCFS1 administration positively influences liver fatty acid composition in mice on a HFD regime.

Western life style, and high calorie diet in particular is causing major health problems such as insulin resistance, hepatic steatosis and heart disease in the modern age. High fat diet (HFD) induces similar changes in mice, such as increased body weight, hypercholesterolemia and accumulation of triglycerides in the liver. These changes can be ameliorated by the administration of some Lactobacillus species. The focus of this study was to analyze the fatty acid content of liver, heart and brain tissues of mice fed HFD and administered with either Lactobacillus plantarum WCFS1 or Lactobacillus rhamnosus LA68, and to analyze the fatty acid content of these organs after a two months washout period. The fatty acid composition of mouse liver tissue changed significantly due to probiotic administration during a 12 weeks HFD regime and active Lactobacillus administration had a slightly reversing effect toward the standard mouse diet group, but after the washout period these changes disappeared. The fatty acid composition of the heart and brain tissues was significantly changed in the HFD regime but probiotic administration had no significant influence on the fatty acid profile of these two organs. Upon the 8 weeks washout period the only remaining beneficial effect was the significantly lower mouse weight in the supplemented groups compared to the HFD group.

Brain and liver fatty acid composition changes upon consumption of Lactobacillus rhamnosus LA68.

Recent reports suggest that the metabolic activity of the enteric microbiota may influence the fatty acid composition of the host tissue. There are many studies dealing with the influence of lactobacilli on various pathological conditions, and some of the effects are strain-specific. This study was designed to test the effects of a particular Lactobacillus strain, Lactobacillus rhamnosus LA68 on fatty acid composition of the liver and the brain of C57BL/6 mice in the absence of an underlying pathological condition. Female mice were supplemented with live L. rhamnosus LA68 bacteria for the duration of 1 month. Serum biochemistry was analyzed and liver and brain fatty acid composition was assessed by gas-liquid chromatography. Significant changes in liver and brain fatty acid composition were detected. In the liver tissue we detected an increase in palmitoleic acid (p = 0.038), while in the brain compartment we found an increase in palmitic (p = 0.042), stearic (p = 0.017), arachidonic acid (p = 0.009) and docosahexaenoic acid (p = 0.004) for control versus experimental group. These results show discrete changes caused by LA68 strain consumption. Even short duration of administration of LA68 influences the fatty acid composition of the host which adds to the existing knowledge about Lactobacillus host interaction, and adds to the growing knowledge of metabolic intervention possibilities.

Long-chain n-3 polyunsaturated fatty acid dietary recommendations are moderately efficient in optimizing their status in healthy middle-aged subjects with low fish consumption: a cross-over study.

Several dietary recommendations have been made for marine n-3 polyunsaturated fatty acid (PUFA) intake; however, the effectiveness of these fatty acids has not been thoroughly examined. The aim of this study was to investigate whether public-aimed dietary recommendations for long-chain n-3 PUFA from oily fish or fish oil supplements are efficient in optimizing their status in red blood cells (RBCs) and platelets of healthy middle-aged subjects with low customary fish consumption. In a randomized, cross-over trial conducted over an 8-week period and separated by a 6-month washout period, 33 participants received an oily fish (salmon), providing 274 mg eicosapentaenoic acid (EPA) + 671 mg docosahexaenoic acid (DHA) per day, or a commercial fish oil supplement, providing 396 mg EPA + 250 mg DHA per day. Blood samples were collected before and after each intervention period, and RBCs and platelets were used for analysis of fatty acids. After 8 weeks, there were significant increases in EPA and DHA content in RBCs and platelets with both salmon and fish oil capsules. The increase in EPA in both RBCs and platelets was higher with capsules, whereas the increase in DHA in both RBCs and platelets was higher with salmon. In spite of the quantitative and qualitative differences between n-3 fatty acid profiles in salmon and the fish oil supplement, the overall incorporation of these fatty acids into RBCs and platelets did not differ in our short-term study (P > .05). The sum of EPA + DHA significantly increased in both compartments following dietary recommendations for oily fish and fish oil supplements intake in middle-aged healthy subjects with low baseline long-chain n-3 PUFA status, although targeted values with optimal cardioprotective effect of more than 8% were not achieved.

Effect of n-3 fatty acids on nutritional status and inflammatory markers in haemodialysis patients.

AIMS: Nutrition as an aetiological factor participates a great deal in premature atherosclerosis in haemodialysis (HD) patients. The basic mechanisms of end-stage renal disease and premature atherosclerosis are connected with changes in cell functions at the membrane level. We investigated the red cell membrane fatty acids and the effects of fish oil supplements on nutritional status and inflammatory markers in HD patients. METHODS: We examined 42 HD patients (mean age 55 +/- 8 years). The control group consisted of 16 healthy subjects of similar age and sex to the tested group. HD patients were administered supplements with 2.4 g of n-3 polyunsaturated fatty acids per day for 2 months. Before and after supplementation, we examined plasma lipids, cell membrane erythrocyte phospholipids content, serum albumin, haemoglobin, interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-alpha). RESULTS: Baseline values in the tested group confirmed the presence of essential fatty acids deficiency. A statistically significant negative correlation between TNF-alpha and eicosapentaenoic acid (EPA) (r = -0.497; P < 0.05) and IL-6 and EPA (r = -468; P = 0.03) was found in HD patients before supplementation. There was a significant increase in docosahexaenoic acids, high density lipoprotein cholesterol, plasma albumin, haemoglobin levels in HD patients after supplementation (P = 0.0001). There was a significant increase in EPA (P = 0.01) after treatment, and there was a significant decrease in inflammatory markers (IL-6 and TNF-alpha, P = 0.0001) after supplementation in the tested group. CONCLUSION: A dietary regime with fish oil could be used in dialysis patients to slow down the development of atherosclerosis and improve nutritional parameters.

The dry plant extract of common bean seed (Phaseoli vulgari pericarpium) does not have an affect on postprandial glycemia in healthy human subject.

The aim of present study was to assess the effects and safety of a dry Phaseoli vulgari pericarpium (PVP) extract on postprandial glycemia in healthy participants. A randomized crossover experiment where participants received either PVP extract or placebo. Chemical compounds in dry extract were assessed by established methods. Eighteen healthy participants (9 male and 9 female) aged 29+/-4,8 years, body mass index (BMI) 23+/-3,7 kg/m(2) were recruited among students and staff at the Faculty of Pharmacy, University of Belgrade. All participants were able to follow the study protocol without difficulty. The participants received either PVP extract or placebo 30 minutes before a 50g oral glucose tolerance test (OGTT). The protocol followed the guidelines for the OGTT with blood samples drawn at 0, 15, 30, 60, 90 and 120 min. This study demonstrated that there was no significantly effect of the PVP extract on incremental blood glucose (IBG) and their areas under the curve (AUC) neither male nor female participants. However, IBG together with AUC changes were significantly lower in male compared with female participants in treated and untreated groups. The presence of chrome, soluble fiber, vitamin C, protein, glucose and lectins were also quantified. The applied amount of PVP extract was unable to produce the postprandial hypoglycemia. We assumed that amounts of chrome, soluble fiber, vitamin C which have beneficial effects on diabetes treatment were sufficient to produce hypoglycemia.